case study of autism spectrum disorder

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• v.14(8); 2022 Aug

Cannabidiol in Treatment of Autism Spectrum Disorder: A Case Study

1 Engineering Science, University of Toronto, Toronto, CAN

Sofia Platnick

2 Health Sciences, Wilfrid Laurier University, Toronto, CAN

Howard Platnick

3 Family Medicine/Chronic Pain and Medical Cannabis, Private Practice, Toronto, CAN

This case study aims to demonstrate the use of cannabidiol (CBD) with low-dose tetrahydrocannabinol (THC) in managing symptoms associated with autism spectrum disorder (ASD) to increase the overall quality of life for these individuals and their families. ASD is a neurodevelopmental disorder affecting cognitive development, behavior, social communication, and motor skills. Despite the increasing awareness of ASD, there is still a lack of safe and effective treatment options. The study includes a nine-year-old male patient who was diagnosed with nonverbal ASD. He exhibited emotional outbursts, inappropriate behaviors, and social deficits including challenges in communicating his needs with others. Since the patient was unable to attain independence at school and at home, his condition was a significant burden to his caregivers. The patient was treated with full-spectrum high CBD and low THC oil formulation, with each milliliter containing 20 mg of CBD and <1 mg of THC. CBD oil starting dose was 0.1ml twice daily, increased every three to four days to 0.5ml twice daily. Overall, the patient experienced a reduction in negative behaviors, including violent outbursts, self-injurious behaviors, and sleep disruptions. There was an improvement in social interactions, concentration, and emotional stability. A combination of high CBD and low-dose THC oil was demonstrated to be an effective treatment option for managing symptoms associated with autism, leading to a better quality of life for both the patient and the caregivers.

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in communication, social interactions, restricted interests, and repetitive behaviors [ 1 ]. ASD is associated with medical conditions such as epilepsy and deficiency in intellectual abilities [ 1 ]. The World Health Organization (WHO) estimates that one in 100 children is diagnosed with autism worldwide [ 2 ]. However, the epidemiology can vary greatly depending on geographic location. For example, the Public Health Agency of Canada reports ASD prevalence of one in every 50 Canadian children [ 3 ].

The WHO Quality of Life Instrument, Short Form (WHOQOL-BREF) developed by the WHO to effectively measure the experience of individuals with ASD, has shown that associated medical conditions negatively impact the individual’s quality of life [ 4 ]. Those with ASD, as well as their families, experience a great deal of stress and disruption with this diagnosis. Most individuals with autism will not live independently or become employable; the majority of individuals will require lifelong, primary support [ 5 ]. Families experience ongoing challenges that can affect the quality of life, including health-related factors, financial barriers, number of children, and parental stress [ 5 ]. More than 70% of those with autism suffer from comorbid conditions, most commonly anxiety, depression, and attention deficit and hyperactivity disorder (ADHD) [ 6 ]. Researchers have explored both genetic and environmental factors that influence the development of the brain and its correlation with ASD risks, such as exposure to lead, ethyl alcohol, and methyl mercury [ 7 ]. 

The objective of this case study is to demonstrate the use of cannabidiol (CBD) in a full-spectrum formulation, with low-dose tetrahydrocannabinol (THC), as a treatment option for managing symptoms associated with ASD to increase the overall quality of life for these individuals and their families. The patient in the case presented resides in Canada, where both medical and recreational cannabis are legal in all forms.

Case presentation

The nine-year-old patient (weight 39 kilograms) was diagnosed with nonverbal ASD when he was three years old and required 24-hour supervision. He had a comorbid diagnosis of insulin-dependent diabetes mellitus (Type I diabetes), which required daily insulin injections. The patient had mild asthma with infrequent use of a salbutamol puffer. Otherwise, he was on no other medications. Due to cultural and personal preferences, the patient's mother declined to use psychiatric medications.

Prior to initiating CBD treatment, the patient exhibited behavioral symptoms with outbursts of anger and physical aggression (punching, kicking, biting, head-butting, and scratching). He required daily insulin injections, which were accompanied by self-injurious actions including head and chest punching. The patient displayed inappropriate behaviors such as playing with feces and rocking on the floor for self-soothing (stimming). He was constantly frustrated by misunderstandings when interacting with others, as he was unable to express his needs verbally. He had difficulty with sleep initiation, taking one to four hours to fall asleep and sleeping a total of four to five hours a night with frequent awakening. He required pull-up diapers each night due to incontinence. The patient attended public school with support and struggled to perform well academically. There were difficulties interacting with the teachers and other students, and following rules. 

The patient began CBD treatments through a medical cannabis clinic at age 7.5 years starting with full-spectrum high CBD and low THC oil formulation. The carrier oil is a medium chain triglyceride (MCT) coconut extract, an industry-standard formulation [ 8 ]. Each milliliter has 20 mg of CBD and < 1 mg of THC. The starting dose was 0.1 ml two times daily with meals and this was increased every three to four days until it reached a therapeutic response or 0.5ml two times a day.

Within the first two weeks of starting treatment, the patient was able to fall asleep in 10-15 minutes and sleep for 8-10 hours. He stopped wearing pull-up diapers as he was able to go to the washroom, wash his hands, and go back to bed without supervision, demonstrating a new behavior. There was reduced anxiety contributing to improved mood and concentration. He was able to practise gripping his pencil and trace letters. He started to follow simple instructions, such as retrieving three separate clothing items. At school, the patient received report cards with better grades and experienced less anger. This improvement allowed him to interact with his peers without signs of aggression. The patient's mother stated, “Since starting CBD, teachers and (the) principal have noted significant positive changes. He sits for over 30 minutes, holds a marker, and is focused enough to try and trace letters or numbers. The change has been amazing for us to witness.”

After initiating CBD, there was a significant reduction in overeating and “grazing” as the patient was content with regular meal intervals. His weight did not change significantly, aside from the expected increase with maturation (current weight 52 kilograms). Self-injurious and violent behaviors diminished with treatment, which allowed for easier administration of his daily insulin injections. Table 1 provides a comparison between the patient’s behaviors and characteristics before and after initiating CBD treatment.

*(normal HbA1C < 5.7% and diabetic > 6.7% with treatment goal of < 7%)

CBD: cannabidiol; HbA1C: hemoglobin A1c

The patient did not have access to the CBD for seven days while on a family trip, and his behavior regressed to pre-treatment levels. Within 24 hours, the patient experienced insomnia. After four hours, he was able to fall asleep although it was described as intermittent and fitful. After two days, there was a reduction in verbal communication and response to verbal cues, and he stopped following simple instructions. On the third day, the patient resumed self-injurious behavior. Upon returning home and restarting treatment, his sleep was regulated within two days. In the following two days, the patient regained his verbal capacity and concentration, resulting in a decrease inself-injurious behaviors.

To match physical growth, the CBD dose was later increased to 0.5ml three times a day with continued positive results including further improvement in communication and a further decline in aggressive behaviors (the upper limit prescribed was 1 ml three times a day). The caregiver did not report any side effects with the cannabidiol treatment. 

Conventional medical treatments such as atypical antipsychotics and selective serotonin reuptake inhibitors are used to reduce or eliminate behavioral symptoms [ 9 ]. However, these psychotropic drugs may lead to side effects such as nephropathy, hepatopathy, and metabolic syndromes [ 9 ]. Of children with autism and behavioral symptoms, 40% do not respond well to standard treatments, which motivates researchers to search for alternative pharmacological treatments, including substances derived from Cannabis sativa [ 10 ]. The use of CBD as a pharmacological treatment has been shown to relieve spasticity, pain, sleep disorders, seizures, and anxiety [ 10 ]. CBD affects the brain by interacting with the endocannabinoid system to modulate cognition, socioemotional responses, susceptibility to seizures, and nociception [ 11 ].

The endocannabinoid system consists of two identified receptors: CB1 and CB2 [ 11 ]. THC is the major psychoactive component of the cannabis plant, which interacts with both the CB1 and CB2 receptors [ 12 ]. CB1 receptors are found most commonly in the central nervous system (CNS), where THC interacts with the CB1 receptors to modulate neuronal excitability to produce psychotropic effects or “feeling high”. CB2 receptors are found primarily in microglia and vascular elements, such as in the circulating immune cells, spleen, and peripheral nerve terminals. Together, the endocannabinoid system is able to modulate emotional responses, mood, pain levels, immune system, and social behaviors [ 12 ].

Two endogenous cannabinoids identified are N-arachidonoylethanolamine (anandamide) and two arachidonoylglycerol (2-AG) [ 13 ]. These endocannabinoids are enzymes that have the ability to activate the CB1 and CB2 receptors [ 11 ]. Anandamide is a major endocannabinoid that has reduced levels in patients with ASD [ 13 ]. CBD acts as an inhibitor of fatty acid amide hydrolase (FAAH), which can break down anandamide, thereby increasing available anandamide levels [ 14 ]. By a similar mechanism, CBD reduces MAGL-mediated degradation of 2-AG, thus increasing its availability [ 15 ]. The anxiolytic and antipsychotic effects of CBD were hypothesized to be mediated by CBD-induced accumulation of anandamide and 2-AG [ 16 ]. This is supported by research conducted on valproate-treated animal models of autism, where CBD was found to act as an inhibitor of the metabolic degradation of anandamide, which leads to the accumulation of the endocannabinoid, resulting in a reduction of social interaction deficits [ 10 ].

The evidence in this case study suggests CBD can alleviate many negative symptoms associated with autism with minimal patient side effects. Oral ingestion is the preferred route for drug delivery by patients and drug developers [ 17 ]. Successful drug delivery also depends on the individual’s physiology and the physicochemical properties of the drug, such as solubility, dissolution, stability, permeability, and metabolism. Since CBD is a highly lipophilic drug, when delivered orally in solution, it can precipitate in the gastrointestinal (GI) tract, resulting in an absorption rate slower than elimination [ 18 ]. Time to peak plasma concentration following oral delivery is slow for CBD (1-4 h), and the half-life of CBD was reported between 1.4 and 10.9 h after oromucosal spray [ 19 ]. One way to increase the oral bioavailability of CBD is to administer CBD with a high-fat and high-calorie meal, since the increased micelle formation allows the CBD to be more readily available for lymphatic transportation while inhibiting drug efflux transporter activities [ 17 ].

A study by Fletcher et al. reports the usage of extracts with a high CBD low THC ratio with average CBD doses ranging from 1.8 to 6.45 mg/kg/day, similar to the range used in this case study [ 18 ]. The routine starting dose recommended for the adult patient is 5mg of CBD-predominant cannabinoid twice daily [ 19 ]. CBD titration should include increasing the dose by 10 mg per day every two to three days until a maximum of 40mg/day is reached [ 19 ]. 

The patient and the caregiver in the case study did not report any side effects with treatment. In a clinical study with 33 children, restlessness was reported in 22% of the patients and decreased with dose adjustment [ 20 ]. In that same study, CBD was discontinued in a 13-year-old male patient with severe autism due to generalized seizures after using 5 mg sublingual CBD, and the seizures resolved after antiepileptic drug treatments [ 20 ]. There is limited pharmacology research on CBD, and the potential hazards of short and long-term use need to be further investigated. Consideration might be given for CBD use when caregivers choose to avoid traditional pharmaceuticals or failure of conservative therapy.

To improve the evidence on CBD efficacy in patients with ASD, a randomized, double-blind, and placebo-controlled clinical trial should be initiated to further research various strains of CBD-enriched cannabis extracts with different dosages and durations to investigate its safety, efficacy, and tolerability.

Conclusions

In this case, the child patient responded positively to the introduction of CBD oil treatment with reduced negative behaviors, better sleep, and improved communication. With the increasing clinical studies on the use of cannabidiol in treating patients with mood disorders, anxiety, chronic pain conditions, and other behavioral problems, it should be considered as a treatment option in managing symptoms related to autism. In the case study presented, the child patient has shown behavioral and cognitive improvements with no side effects reported. Altogether, this study presents a case that motivates further research and clinical studies to understand the molecular mechanism of CBD as well as the dosing regimes for pediatric populations, the etiology of ASD, and how various dosing affect different demographics.

Acknowledgments

Lucy Ma and Sofia Platnick contributed equally to the article and should be considered co-first authors.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study

• Case report
• Open access
• Published: 22 September 2020

A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report

• Juliana Andrea Ponton   ORCID: orcid.org/0000-0002-7405-1797 1 ,
• Kim Smyth 2 ,
• Elias Soumbasis 1 ,
• Sergio Andres Llanos 1 ,
• Mark Lewis 1 ,
• Wilhelm August Meerholz 1 &
• Robert Lawrence Tanguay 1  

Journal of Medical Case Reports volume  14 , Article number:  162 ( 2020 ) Cite this article

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The pharmacological treatment for autism spectrum disorders is often poorly tolerated and has traditionally targeted associated conditions, with limited benefit for the core social deficits. We describe the novel use of a cannabidiol-based extract that incidentally improved core social deficits and overall functioning in a patient with autism spectrum disorder, at a lower dose than has been previously reported in autism spectrum disorder.

Case presentation

The parents of a 15-year-old boy, of South African descent, with autism spectrum disorder, selective mutism, anxiety, and controlled epilepsy, consulted a medical cannabis physician to trial cannabis extract to replace seizure medications. Incidentally, at a very low cannabidiol-based extract dose, he experienced unanticipated positive effects on behavioral symptoms and core social deficits.

This case report provides evidence that a lower than previously reported dose of a phytocannabinoid in the form of a cannabidiol-based extract may be capable of aiding in autism spectrum disorder-related behavioral symptoms, core social communication abilities, and comorbid anxiety, sleep difficulties, and weight control. Further research is needed to elucidate the clinical role and underlying biological mechanisms of action of cannabidiol-based extract in patients with autism spectrum disorder.

Peer Review reports

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in two major domains: restrictive, repetitive patterns of behavior, interests, or activities; and deficits in social communication and interaction [ 1 , 2 ]. ASD is associated with a higher incidence of comorbid conditions including attention deficit hyperactivity disorder, anxiety, gastrointestinal disturbances, motor impairments, and epilepsy. Symptoms appear in early childhood and vary in severity leading to a broad range of clinical manifestations [ 2 ].

The pathogenesis of ASD is not completely understood [ 3 ]. Given its complexity and diverse clinical manifestations, it is believed that the etiopathogenesis of ASD is a combination of genetic, epigenetic, neurobiological, diet, and other environmental factors [ 4 ]. Hundreds of genes ( NLGN , SHANK3 , ZNF8034A, and UNC13A) [ 5 , 6 ] have been linked to ASD, most of which are closely related to the development of the nervous system [ 1 ].

There is a myriad of theories that attempt to explain the occurrence of ASD [ 1 , 3 , 7 ], although the two most accepted are impaired synaptic transmission and disruption of neural connectivity. The endocannabinoid system (ECS) has attracted considerable attention as a potential contributor to ASD, as the development of the ECS is essential for regulating synaptic function by inhibiting the release of neurotransmitters from presynaptic neurons [ 1 ].

The management of ASD requires individualized, comprehensive treatment. Non-psychopharmacologic interventions (for example, cognitive behavioral therapy) modify disruptive behaviors and improve social communication skills with varying degrees of success. Traditional psychopharmacologic medications target specific ASD core behaviors (for example, repetitive behaviors) and associated behaviors (for example, hyperactivity, aggression, anxiety, and sleep disturbances), but do not treat core social communication deficits [ 8 , 9 ]. These medications are well known for their substantial side effects. For example, aripiprazole and risperidone, the only two medications approved by the US Food and Drug Administration (FDA) to treat irritability and agitation in ASD, frequently cause somnolence, increased appetite, and weight gain [ 10 ]. No other medication has been approved for management of behavioral and/or core ASD symptoms. Challenges with these traditional treatment approaches include barriers to access (economical, geographic), lack of efficacy, and undesirable side effects, which have led many families to seek complementary and alternative medicine (CAM) to augment or replace standard therapy [ 8 ]. One of the newest CAM options now being explored in ASD (and, in fact, the wider medical community) is cannabinoids: for example, cannabidiol-based extract (CBE), which is an extract from the cannabis plant, rich in cannabidiol (CBD) [ 11 ].

Follow-up of these patients must also be individualized as presentation of the disorder is highly variable. There are no validated questionnaires to accurately assess clinical progress, therefore, conducting an objective clinical assessment of related behavioral and core symptoms is challenging. Despite this, there are tools available for characterizing the overall functionality of patients with ASD, for example, Autism Spectrum Quotient (AQ) adults version [ 3 ].

The World Health Organization stated that CBD should not be scheduled with the International Drug Control Conventions because of growing evidence of its medicinal applications [ 12 , 13 ]. It is imperative for health care providers to understand the minutiae of how cannabinoids interact with the human body and the different forms of cannabinoids that are available for medical use (for example, synthetocannabinoids, phytocannabinoids) [ 1 ]. Delta-9-tetrahydrocannabinol (THC) and CBD are the most well-known and studied phytocannabinoids. THC is associated with the impairing psychoactive effects of cannabis, resulting in potentially undesirable side effects (dizziness, anxiety, paranoia, dependency, cognitive impairment, and so on). In contrast, CBD is only minimally psychoactive and not impairing or intoxicating at typically used doses (for example, ≥ 20 mg/kg of CBD referred in the majority of intractable seizures studies) [ 1 , 8 , 10 , 11 ].

A multitude of studies have analyzed the use of high-dose CBD extract (~ 20 mg/kg of weight per dose) in the context of intractable seizure treatment [ 14 , 15 ]. It has been reported that CBD effects are dose-dependent (for example, > 160 mg/day elicits a sedating effect and lower doses have been associated with increased wakefulness) [ 16 ]. A few case reports and observational studies have suggested the safety and efficacy of lower dose CBD, for treating behavioral symptoms in ASD [ 11 , 17 , 18 ]. In a prospective study, 188 patients with ASD were treated with lower to medium doses of phytocannabinoids (from 15 mg of CBD three times a day to 300 mg of CBD three times a day), the majority taking 1:20 CBE: 30% CBD to 1.5% THC [ 19 ]. This study found that cannabis was well tolerated, safe, and effective in relieving certain ASD symptoms. More research is needed to assess the long-term effects of CBD, as well as optimal dosing, formulation, delivery method, and so on to maximize both safety and efficacy.

This case report describes the clinical presentation of a pediatric, overweight patient with ASD, epilepsy, anxiety, insomnia, and social deficits who benefited clinically with even lower doses of CBE (4 mg of CBD and 0.2 mg of THC twice a day) compared to the ones already studied [ 19 ].

A 15-year-old boy, of South African descent, is presented with a long-standing history of social and communicative challenges dating back to early childhood, including difficulties in appropriate use of facial expressions, eye contact, and gestures to regulate social interaction (see Fig. 1 for patient’s timeline). He has a history of difficulty in establishing and maintaining relationships, although he has been able to establish some friendships. His mother notes a history of selective mutism dating back to age 3. He has areas of fixated interests and some ritualized behaviors that on assessment were below the threshold for a diagnosis of obsessive-compulsive disorder. In 2016, he was formally diagnosed as having ASD by a specialized organization in British Columbia (BC), the Interior Health Children’s Assessment Network (IHCAN), with supporting evidence from Autism Diagnostic Interview – Revised (ADI-R) and the Autism Diagnostic Observation Schedule 2 (ADOS-2). He does well academically and there are no cognitive concerns. Sometimes he shows aggressive behaviors towards his mother and other relatives.

Patient’s timeline depicting important dates and events. ACH Alberta Children’s Hospital, ADI-R Autism Diagnostic Interview – Revised, ADOS-2 Autism Diagnostic Observation Schedule 2, ASD autism spectrum disorder, AQ Autism Spectrum Quotient (Adult), BC British Columbia, BMI body mass index (calculated by Du Bois method), CBD cannabidiol, CBE cannabidiol-based extract, CSHQ Children’s Sleep Habits Questionnaire (Abbreviated), CYMH Child and Youth Mental Health, IHCAN Interior Health Children’s Assessment Network, OCD obsessive-compulsive disorder, THC delta-9-tetrahydrocannabinol, upset stomach gastrointestinal side effects, VAS visual analog scale, VPA valproic acid. VAS severity for overall anxiety, social anxiety, aggressiveness and irritability, 0 = least severe, 10 = most severe. VAS for talkativeness, 0 = quiet, 10 = very talkative. VAS for focus, 0 = unfocused, 10 = focused

He was diagnosed as having epilepsy characterized by focal seizures at age 7 at an emergency department service in BC and was subsequently treated by his pediatrician and a pediatric neurologist at the Alberta Children’s Hospital (ACH). He was initially prescribed carbamazepine for seizures which was stopped in 2015 due to side effects (upset stomach), followed by clobazam (stopped in 2016 due to suicidal ideation) and valproic acid (VPA) (stopped in 2017 due to alopecia, tremor, and reflux). The latter also caused a significant weight gain of approximately 13 kg in 1 year, resulting in a calculated body mass index (BMI) with the Du Bois method of 25.5 kg/m 2 . He is currently on lamotrigine for seizures, lorazepam for breakthrough seizures, melatonin for insomnia, riboflavin, ranitidine, magnesium, and orally administered CBE 0.2 mL (4 mg of CBD and 0.1 mg twice a day). No therapy had been tried for behavioral symptoms, although his mother mentioned that VPA and lamotrigine were also prescribed for their effect on mood.

He is currently in psychotherapy at the Child and Youth Mental Health (CYMH) clinic in BC for his selective mutism and anxiety disorder diagnosed by psychiatrists in the same province. He has also had sleep difficulties since 2016. His perinatal history is unremarkable. His birth followed a full-term pregnancy and was uncomplicated except for a required caesarean section due to macrosomia (> 4000 g) and macrocephaly (his mother does not remember the measurement), and subsequent hospitalization for neonatal jaundice. No genetic syndrome was suspected; no genetic testing was ever done. He met expected neurodevelopmental milestones for his age. His mother and grandmother have a history of depression and anxiety. There is other familial history of eating disorders and alcoholism, but no history of genetic syndromes.

In mid-2017, his parents consulted a medical cannabis physician from Caleo Health to assess the suitability of cannabis-based medicines as adjunctive or replacement therapy for seizures. At the time, a physical examination and laboratory findings were normal. A neurologic examination was unremarkable; mental status – awake, alert, cooperative; cranial nerves – normal; motor – normal tone, bulk, strength, and reflexes in upper and lower extremities, proximal and distal, deep tendon reflexes 2+ symmetric. A skin examination was unremarkable, there were no hypopigmented macules, café-au-lait macules, neurofibromas, or axillae ephelides. A long-term (48-hour) electroencephalogram done in 2016 did not record any epileptogenic potentials; magnetic resonance imaging (MRI) showed no intracranial abnormalities and a computed tomography (CT) scan of his head was normal (2015). Laboratory results done mid-2017 were normal: complete blood count and differential, vitamin B12, creatinine, sodium, potassium, calcium, magnesium, total bilirubin, albumin, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, alanine aminotransferase, and triacylglycerol lipase. He had low ferritin (11 μg/L) but normal hemoglobin (159 g/L), due to starting a vegetarian diet, which was followed up by the family physician.

He had not had a clinical seizure in 6 months (last seizure in March 2017). Medications at the time of initiation of CBE were: lamotrigine 200 mg twice a day for seizures, lorazepam 1 mg sublingual (SL)/buccal as necessary, infrequently used for seizures, melatonin 6 mg for sleep initiation, riboflavin 400 mg administered orally once daily, magnesium 1 tablet administered orally once daily, and ranitidine 150 mg twice a day. When asked for symptom severity on a visual analog scale (VAS) (0 = least severe, 10 = most severe), his mother reported overall anxiety, social anxiety, aggressiveness, and irritability severity, at 10/10, 10/10, 6/10, and 9/10, respectively. On VAS to assess for talkativeness (0 = quiet, 10 = very talkative) in social situations, the mother reported 0/10. On VAS for concentration (0 = unfocused, 10 = very focused), 4/10 was reported. In regards to sleep, the mother stated he was sleeping approximately 5 to 6 hours, and was having trouble falling asleep. After the initial assessment, his parents gave consent to start therapy and CBE was prescribed (60 mL bottle of 1:20 CBE – 0.001% THC and 0.02% CBD), from CanniMed, with an olive oil carrier. His parents were instructed to administer 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) and increase by 0.1 mL (2 mg CBD and 0.1 mg THC) per dose if no effects were shown to a maximum of 0.5 mL (10 mg CBD and 0.5 mg THC) per dose.

In December 2017, after 3 months of the CBE prescription, his mother increased the dose to 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) as the family noted only mild improvements in anxiety symptoms. In August 2018, a medical cannabis follow-up was conducted. At 0.2 mL twice a day for almost 9 months, our patient’s family reported an improvement of 7 points for overall and social anxiety and irritability, and 6 points on aggressiveness on their respective VAS. Talkativeness improved by 4 points and focus by 2 points. In February 2020, another medical cannabis follow-up was conducted and positive effects were still evident at the same dose. When the mother was asked to complete the Children’s Sleep Habits Questionnaire (CSHQ) Abbreviated, she stated that he slept 7 hours and only had trouble falling asleep in his own bed as he resists going to bed. No side effects were reported (nausea/vomiting, diarrhea, headaches, euphoria, feeling high, anxiety, panic attacks, palpitations, somnolence during the day or drowsiness). Laboratory results remained normal and low ferritin was corrected. He began to initiate and reciprocate conversations with acquaintances he had previously been unable to speak to (for example, doctors, community members). He became more motivated and energetic, starting his own vegetarian diet and exercise programs, ultimately losing 6.4 kg after starting CBE for a calculated BMI of 21.33 kg/m 2 . He was able to start his first part-time job helping customers and interacting with them. He was instructed to fill out the self-administered Adult AQ which resulted in a normal score of 10 as shown in Table  1 . His mother stated he now also has a girlfriend. Recently, his mother started weaning him off CBE to go on a trip and noted an immediate change. He became more irritable and aggressive.

In discussion with their neurologist, the family decided to wean lamotrigine while remaining on CBE (0.2 mL twice a day – 4 mg CBD and 0.2 mg THC). Unfortunately, there was a recurrence of seizures and lamotrigine was titrated back to the full 200 mg twice a day dose.

Currently, our patient remains on the same medication as mentioned above, as well as low dose of CBE. He has maintained the positive effect on his behavioral symptoms, anxiety, sleep, and social deficits on CBE 1:20 ratio, 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) and no side effects have been reported.

This case demonstrates the benefit of a lower than previously studied CBE dose for core social communicative and behavioral ASD symptoms, as well as improvements in co-occurring anxiety, sleep dysregulation, and weight, which led to substantial improvements in both our patient’s and his family’s quality of life and daily functioning. There was partial response at the initial dose of 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) and a dramatic response at 0.2 mL twice a day (4 mg CBD and 0.2 mg THC). Seizures recurred when conventional anti-epileptic medication (lamotrigine) was weaned while on the CBE at the 0.1 mL twice a day dose (low doses), reiterating CBE at this dose did not have any significant anti-epileptic effect; lamotrigine has not been weaned while on the 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) dose of CBE. Typically, significant higher CBD doses are needed for seizure control (> 20 mg/kg per day) [ 14 , 15 ].

The symptom improvement occurred within a 6-month period following the initiation of CBE treatment, during which time there were no new additions or significant alterations of/to any concurrent medications or therapies that could otherwise explain the improvements in symptomatology. It remains unclear whether the CBE directly modified the core ASD symptoms in some way, or whether the impact of CBE was secondary to its positive effects on comorbid conditions, namely anxiety and/or sleep dysregulation, which were producing or exacerbating underlying ASD behaviors. We must also consider there are limitations inherent in the method used to assess his clinical improvement, as the VAS and the AQ are not yet validated. These measures were chosen by default, as no scale is currently validated to assess clinical progress [ 3 ]. Seizures recurred at the initial 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) dose of CBE. In addition to the fact that seizures were well controlled prior to starting CBE, the recurrence of seizures on the initial 0.1 mL twice a day dose of CBE, a dose at which symptoms were already starting to improve, suggests that improvements in ASD symptoms were not related to improvements in epilepsy control; the anti-seizure properties of CBD alone are unlikely to be the predominant mechanism responsible for the improvements in this patient’s ASD symptoms.

The ECS is a unique biological system that is present in the majority of body tissues. It plays an important role in cellular processes at the early stages of development [ 21 ]. The ECS is an essential regulatory system of the central nervous system that modulates both neurotransmission and synaptic plasticity. It is also involved in emotional and social functioning, and cognition [ 1 , 21 ]. There is evidence that the ECS is underdeveloped in ASD [ 1 , 22 ]. CBD may be treating core symptoms in ASD by interacting with the ECS to boost function in one way. CBD may increase the availability of the endogenous cannabinoids, anandamide (AEA), by directly inhibiting one of its degrading enzymes, that is, fatty amide acid hydrolase (FAAH) [ 1 , 23 , 24 ]. Wei et al. demonstrated that selective inhibition of FAAH in BTBR animals, increased AEA activity [ 25 ]. Further to this, a case–control study by Karhson et al . assessed AEA concentrations in ASD ( n  = 59) versus controls, and found lower AEA concentrations associated with ASD [ 26 ].

High-dose CBD has been studied for seizures and has been approved by the FDA (Epidiolex) for the treatment of intractable epilepsy [ 14 , 15 , 27 , 28 ], but there remains a lack of evidence for the use of phytocannabinoids in ASD [ 11 ]. Only a few low-powered studies address the clinical efficacy of cannabinoids for such symptoms, and there are no established recommendations for its use in ASD treatment [ 5 , 6 ]. The majority of published studies for ASD either involve synthetic cannabinoids [ 11 , 17 , 18 ] or synthetic enzyme-inhibitors [ 25 , 29 ]. Only a few studies offer evidence for the use of phytocannabinoids in ASD. An observational study by Bar-Lev Schleider et al. provided valuable information on safety and efficacy, but the study design was insufficient to draw strong conclusions on standard clinical care [ 19 ]. Clinicaltrials.gov lists an ongoing randomized trial comparing different phytocannabinoid extracts in the setting of behavioral symptoms, but results are not yet available [ 30 ]. Therefore, this case report is rare as it documents observed effects of CBE in ASD-related symptoms as opposed to other forms of cannabinoids (for example, nabilone, dronabinol, and nabiximols).

From a clinical perspective, the use of CBD-based products to treat neuropsychiatric symptoms must be done only after appropriate education and informed discussion with families, including consideration of risks and benefits of CBD compared to other available treatment options, and with vigilant monitoring.

Research into the role of cannabinoids in treating ASD symptoms and associated behaviors is in its infancy. Although there is an increasing amount of evidence providing biological plausibility for the use of CBD in treating ASD [ 1 , 5 , 25 , 26 , 31 ], further research is essential to better understand the effects of phytocannabinoids on neurobiological pathways and their impact on behavior and brain function. Rigorous, controlled clinical trials are needed to further establish safety, especially long-term safety, optimal dosing, and efficacy, including further delineation of the effect of CBE on core versus associated ASD symptoms. Until sufficient, supportive evidence is found, CBE remains an unproven alternative treatment and should not replace conventional evidence-based treatments for children with autism. However, the unexpected and significant benefits of CBE in this case report highlight the urgent need and potential benefits of continuing to pursue research in this area.

While there is a lack of strong evidence to support the use of CBE in ASD, this case report provides the first insight about lower than previously reported doses of phytocannabinoids in the form of CBE, which may benefit ASD-related behavioral and core social symptoms, as well as anxiety, sleep disturbances, and weight. We encourage scientists and clinicians to pioneer placebo-controlled studies to validate the clinical efficacy of very low doses of CBE in a larger cohort.

Availability of data and materials

The dataset generated and analyzed during this case report are available in Netcare (Alberta’s public Electronic Health Record used to store patient information).

Abbreviations

Autism spectrum disorder

Endocannabinoid system

Food and Drug Administration

Complementary and alternative medicine

Cannabidiol

Computed tomography

Child and Youth Mental Health

Fatty amide acid hydrolase

Delta-9-tetrahydrocannabinol

Cannabidiol-based extract

Interior Health Children’s Assessment Network

Magnetic resonance imaging

Autism Diagnostic Interview – Revised

Autism Diagnostic Observation Schedule 2

Alberta Children’s Hospital

Valproic acid

Body mass index

British Columbia

Visual analog scale

Children’s Sleep Habits Questionnaire

Autism Spectrum Quotient

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We want to thank Caleo Health and all the administrative staff. Special thanks to Michelle Andoy for supporting us.

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JAP conceptualization, writing – draft and final manuscript, and analyzed information. WAM and ES made substantial contributions to acquisition of data. KS contributed with analysis as well as acquisition of the data. RLT investigated, conceived, and supervised the project. KS, RLT, and ES provided critical feedback and helped shaped the analysis of the case. JAP, WAM, and SAL assisted with acquisition of data. KS, ES, ML, and RLT participated in manuscript editing. WAM and RLT participated in funding acquisition. JAP and SAL coordinated and designed graphics. All authors discussed and contributed to the final manuscript. The authors read and approved the final manuscript.

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Ponton, J.A., Smyth, K., Soumbasis, E. et al. A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report. J Med Case Reports 14 , 162 (2020). https://doi.org/10.1186/s13256-020-02478-7

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Advances in Autism

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Article publication date: 19 June 2020

Issue publication date: 11 August 2021

This paper aims to report the personal experiences of an adult male diagnosed with autism at the age of 48 years.

Design/methodology/approach

A personal case study methodology was used to illustrate the journey to autism diagnosis, the experience of diagnosis and post-diagnosis support.

This case study illustrates how stress and mental health difficulties can precede autism diagnosis in adults. The personal experiences detailed highlight how an adult autism diagnosis can bring about positive change, prompting increased self-knowledge and coping skills, improved relationships and. Furthermore, it highlights how a supportive employer can make reasonable adjustments in the workplace to improve productivity of an autistic employee.

Research limitations/implications

This case study has implications for various practice issues, including post-diagnosis counselling and access to support for autistic adults nationally.

Originality/value

This paper provides an original case study highlighting the personal experiences of an adult diagnosed with autism.

• Mental health
• Autism spectrum condition
• Mental disorder

Henley, R. (2021), "Being diagnosed with autism in adulthood: a personal case study", Advances in Autism , Vol. 7 No. 3, pp. 256-261. https://doi.org/10.1108/AIA-03-2020-0018

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A Case Study of Autism: Paul, 3 Years Old

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Arun was brought for consultation with Dr. A M Reddy by his parents. He was about 4 years old, the second child to the parents. Even while he was being brought into the room, we could hear his loud wailing. It took some time for the child to calm down and later we could observe that the child was very restless. He was running around the room, pulling down cushions and generally creating chaos in the room and mother was quite harried in trying to control him. He was diagnosed with ASD (Autism Spectrum Disorder).

What is ASD?

Autism or Mutinism as it was earlier known was thought primarily to affect communication skills but with more studies, it was understood that autistic children display a wide range of symptoms, hence the word “spectrum” was added to Autism disorder. Autism is a complex neurodevelopmental disorder which affects a person’s social behavior and communication skills.

Why it occurs?

The exact reason why ASD occurs is not known but many risk factors have been identified like age of the parents, poor ovulation, infections or exposures to harmful chemicals or radiation during pregnancy, thyroid, diabetes type of hormonal disorders, birth injuries, infections in childhood, vaccinations, etc.

What are its symptoms?

As its name suggests, ASD displays a myriad of symptoms but some of the common symptoms of ASD is lack of speech. While some children have no speech, in some children speech that was developed before may regress. Many of them do not prefer to mingle with children of their age group. Repetitive action, physical restlessness, inability to understand emotions, mood swings like sudden bouts of excitement, crying without any reason, are few symptoms displayed by many autistic children.

Aggressive behaviors like self-harming, head-banging, tantrum-throwing, biting/pushing others, destructiveness, can be displayed by few. Response to name call, having sustained eye contact, unable to understand commands, stereotypical actions and stimming are some of the common symptoms exhibited by many.

Coming back to the case of Arun, a detailed case history was noted down by our doctors, a summary of which is given below.

He is the second child and the age difference between both the siblings is seven years. After the first child was born, the mother developed hypothyroidism for which she was on thyroxine 50 mcg daily tablets. No history of abortions or contraceptive use was reported. Father was apparently healthy. The age of the parents was 35 and 38 years respectively during conception. She conceived naturally and pregnancy was apparently uneventful. But on deeper probing few differences were found out between both the pregnancies.

While during the first pregnancy the parents were in India, but during second there were in the United States. She was advised to continue with the same dosage of thyroxine and during 6-7 months of the pregnancy, she was given flu and T Dap vaccine. The child was born of emergency C – section as the water broke early. The birth cry was normal and seemingly the child was progressing well but after his first birthday, the child had a bout of severe gastrointestinal infection when they visited India where he was hospitalized for three days and given medicines.

Parents were worried that he seems to put everything in his mouth and his favorite items were paper, cloth, wall plaster. His demands have to be met, else he used to become very upset. Emotional connectivity towards parents was less. He would not follow simple commands and it was becoming increasingly difficult for the parents to manage him. With therapies, his eye contact improved a little and was able to follow a few simple commands but the progress was slow.

He was a picky eater and liked crunchy foods. His bowels were constipated and he was not yet toilet trained. He was given Cuprum Sulph 10 M and was kept on regular follow up.

On the next visit to Dr. A M Reddy Autism Center , the parents complained that their child developed itching on the skin but his restlessness reduced slightly. The medication was continued for about three months during which the child’s anger reduced by 30%, his eye contact improved and he was no longer constipated. His itching too reduced in the meanwhile. A second dose was repeated and about six to seven months of treatment, he started saying few words, tantrum-throwing reduced and his habit of putting everything in the mouth was gone.

The dose was repeated in 50M potency. After about a year and half of treatment, he started interactive communication, giving relevant answers to questions and was doing much better. On the advice of Dr. A M Reddy, they placed him in normal school and he is doing well.

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• Open access
• Published: 10 April 2024

Additive interaction between birth asphyxia and febrile seizures on autism spectrum disorder: a population-based study

• Xindi Lin 1 ,
• Yuhan Wu 1 ,
• Jiayi Lu 1 ,
• Jiayao Shen 2 ,
• Shaogen Zhong 1 ,
• Xingming Jin 1 &
• Jun Ma   ORCID: orcid.org/0000-0001-5236-2239 1  

Molecular Autism volume  15 , Article number:  17 ( 2024 ) Cite this article

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Metrics details

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder that can significantly impact an individual’s ability to socially integrate and adapt. It’s crucial to identify key factors associated with ASD. Recent studies link both birth asphyxia (BA) and febrile seizures (FS) separately to higher ASD prevalence. However, investigations into the interplay of BA and FS and its relationship with ASD are yet to be conducted. The present study mainly focuses on exploring the interactive effect between BA and FS in the context of ASD.

Utilizing a multi-stage stratified cluster sampling, we initially recruited 84,934 Shanghai children aged 3–12 years old from June 2014 to June 2015, ultimately including 74,251 post-exclusion criteria. A logistic regression model was conducted to estimate the interaction effect after controlling for pertinent covariates. The attributable proportion (AP), the relative excess risk due to interaction (RERI), the synergy index (SI), and multiplicative-scale interaction were computed to determine the interaction effect.

Among a total of 74,251 children, 192 (0.26%) were diagnosed with ASD. The adjusted odds ratio for ASD in children with BA alone was 3.82 (95% confidence interval [CI] 2.42–6.02), for FS alone 3.06 (95%CI 1.48–6.31), and for comorbid BA and FS 21.18 (95%CI 9.10–49.30), versus children without BA or FS. The additive interaction between BA and FS showed statistical significance ( P  < 0.001), whereas the multiplicative interaction was statistically insignificant ( P  > 0.05).

Limitations

This study can only demonstrate the relationship between the interaction of BA and FS with ASD but cannot prove causation. Animal brain experimentation is necessary to unravel its neural mechanisms. A larger sample size, ongoing monitoring, and detailed FS classification are needed for confirming BA-FS interaction in ASD.

In this extensive cross-sectional study, both BA and FS were significantly linked to ASD. The coexistence of these factors was associated with an additive increase in ASD prevalence, surpassing the cumulative risk of each individual factor.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder encompassing a broad spectrum of developmental impairments, profoundly affecting an individual’s functional abilities in various domains, including social interaction, communication, and adaptive behavior [ 1 ]. A substantial body of research suggests that ASD is characterized by a widespread disruption of brain neural networks resulting from a combination of genetic and environmental factors [ 2 , 3 , 4 ]. Therefore, seeking important factors associated with ASD, especially those with larger effect sizes, is of significant importance for gaining a deeper understanding of the nature of ASD and its potential etiology.

Birth asphyxia (BA) is a primary neonatal pathology, often resulting in long-term cognitive deficits including learning disabilities, epilepsy, developmental delays, and intellectual disability [ 5 ]. Some cohort studies have found that children exposed to asphyxia during perinatal period were at an increased risk of developing ASD in later life [ 6 , 7 ]. Febrile seizures (FS), characterized as convulsive episodes in association with fever, are distinct from seizures caused by intracranial pathologies, metabolic imbalances, or acute neurological insults [ 8 ]. Previous studies indicated that FS is related to a range of developmental and behavioral problems [ 9 , 10 , 11 , 12 ]. According to a nationally representative sample of twins, FS is associated with increased ASD prevalence [ 13 ]. Numerous pieces of evidence suggest that BA, as a perinatal brain injury, could compromise the early foundational structures and functions of the brain, thereby increasing its susceptibility to subsequent injuries [ 5 , 14 , 15 , 16 ]. This vulnerability reflects a critical period wherein the developing brain is particularly sensitive to environmental insults. In comparison, FS, as postnatal factors potentially impacting brain integrity, were generally considered to have a minimal detrimental effect on a healthy brain [ 17 , 18 ]. However, in brains with foundational vulnerabilities, such as those subjected to BA-induced damage during the perinatal period, the deleterious effects of FS could be significantly amplified, suggesting a heightened risk of exacerbated neurological damage in these susceptible populations. In instances where basic brain structures and functions are compromised, the subsequent occurrence of FS can be likened to a hurricane striking a house with an unstable foundation, exacerbating an already precarious situation. Therefore, even though FS typically exert a milder impact on neural integrity, their occurrence on a backdrop of BA can potentially lead to more severe neurodevelopmental injuries [ 19 ]. This interaction may result in a synergistic effect, where the combined impact is greater than the sum of the individual conditions, illustrating a ‘1 + 1 > 2’ scenario in terms of neurodevelopmental injuries. Furthermore, both BA and FS have the potential to initiate or aggravate immune dysfunction and neuroinflammation [ 20 , 21 , 22 , 23 , 24 ]. The concurrent presence of BA and FS might act as a ‘two-hit’ insult to the brain, culminating in extensive neurodevelopmental injuries. It is well established that extensive neurodevelopmental injuries significantly elevate the risk of ASD onset [ 25 , 26 ].

Consequently, we hypothesized that BA and FS may exhibit an additive interaction, correlating with an increased prevalence of ASD. Additionally, to comprehensively understand the interplay between FS and BA and their relationship with ASD, we have also explored the presence of a potential multiplicative interaction between these factors.

Study design and sampling

An epidemiological survey was conducted among children aged 3–12 years old in Shanghai (population 24,197,000) from June 2014 to June 2015. Employing a stratified random cluster sampling approach, three urban districts (Yangpu, Xuhui, Jingan) from Shanghai’s seven urban districts, and four suburban districts (Pudong, Minhang, Chongming, Fengxian) from the nine suburban districts were systematically selected. This method ensured a comprehensive and representative cross-section of Shanghai’s diverse urban and suburban populations for the study. A total of 15% kindergartens and primary schools from the sampled districts were incorporated into our study, encompassing all children attending these schools as survey subjects. Recognizing that the majority of children with ASD were recruited in special education schools, all children from every special education school within the sampled districts were included to ensure comprehensive representation in our research.

In total, 84,934 children aged 3–12 years, drawn from 96 kindergartens, 55 primary schools, and 28 special education schools, were enrolled in this study. Following the application of specific exclusion criteria to remove cases that did not meet the study’s requirements, 74,251 children were selected for the analysis (Fig.  1 ). The described sampling method has been thoroughly detailed in prior published papers [ 27 , 28 ].

Children’s family social environment and growth questionnaire

This questionnaire, designed for investigating the growth, development, family and social environmental conditions of children, was extracted from key items of well-validated questionnaires in existing literature [ 29 , 30 , 31 ]. It includes a detailed survey of the child’s general health history during the fetal and perinatal periods, previous medical conditions, and a thorough assessment of family background. Key factors such as the child’s age [ 32 ], sex [ 33 ], district [ 34 ], Body Mass Index (BMI) [ 35 ], birth weight [ 36 ], gestational age [ 37 ], mode of delivery [ 38 ], feeding practices [ 39 ], parental age [ 40 , 41 ], educational levels of the parents [ 42 ], parents’ personalities [ 43 ], maternal psychological status [ 44 ], complications during pregnancy [ 45 ] and the annual household income [ 34 ] are all considered. The questionnaire is comprehensive, comprising 44 items in total, each designed to capture essential data points crucial for understanding the multifaceted influences on a child’s development. For instance, the mode of delivery refers to whether the birth was vaginal or via cesarean section; parents’ personalities are categorized as introverted or extroverted, based on self-assessment and the predominant perception of others; feeding practices are defined as exclusive breastfeeding, formula feeding, or a combination of both; complications during pregnancy referred to the presence of one or more adverse factors, such as threatened abortion, medication during pregnancy, high fever (above 39℃), heart disease, intense mental stress, hyperemesis gravidarum, and anemia [ 30 , 31 ]. This approach has been applied in multiple published studies, demonstrating its effectiveness and relevance in research contexts [ 46 , 47 , 48 ].

Diagnostic criteria for BA and FS

BA occurs when a newborn fails to initiate and maintain spontaneous breathing at birth, potentially leading to permanent brain cell damage and posing a serious threat to the infant’s life [ 49 ]. This condition is characterized by evidence of anoxic events during birth and is diagnosed based on meeting at least two of the following criteria: an Apgar score below 5 at 5 to 10 min post-birth, the need for mechanical ventilation or resuscitation, the fetal umbilical artery acidemia, multi-system organ failure, and radiological evidence of hypoxic-ischemic encephalopathy [ 50 ]. For parents who indicated ‘yes’ to the question in the questionnaire regarding ‘oxygen deficiency or asphyxia at birth’, we conducted a comprehensive review of their child’s medical history records and imaging reports. The diagnosis was made rigorously in accordance with the established diagnostic criteria for BA.

The diagnostic criteria for FS, according to the International League Against Epilepsy (ILAE) and the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), require a child over a month old to experience a fever-related epileptic seizure, with the fever not being attributable to any central nervous system (CNS) infection. The child should have no history of neonatal seizures or prior seizures without a clear cause, and the event should not fit the profile of other specified acute symptomatic seizures [ 51 , 52 ]. For parents who indicated ‘yes’ to the question in the questionnaire regarding a history of FS, we conducted a thorough review of their child’s medical history records. The diagnosis was made in accordance with the established diagnostic criteria. Due to caregivers’ apprehension of the alarming convulsions induced by FS, almost all children with FS are promptly brought to hospitals, resulting in a minimal rate of missed diagnoses.

The social communication questionnaire (SCQ)

The SCQ, derived from Autism Diagnostic Interview-Revised (ADI-R), screens for ASD risk in children [ 53 ]; scores over 15 suggest possible ASD [ 54 ]. The Chinese version of the SCQ demonstrates a sensitivity of 0.93 and a specificity of 0.98 [ 55 ], with a false-negative rate of 1.2 per 10,000 [ 28 ]. Moreover, it demonstrates high internal consistency (a Cronbach’s alpha of 0.92), affirming its reliability in ASD screening [ 55 ].

ASD diagnostic procedure

Initially, Children’s Family Social Environment and Growth Questionnaire and the SCQ were distributed to parents and teachers of each child for completion. This was to screen for the potential presence of ASD. If either the parent or teacher questionnaire results in an SCQ score of 15 or higher, the child is then directed to undergo a diagnostic evaluation process for ASD.

The clinical assessment and diagnosis of ASD were conducted at the Shanghai Children’s Medical Center’s Developmental and Behavioral Pediatrics department. This process was overseen by two developmental and behavioral pediatricians with extensive clinical experience. They conducted comprehensive clinical interviews and physical examinations (with a particular focus on neurological assessments) for all children suspected of having ASD. This was followed by detailed auxiliary examinations, including electroencephalogram (EEG), cranial magnetic resonance imaging (MRI), Wechsler Intelligence Scale testing, and developmental-behavioral evaluations. The final diagnosis was in strict accordance with the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria.

Quality assurance

A comprehensive training program was implemented for researchers to thoroughly comprehend the study’s objectives, procedures, methodologies, and safety measures, ensuring uniform understanding and adherence to the research protocol. During the data collection phase, a standardized guideline was employed to instruct parents and teachers on the critical aspects of completing the questionnaires. Following collection, we scrutinized the questionnaires to pinpoint and correct any inaccuracies or gaps. This process entailed engaging with parents and teachers for essential adjustments. Moreover, all data were coded adhering to uniform standards and subjected to an anonymous screening process. Another researcher re-entered 15.0% of the questionnaire data, yielding high agreement rates, ensuring data validation. Epidata 3.1 was employed for efficient data entry and rigorous logic error verification.

Statistical analysis

Two-sample t-tests compared ASD and normal groups. Logistic regression models were employed to calculate odds ratios (ORs) and 95% confidence interval (CI) for ASD prevalence, analyzing BA, FS, and their interaction. To adjust for demographic features, we incorporated a predetermined set of covariates, including age, sex, district, and income. Additionally, we established three models to better isolate the association between BA/FS and ASD as well as reduce potential bias:1) unadjusted (Model 1); 2) adjusted for demographic features (Model 2); 3) adjusted for demographics plus BA, FS, or ASD-related covariates (Model 3). The selection of covariates was based on factors extensively reported in the literature as having significant associations with either the independent variables (BA, FS) or the dependent variable (ASD) [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. These factors may potentially alter the relationship between the independent and dependent variables within the model. Subgroup analyses were conducted to explore not only the independent associations of BA and FS with ASD, but also their interactive effects within different sex and age groups.

In line with our hypothesis, our study primarily focused on the additive interaction of BA and FS in ASD. To enhance our understanding of the BA, FS, and ASD relationship and to probe the synergistic effect where combined impact exceeds individual contributions (1 + 1 > 2), our investigation centered on assessing additive interactions. Moreover, we delved into the potential multiplicative interaction between BA and FS in ASD, aiming for a comprehensive grasp of their interconnected roles. Additive scale interaction implies that the aggregate impact of two exposures exceeds (or falls below) their individual effects summed, while multiplicative scale interaction [Eq. (4)] denotes the combined effect surpassing (or being less than) their individual impacts multiplied [ 56 ]. The relative excess risk of interaction [RERI; Eq. ( 1 )], the attributable proportion to interaction [AP; Eq. ( 2 )] and the synergy index [SI; Eq. ( 3 )] are represented to calculate the results of additive interaction [ 57 ]. In Eqs. ( 1 – 4 ), \({\varvec{O}\varvec{R}}_{BA\&FS}\) represents the Odd Ratio (OR) for both BA and FS, \({\varvec{O}\varvec{R}}_{BA} and {\varvec{O}\varvec{R}}_{FS}\) represent the OR for BA or FS alone, respectively.

All analyses were performed using Statistical Program for Social Science (SPSS) software (version 26.0) and R statistics software (version 4.2.2). We considered a two-tailed P  value of less than 0.05 as statistically significant.

Participants characteristics and ASD prevalence

The baseline characteristics of participants were presented in Table  1 . Among the initial cohort of 84,934 children, a total of 10,683 were excluded from the study for the following reasons: (1) Questionnaires exhibiting contradictory responses between parents and teachers resulted in the exclusion of 8,503 participants; (2) Questionnaires deemed invalid due to more than 67% of the questions being incomplete led to the exclusion of 2,155 participants; (3) Children diagnosed with chronic diseases or those who were blind, deaf, mute, or had cerebral palsy were excluded, accounting for 25 participants. Consequently, the study proceeded with a final sample of 74,251 participants, with a median age of 7.5 years. The cohort achieved gender balance, comprising 53.3% boys. Prevalence of BA was noted in 3.7% of cases, whereas FS affected 1.7%. Our findings of 192 participants with ASD (0.26%) were consistent with similar database research [ 58 ]. Variance Inflation Factor (VIF) was used to evaluate multicollinearity. All square roots of the VIF values were below 2, thereby excluding the possibility of high correlation among the independent variables. Figure  1 categorizes participants into four groups based on BA and FS status. The prevalence of ASD in the reference group (no BA or FS) was 0.2% ( N  = 148/69,097), 1.0% in the BA-only group ( N  = 27/2,590), 0.8% in the FS-only group ( N  = 9/1,150), and markedly higher at 7.1% in the group with both BA and FS ( N  = 7/99).

Flowchart of study population. BA: birth asphyxia; FS: febrile seizures; ASD: autism spectrum disorder

The association between BA/FS and ASD occurrence

A significant association of BA and FS with increased ASD prevalence was found in Table  2 . The analysis indicated a significant link between BA/FS and an increased prevalence of ASD, as detailed in Table  2 . In the fully adjusted model (Model 3), participants with BA were associated with a 290% increased prevalence of ASD (OR 3.90, 95%CI 2.60–5.86) compared to participants without BA. Similarly, participants with FS showed a 252% increased prevalence (OR 3.52, 95%CI 2.03–6.10) relative to participants without FS. Deeper subgroup analysis factoring in age and sex revealed that the association between BA and ASD was particularly pronounced in participants aged 7–10 years (OR 4.71, 95%CI 2.57–8.65), and even more so in girls (OR 7.51, 95%CI 3.63–15.50), when in contrast to the correlations observed in age groups 3–7 and 10–12 years, as well as in boys. It was noteworthy that FS, a significant association with ASD was also observed in the 7–10 year age group (OR 6.02, 95%CI 2.78–13.05) and in girls (OR 3.62, 95%CI 1.08–12.12). Pertaining to the stratification by sex and age, detailed sample sizes and the corresponding effect sizes for BA, FS, and ASD across the three models are comprehensively presented in Additional file 1: Table S1 .

Interaction effect of BA and FS in relation to ASD

In Table  3 , our analysis revealed that, relative to the reference group without BA or FS, the BA-only group demonstrated a significantly increased prevalence of ASD with OR of 3.82 (95%CI 2.42–6.02). Similarly, the FS-only group exhibited an OR of 3.06 (95%CI 1.48–6.31), indicating a heightened ASD prevalance. Most notably, the group with comorbid BA and FS showed a markedly elevated ASD prevalence with an OR of 21.18 (95%CI 9.10–49.30). The additive interaction indices for BA and FS in Model 3 were statistically significant (AP 0.72, 95%CI 0.24–0.86; RERI 15.30, 95%CI 2.95–43.27; SI 4.14, 95%CI 1.49–11.46). The AP suggests that a portion of 72% ASD risk in children with both BA and FS can be attributed to the additive interaction of these two factors. A positive RERI indicates a significant excess risk of ASD due to the combined effect of BA and FS over their individual effects and the value of SI greater than 1 demonstrates a synergistic effect between BA and FS, where their combined effect on ASD risk is greater than the sum of their individual effect. The additive interaction effect showed positively statistical significance in age 7–10 years (AP 0.85, 95%CI 0.36–0.93; RERI 46.83, 95%CI 8.04-173.02; SI 7.37, 95%CI 1.79–30.36) and girls (AP 0.90, 95%CI 0.36–0.95; RERI 74.72, 95%CI 8.76-394.17; SI 11.87, 95%CI 1.95–72.24). Given that all multiplicative interaction intervals included 1, aligning with the null hypothesis, there was insufficient evidence to demonstrate a significant multiplicative interaction between BA-FS and ASD in this study.

This study marked the initial foray into a population-based epidemiological analysis focusing on the interplay between BA and FS in the context of ASD. Post-adjustment for covariates, we discerned a significant additive interaction between BA and FS related to ASD prevalence (AP 0.72, 95%CI 0.24–0.86; RERI 15.30, 95%CI 2.95–43.27; SI 4.14, 95%CI 1.49–11.46). In Model 3, which controlled for as many covariates as possible, the OR for the interaction between BA and FS in association with ASD was 21.18 (95%CI 9.10–49.30). This indicated that in the population of children with both BA and FS, the prevalence of ASD was 21.18 times higher compared to the population without BA and FS. This was consistently validated through analysis using three diverse and robust statistical models (Table  3 ).

Nevertheless, it is crucial to emphasize that our study primarily identified the correlation between the interplay of BA and FS in relation to ASD, without asserting a causal relationship. Given the intricacy of these mechanisms, there were three possible explanations that merit consideration:

1) The additive interaction between BA and FS might result in a more pronounced impairment of the developing neural networks in children, ultimately leading to the onset of ASD.

BA typically inflicts extensive and severe damage on the brain, with the cerebral cortex and hippocampus being particularly vulnerable [ 59 , 60 , 61 ]. This damage was evidenced by reduced arborization in the cerebellum and cortex, a marked decrease in Purkinje cells, and a thinning of both the orienting and pyramidal layers in the dorsal hippocampus [ 59 , 60 , 61 ]. Such neuroanatomical changes were consistent with those identified in ASD, as supported by findings from both animal models and human neuroimaging studies [ 62 ]. Additionally, early life trauma induced by BA could lead to the recruitment of astrocytes and microglia at the injury site [ 63 ]. This response triggered alterations in neural circuit excitability, effectively lowering the brain’s threshold for excitation. Consequently, this heightened sensitivity could precipitate seizures, particularly when the brain is subjected to further stressors, such as ‘fever’ [ 64 ]. Moreover, research indicated that FS also exerted varying degrees of influence on the development of the CNS [ 65 , 66 ]. In a recent study, it was observed that FS could lead to notable changes in the neural connectivity, specifically between the bilateral temporal lobes and the thalamus in children [ 22 ]. This included an increased dissociation and diminished integration of select subcortical structures, as well as alterations in the right frontal lobes. Concurrently, prolonged exposure to certain FS might induce enduring changes in dendritic complexity, alongside abnormal neuronal gene expression and the growth of excitatory synapses [ 67 ].

Due to the vulnerability induced by early brain damage from BA, the brain became more susceptible to even relatively mild risk factors, such as FS. This susceptibility could lead to further significant damage to the brain’s neural networks and adversely impact the development of CNS. However, in cases where the fundamental neuroanatomical structures and functions remain intact, certain milder risk factors, such as FS, might struggle to inflict significant damage to the brain [ 68 ]. It is predominantly in brains where the foundational structures and functionalities were compromised and exhibited vulnerability, that the deleterious effects of FS might manifest [ 69 ]. This could lead to a synergistic interaction, resulting in more severe consequences for the development of the nervous system. Moreover, a substantial body of research has established that abnormalities in the development of the CNS were a significant contributing factor in the etiology of ASD [ 70 , 71 , 72 ]. Therefore, it is highly plausible that BA and FS interact synergistically, substantially elevating the risk of ASD development.

2) The progression of ASD might contribute to an increased prevalence of both BA and FS, thereby intensifying the interactive dynamic between these two factors.

Research conducted by Gayle C and colleagues has identified that children with ASD detected in prenatal screenings exhibited distinctive biochemical markers, notably lower levels of unconjugated estriol (uE3) and higher concentrations of maternal serum alpha-fetoprotein (MSAFP) [ 73 ]. The uE3 levels during gestation were indicative of both fetal and placental health. Diminished uE3 has been correlated with various adverse pregnancy outcomes, including preeclampsia, preterm birth, infants small for gestational age, and compromised placental function [ 74 ]. In a similar vein, elevated MSAFP levels served as a significant prognosticator for adverse maternal/fetal health outcomes, potentially leading to the emergence of BA [ 75 ]. Furthermore, ASD encompassed variations in neurodevelopment and brain connectivity, which might render the brain more vulnerable to perturbations induced by fever, potentially precipitating FS [ 76 , 77 , 78 , 79 , 80 ]. Additionally, in individuals with ASD, there was often a dysregulated immune response to infections, commonly associated with fever, which might elevate the risk of FS. This altered immune reactivity in ASD could exacerbate the neurological impact of common infections, thereby increasing the likelihood of FS [ 81 ]. Therefore, ASD itself might contribute to an increased prevalence of BA and FS. This heightened occurrence served as a foundation for the amplified synergistic interaction between BA and FS.

3) Specific genetic anomalies might concurrently heighten the risk of BA, FS, and ASD; consequently, these genetic factors collectively might contribute to an elevated prevalence of BA, FS, and ASD, thus reinforcing their interplay.

Previous studies have documented that deletions and mutations in genes such as DYRK1A, SCN9A, SCN1A, and CACNA1A could lead to both ASD and FS [ 82 , 83 , 84 , 85 ]. Additionally, as genetic research progresses, it’s likely that more genetic defects contributing to the increased risk of developing ASD, FS, and BA would be identified. Under the influence of these genetic factors, an increased prevalence of these conditions might intensify their interplay. This represents a significant causal mechanism pathway that should not be overlooked.

This study found that the interaction between BA and FS in association with ASD demonstrated an additive interaction, with no evidence of a multiplicative interaction. Within the ‘interaction continuum’ theory, interactions were categorized into 11 levels of varying strengths [ 86 ]. In this continuum, the strongest positive interaction is positive-multiplicative positive-additive. The interaction between BA and FS in relation to ASD is classified as no-multiplicative positive-additive, ranking it as the second strongest. Therefore, from a biological and clinical medical perspective, this significant interaction warrants further in-depth investigation and should not be overlooked. Given the strong interaction between BA and FS associated with ASD, this study carries significant clinical implications. It suggests that for children clinically suspected of ASD, a detailed history regarding the presence of BA and FS should be meticulously assessed. Particularly, children exhibiting both BA and FS warrant intensified screening and monitoring for ASD.

In our study, the prevalence of ASD in the assessed population was approximately 0.26%, which was below the global estimate of 0.76% as reported by the World Health Organization (WHO) [ 87 ]. A systematic review reported an ASD prevalence of 0.34% (95%CI 0.08%-1.4%) [ 88 ] in Southeast Asian populations. A meta-analysis reported ASD prevalence in China, including Hong Kong and Taiwan regions, at 0.27% (95%CI 0.19%-0.35%) [ 89 ]. Furthermore, the most extensive cross-sectional epidemiological study on ASD to date, encompassing children aged 6–12 across eight representative cities in China, reported a prevalence of 0.29% (95%CI 0.26%-0.32%) [ 90 ]. Consequently, the ASD prevalence observed in our study aligned with the majority of research conducted in China but was lower than the rates reported in some other countries [ 91 ]. Potential reasons for this discrepancy could include significant variations in ASD prevalence across different ethnic populations. Additionally, our study adhered strictly to the DSM-5 diagnostic criteria for ASD, which tended to identify fewer cases compared to the DSM-4 criteria [ 92 ].

Furthermore, in a multivariable logistic regression model, we identified associations with ASD that align with findings reported in prior studies. These associations included age [ 93 ], sex [ 94 ], feeding practices [ 39 ], introverted father [ 95 ], paternal educational level [ 96 ], maternal educational level [ 96 ], maternal psychological status [ 97 ], and complications during pregnancy [ 7 ]. In three statistical models, both crude and adjusted ORs showed statistical significance, affirming these variables’ association with ASD, independent of other factors.

The study’s robust methodology, utilizing a large and representative sample from one of the world’s largest cities, Shanghai, is a significant strength. Including children from all special education schools within the sampled districts substantially minimized the risk of undetected ASD cases, enhancing the study’s validity and reliability. Second, the age range of the sample, from 3 to 12 years, was comprehensive, covering the typical age range for ASD diagnosis and the onset of pronounced symptoms. Third, diagnostic protocols conformed to DSM-5 and best practices, integrating parent-teacher feedback with evidence-based tools. Children with suspected ASD were referred to two seasoned developmental and behavioral pediatricians for in-depth clinical evaluations, including history, physical exams, MRI, EEG, and behavioral assessments, ensuring accurate diagnoses. Fourth, our study adjusted for numerous covariates, enabling a detailed analysis of the additive interaction between BA and FS and its association with ASD. This interaction showed a significant effect size and was consistently evident across three stringent statistical models. Fifth, given our substantial sample size, we also explored this BA-FS interaction in relation to ASD across different age and sex strata, enhancing the robustness of our findings.

Several key limitations warrant attention. First, based on the evidence presented in this paper, we can only assert a notable association between the interaction of BA and FS, and their correlation with ASD. However, this did not establish causality between these factors, nor did it elucidate the underlying mechanisms. Second, given the cross-sectional nature of the research, we were unable to trace longitudinal changes in participants, thereby lacking precise information on the timing of events. This limitation hampers understanding of the long-term cumulative effects of BA and FS on the risk trajectory for ASD. Third, SCQ screening phase might have overlooked some ASD cases, but considering the SCQ’s role as a standardized screening instrument, the rate of missed diagnoses is remarkably low, at only 1.2 per 100,000 [ 28 ]. Fourth, while we noted a more pronounced effect of the BA and FS interaction linked to ASD in children aged 7–10 and girls, the broad and overlapping 95%CI suggested uncertainty in these age and sex-specific differences. In addition, our study’s low ASD prevalence meant that, despite a large sample, only 7 children with BA and FS were diagnosed with ASD, hence the OR values were susceptible to fluctuations in case numbers. Thus, our findings necessitate replication through multicenter, multicity, and nationwide studies with larger samples for more reliable conclusions. Fifth, our epidemiological study did not encompass genetic testing for each participant, their parents, or information on the BA, FS, and ASD conditions among first- and second-degree relatives. This omission presents a significant challenge in fully accounting for genetic influences. Future research is needed to unravel the potential genetic contributions to these correlations. Sixth, while our study identified the significant additive interaction between BA and FS in ASD, it did not explore their interplay with broader neurodevelopmental or physical health domains. This area awaits exploration in future research.

This study highlighted a robust synergistic interplay between BA and FS as they pertain to ASD. These insights are pivotal for the progression of ASD research and clinical practice, guiding us to: 1) offer clues for deeper investigation into the causes of ASD; 2) assess the detailed history of BA and FS in children clinically suspected of ASD; and 3) emphasize the critical need for vigilant ASD or developmental disorders screening and surveillance in children with BA and FS histories.

Data availability

The data that support the findings of this study are available on request from the corresponding author, JM. The data are not publicly available due to privacy restrictions.

Abbreviations

Autism Diagnostic Interview

Attributable Proportion

Autism Spectrum Disorder

Birth Asphyxia

Body Mass Index

Confidence Interval

Central Nervous System

The Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders

Electroencephalogram

Febrile Seizures

International Statistical Classification of Diseases and Related Health Problems 10th Revision

The International League Against Epilepsy

Magnetic Resonance Imaging

Maternal Serum Alpha-Fetoprotein

Relative Excess Risk of Interaction

Social Communication Questionnaire

Synergy Index

Statistical Program for Social Science

Unconjugated Estriol

Variance Inflation Factor

World Health Organization

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Acknowledgements

The authors are grateful to the support and participation of all the teachers, children and their parents.

This study was supported by Shanghai Science and Technology Innovation Action Plan Medical Innovation Research Special Project in 2022 (Grant No. 22Y11920100); Science and Technology Commission of Shanghai Municipality (Grant No. 18411960200 and Grant No. 20ZR1434700); Shanghai Municipal Commission of Health and Family Planning: Shanghai Municipal Enhancing Public Health 3-Year Prevention and Control of ASD Program, 2011–2013 (Grant No. 11PH1951202).

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Yi Mao, Xindi Lin, Yuhan Wu, Jiayi Lu, Shaogen Zhong, Xingming Jin & Jun Ma

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Study conceptualized by JM and XJ; manuscript drafting by YM, XL; data collected and quality assured by JL, YW; YM, JS, SZ conducted rigorous statistical analysis and result interpretation; manuscript critically reviewed and revised by JM. All authors approved the final manuscript, confirming no conflict of interest.

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Logistic regression: associations between BA/FS and ASD, including age and sex stratification in all three statistical models

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Mao, Y., Lin, X., Wu, Y. et al. Additive interaction between birth asphyxia and febrile seizures on autism spectrum disorder: a population-based study. Molecular Autism 15 , 17 (2024). https://doi.org/10.1186/s13229-024-00596-3

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Study identifies new metric for diagnosing autism

Autism spectrum disorder has yet to be linked to a single cause, due to the wide range of its symptoms and severity. However, a study by University of Virginia researchers suggests a promising new approach to finding answers, one that could lead to advances in the study of other neurological conditions.

Current approaches to autism research involve observing and understanding the disorder through the study of its behavioral consequences, using techniques like functional magnetic resonance imaging that map the brain's responses to input and activity, but little work has been done to understand what's causing those responses.

However, researchers with UVA's College and Graduate School of Arts & Sciences have been able to better understand the physiological differences between the brain structures of autistic and non-autistic individuals through the use of Diffusion MRI, a technique that measures molecular diffusion in biological tissue, to observe how water moves throughout the brain and interacts with cellular membranes. The approach has helped the UVA team develop mathematical models of brain microstructures that have helped identify structural differences in the brains of those with autism and those without.

"It hasn't been well understood what those differences might be," said Benjamin Newman, a postdoctoral researcher with UVA's Department of Psychology, recent graduate of UVA School of Medicine's neuroscience graduate program and lead author of a paper published this month in PLOS: One . "This new approach looks at the neuronal differences contributing to the etiology of autism spectrum disorder."

Building on the work of Alan Hodgkin and Andrew Huxley, who won the 1963 Nobel Prize in Medicine for describing the electrochemical conductivity characteristics of neurons, Newman and his co-authors applied those concepts to understand how that conductivity differs in those with autism and those without, using the latest neuroimaging data and computational methodologies. The result is a first-of-its-kind approach to calculating the conductivity of neural axons and their capacity to carry information through the brain. The study also offers evidence that those microstructural differences are directly related to participants' scores on the Social Communication Questionnaire, a common clinical tool for diagnosing autism.

"What we're seeing is that there's a difference in the diameter of the microstructural components in the brains of autistic people that can cause them to conduct electricity slower," Newman said. "It's the structure that constrains how the function of the brain works."

One of Newman's co-authors, John Darrell Van Horn, a professor of psychology and data science at UVA, said, that so often we try to understand autism through a collection of behavioral patterns which might be unusual or seem different.

"But understanding those behaviors can be a bit subjective, depending on who's doing the observing," Van Horn said. "We need greater fidelity in terms of the physiological metrics that we have so that we can better understand where those behaviors coming from. This is the first time this kind of metric has been applied in a clinical population, and it sheds some interesting light on the origins of ASD."

Van Horn said there's been a lot of work done with functional magnetic resonance imaging, looking at blood oxygen related signal changes in autistic individuals, but this research, he said "Goes a little bit deeper."

"It's asking not if there's a particular cognitive functional activation difference; it's asking how the brain actually conducts information around itself through these dynamic networks," Van Horn said. "And I think that we've been successful showing that there's something that's uniquely different about autistic-spectrum-disorder-diagnosed individuals relative to otherwise typically developing control subjects."

Newman and Van Horn, along with co-authors Jason Druzgal and Kevin Pelphrey from the UVA School of Medicine, are affiliated with the National Institute of Health's Autism Center of Excellence (ACE), an initiative that supports large-scale multidisciplinary and multi-institutional studies on ASD with the aim of determining the disorder's causes and potential treatments.

According to Pelphrey, a neuroscientist and expert on brain development and the study's principal investigator, the overarching aim of the ACE project is to lead the way in developing a precision medicine approach to autism.

"This study provides the foundation for a biological target to measure treatment response and allows us to identify avenues for future treatments to be developed," he said.

Van Horn added that study may also have implications for the examination, diagnosis, and treatment of other neurological disorders like Parkinson's and Alzheimer's.

"This is a new tool for measuring the properties of neurons which we are particularly excited about. We are still exploring what we might be able to detect with it," Van Horn said.

• Birth Defects
• Medical Devices
• Nervous System
• Brain Tumor
• Learning Disorders
• Disorders and Syndromes
• Autistic spectrum
• Brain damage
• Social cognition
• Rett syndrome
• Attention-deficit hyperactivity disorder
• Learning disability

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Materials provided by University of Virginia College and Graduate School of Arts & Sciences . Original written by Russ Bahorsky. Note: Content may be edited for style and length.

Journal Reference :

• Benjamin T. Newman, Zachary Jacokes, Siva Venkadesh, Sara J. Webb, Natalia M. Kleinhans, James C. McPartland, T. Jason Druzgal, Kevin A. Pelphrey, John Darrell Van Horn. Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder . PLOS ONE , 2024; 19 (4): e0301964 DOI: 10.1371/journal.pone.0301964

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Brain organoids and assembloids are new models for elucidating, treating neurodevelopmental disorders

Stanford Medicine research on Timothy syndrome — which predisposes newborns to autism and epilepsy — may extend well beyond the rare genetic disorder to schizophrenia and other conditions.

April 24, 2024 - By Bruce Goldman, Erin Digitale

In this 2019 photo, Timothy syndrome patient Holden Hulet, left, rides in a side-by-side ATV driven by his dad, Kelby Hulet, at sand dunes near their home in southern Utah.  Courtesy of the Hulet family

For a long time, no one understood that Holden Hulet was having seizures.

“He would just say ‘I feel tingly, and my vision kind of goes blurry,’” said Holden’s mom, JJ Hulet. “But he couldn’t communicate exactly what was going on.”

JJ and Kelby Hulet could see their son was having short spells of incoherent speech, rapid back-and-forth eye movements and odd physical changes. “He’d kind of go — I don’t want to say ‘limp’ because he would stand just fine — but his body would just be in zombie mode,” JJ said. The episodes lasted less than a minute.

The parents were puzzled and worried, as they had been many times since Holden was born in 2008 and they learned that their newborn had an extremely rare genetic disease. “I was thinking it was his heart,” Kelby Hulet, Holden’s dad, said.

Holden’s condition, Timothy syndrome, causes long, irregular gaps in heart rhythm. He spent his first six months hospitalized in a neonatal intensive care unit in his family’s home state of Utah while he grew big enough to receive an implantable cardioverter defibrillator. The device sends an electrical signal to restart his heart when it pauses for too long.

As a small child, Holden would sometimes pass out before the defibrillator shocked his heart back into action. When Holden started telling his parents about the blurry-vision episodes at age 6, Kelby initially believed it was a new version of the same problem, and he kept a time stamp on his phone for each episode. But the records from Holden’s defibrillator showed that these times did not line up with any heart-rhythm problems.

The family’s pediatrician was confused, too. Perhaps Holden was having periods of low blood sugar, another possible Timothy syndrome complication, he suggested. Initial testing at the local medical center did not turn up clear answers.

But Kelby, who was training to become an operating room nurse, realized Holden’s episodes reminded him of what he was learning about warning signs for stroke. JJ called Holden’s cardiologist in Utah and asked for a detailed neurologic evaluation, which enabled the mysterious episodes to be diagnosed as seizures. Holden began taking anti-seizure medication, which helped, to his parents’ great relief.

Researching a rare disease

A few months after Holden was born, Sergiu Pasca , MD, arrived at Stanford Medicine to pursue a postdoctoral fellowship in the lab of Ricardo Dolmetsch, PhD, then an assistant professor of neurobiology, who was redirecting his research to autism spectrum disorder. At the time, Pasca did not know the Hulet family. But his work soon became focused on the disorder that has shaped Holden’s life.

Caused by a defective gene on the 12th chromosome, Timothy syndrome is vanishingly rare, with no more than 70 diagnosed cases. Children with this disorder rarely survive to late adolescence. It is caused by a mutation in the gene coding for a type of calcium channel — a protein containing a pore that selectively opens or closes, respectively permitting or blocking the flow of calcium across cells’ membranes. While a prominent feature — severe heart malfunction — can be tackled with a pacemaker, most children with Timothy syndrome will end up with lifelong brain disorders including autism, epilepsy and schizophrenia.

By mid-2009, Pasca had succeeded in generating nerve cells from induced pluripotent stem cells (which can be induced to form virtually any of the body’s numerous cell types). These included cells derived from the skin of two patients with Timothy syndrome. Later that year he observed defects in how the patient-derived neurons were handling calcium. This advance — the creation of one of the initial in-a-dish models of brain disease, built from neurons with defects that precisely mirrored those of a patient’s brain — was published in Nature Medicine in 2011.

Pasca and colleagues continued to monitor these Timothy-syndrome neurons in standard two-dimensional culture — growing as single layers in petri dishes — over the next few years. While this two-dimensional culture method was limited in its ability to sustain viable neurons, it was soon superseded by a genuine scientific breakthrough.

Pioneering the first assembloids

The constraints of two-dimensional culture, including the inability to keep these neurons for long periods of time so that they could reach key stages of neural development, prompted Pasca in 2011 to start developing an unprecedented three-dimensional method. The novel technology produced what came to be known as brain organoids. These constructs recapitulated some of the architecture and physiology of the human cerebral cortex. The organoids can survive for several years in culture, enabling neuroscientists to view, non-invasively, the developing human brain up close and in real time. The scientists wrote a seminal Nature Methods paper , published in 2015, that described their discovery.

Pasca’s group subsequently showed that culturing brain organoids in different ways could generate organoids representing different brain regions (in this case, the cerebral cortex and a fetal structure called the subpallium). In a breakthrough set of experiments, Pasca’s team found ways to bring these organoids into contact so that they fuse and forge complex neuronal connections mimicking those that arise during natural fetal and neonatal development. Pasca named such constructs assembloids.

In their paper on the research, which was published in Nature in 2017, Pasca’s team showed that after fusion, a class of inhibitory neurons originating in the subpallium migrates to the cortex, proceeding in discrete, stuttering jumps. (See animation .) These migrating neurons, called interneurons, upon reaching their destinations — excitatory neurons of the cortex — form complex circuits with those cortical neurons.

But in assembloids derived from Timothy syndrome patients, the motion of interneurons as they migrate from the subpallium is impaired — they jump forward more often, but each jump is considerably shorter, so they fail to integrate into the appropriate circuitry in the cortex. This wreaks havoc with signaling in cortical circuits. Pasca’s team tied this aberrant neuronal behavior on the part of Timothy syndrome neurons to the key molecular consequence of the genetic defect responsible for the condition: namely, malfunction of the critical channels through which calcium must pass to cross neurons’ outer membranes.

A family’s struggles

While Pasca was developing assembloids, the Hulet family was progressing through their own journey of discovery with Holden. They faced painful uncertainty at every stage, starting when Holden was discharged from the NICU in the summer of 2009, after several months of hospitalization and multiple heart surgeries.

“Even when we brought him home, [his doctors] said ‘Don’t get your hopes up. We don’t usually see them make it past age 2,” JJ recalled. Many children with Timothy syndrome die from cardiac failure in early life.

“It’s really hard to be positive in that kind of situation, and for a long time I did let it get to me,” JJ said. “I finally got to a point where I said, ‘I have to live my life and we just keep fighting.’”

JJ runs a child care center and has years of experience working with special-needs kids, which motivated her to push for an autism evaluation when she saw signs of autism in Holden. He’s much more verbal than many children with autism, which paradoxically made it more difficult to get an official diagnosis.

“That was frustrating,” JJ said. Although the family’s pediatric cardiologist in Salt Lake City was familiar with the vagaries of Timothy syndrome, their local caregivers in the small town where they live in southern Utah were not. “They kept saying ‘Oh, no, it’s just developmental delays because he was so premature,’” she said. She wonders whether it would have been easier to have Holden’s autism diagnosed had more been known about Timothy syndrome at the time.

“I think research is important so that parents and children have the support they need,” she said, noting how lonely and painful it can be to advocate for a child when his condition is poorly understood — and when, as a parent, you may be doubted by medical professionals. “It’s a really hard thing to deal with.”

Her voice breaks briefly. She continues, “I think research brings validity to that.”

Sergiu Pasca

Implanting organoids

In 2022, Pasca published a  study in  Nature describing the transplantation of human cortical organoids into neonatal rats’ brains, which resulted in the integration of human neurons along with supporting brain cells into the brain tissue of rats to form hybridized working circuits. The implanted human organoids survived, thrived and grew. Individual neurons from the human organoids integrated into young rats’ brains were at least six times as big as those — generated the same way, at the same time — that remained in a dish. The transplanted neurons also exhibited much more sophisticated branching patterns. Pasca and his colleagues observed marked differences in the electrical activity of, on one hand, human neurons generated from a Timothy syndrome patient, cultured as organoids and transplanted into one side of a rat’s brain, and, on the other hand, those generated from a healthy individual and transplanted, as an organoid, into the corresponding spot on the other side of the same rat’s brain. The Timothy syndrome neurons were also much smaller and were deficient in sprouting branching, brush-like extensions called dendrites, which act as antennae for input from nearby neurons.

“We’ve learned a lot about Timothy syndrome by studying organoids and assembloids kept in a dish,” Pasca said. “But only with transplantation were we able to convincingly see these neuronal-activity-related differences.”

That same year, the FDA Modernization Act 2.0 was signed into law, exempting certain categories of new drug-development protocols from previously mandated animal testing. The act was predicated on the understanding that recent advancements in science offer increasingly viable alternatives to animal testing, so the findings based on the organoid- and assembloid-culture technologies may be adequate to justify clinical trials in some neurodevelopmental conditions.

Most recently, in a Nature paper published April 24, Pasca and his colleagues demonstrated, in principle, the ability of antisense oligonucleotides (ASOs) to correct the fundamental defects that lead to Timothy syndrome by nudging calcium-channel production toward another form of the gene that does not carry the disease-causing mutation. Using ASOs to guide production of the functional rather than defective form of this channel reversed the defect’s detrimental downstream effects: Interneuronal migration proceeded similarly to that procedure in healthy brains, and the altered electrical properties of the calcium channel reverted to normalcy. This therapeutic correction was demonstrated in a lab dish — and, critically, in rat-transplantation experiments, suggesting that this therapeutic approach can work in a living organism.

Pasca is now actively searching the globe for carriers of the genetic defect, in preparation for the pursuit of a clinical trial at Stanford Medicine to test the safety and therapeutic potential of ASOs in mitigating the pathological features of Timothy syndrome.

“We are also actively engaged in conversations with other scientists, clinicians in the field and ethicists about the best way to move forward and safely bring this therapeutic approach into the clinic,” he said.

Pasca added that the calcium channel that is mutated in Timothy syndrome is, in fact, “the hub” of several neuropsychiatric diseases including schizophrenia and bipolar disorder. So it may be that the lessons learned — and the therapies derived — from his 15-year focus on a rare disease may have broad application in a number of widespread and troubling psychiatric conditions.

‘Amazing’ teenager

Today, in defiance of his doctors’ warning that he might not live past age 2, Holden Hulet is 15 years old and doing well.

“I think a lot of times, autism is perceived as ‘They’re not neurotypical and they’re not capable of certain things.’ But he is brilliant,” JJ said. “He’s amazing with techie stuff or Legos. He’s funny and super honest and very self-aware.”

Kelby often takes Holden to visit the farm where he grew up. Holden loves to ride the farm equipment and enjoys hanging out with the animals, especially the farm dogs and calves. Like a lot of kids, he keeps an eye out for good rocks, Kelby said with a chuckle.

“He’s always either throwing them or collecting them,” JJ said. “That’s something I really like about him: He’s always got a pocket full of something.”

Although navigating a rare disease is one of the most challenging things they have faced, the Hulets see light in their situation, and would offer encouragement to any family facing a new Timothy syndrome diagnosis.

“There is hope,” JJ said. “There are people out there who care, people out there who fight for you who don’t even know you. I think that’s what is so important about research — that you’re fighting a battle for people you don’t even know.”

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Exploring ways AI is applied to health care

The Interdisciplinary Diagnostics of Autism Spectrum Disorder Using DC:0-5 TM : A Case Report

Affiliations.

• 1 Association of Child Psychiatrists and Psychologists.
• 2 Mental Health Research Center.
• PMID: 38618633
• PMCID: PMC11009971
• DOI: 10.17816/CP14783

Background: The Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC:0-5 TM ) is widely used in many Western countries. For Russian specialists, such classification represents a relatively new tool for the comprehensive diagnosis of mental disorders in children from birth to the five-year-old threshold. The purpose for presenting this case study report is to showcase the practical application of the DC:0-5 TM .

Aim: This study aims to illustrate the diagnostic process according to the DC:0-5 TM criteria using the example of a specific clinical case report involving the collaborative efforts of two specialists: a child psychiatrist and a clinical child psychologist.

Methods: DC:0-5 TM consists of five axes. The main axis focuses on clinical diagnosis criteria for mental disorders, considering their age specificity. The remaining four axes allow one to take into account and specify data related to biological, social, and psychological factors, which play a crucial role in understanding the causes and characteristics of a mental disorder in a child.

Results: In the examined case, an analysis of symptoms by means of the Clinical Disorders axis revealed that they were consistent with the diagnostic criteria for autism spectrum disorder. The use of the remaining axes supplemented the clinical diagnosis with specific details about the adverse physical health factors in the child, a high cumulative stress burden, significant developmental delays in the emotional, speech, and social dimensions, as well as dysfunction in the mother-child dyad. Since the parents declined medication for their son, this information proved crucial in developing a support program for both the child and the family.

Conclusion: The comprehensive diagnostic approach using the DC:0-5 TM axes proved highly effective, not only in psychiatric diagnosis but also in establishing goals and objectives for subsequent intervention. Its application in psychiatric, clinical psychology, and corrective educational practices has the potential to make support for children in their early years a more personalized and family-oriented undertaking.

Keywords: DC:0-5TM; autism spectrum disorder; case report.

Copyright © 2023, Skoblo G.V., Trushkina S.V.

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Researchers uncover SNUPN gene responsible for a new muscular disorder

by Koc University

A study , published in Nature Communications , sheds light on a newly identified subtype of muscular dystrophy, revealing an unsuspected role of SNUPN gene in muscle cell function.

Led by Assistant Prof. Dr. Nathalie Escande Beillard, Prof. Dr. Hülya Kayserili, and Prof. Dr. Piraye Oflazer, a team of Ph.D. students and postdoc from Koç University Faculty of Medicine embarked on a broad investigation to decipher the genetic underpinnings of a mysterious condition identified in a case evaluated at Koç University Hospital.

Eighteen new patients recruited from 11 different countries with similar muscular dystrophy and neurological symptoms revealed a potentially wider prevalence of this condition than initially presumed. Through deep genetic and functional analyses on patient's cells and tissues, the team identified alterations in the SNUPN as the causative factor for this debilitating disorder.

"This study represents a significant leap forward in our understanding and diagnosis of muscular dystrophies," said Assistant Prof. Dr. Nathalie Escande Beillard. "Our findings underscore for the first time the critical role of the Snurportin-1 protein encoded by the SNUPN gene in maintaining the structural integrity and function of muscle cells."

The illness shares similarities with SMA, not just in its impact on muscle tissue , but also in its progressive course and potential lethality. The Snurportin-1 protein involved in the newly identified disease interacts within the cell with the protein causing SMA.

Since SMA treatment is currently applied but still lacks full efficacy, ongoing research aims to provide evidence that may help SMA patients as well. Thanks to the animal model that has been generated in the zebrafish laboratory, researchers will continue to explore the role of this protein in muscle homeostasis and develop new treatment strategies.

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Schizoid vs. Schizotypal Personality Disorders

A comprehensive look at two commonly confused conditions

Hannah Owens is the Mental Health/General Health Editor for Dotdash Meredith. She is a licensed social worker with clinical experience in community mental health.

Steven Gans, MD is board-certified in psychiatry and is an active supervisor, teacher, and mentor at Massachusetts General Hospital.

master1305 / iStock / Getty Images

Definition of Schizoid and Schizotypal Personality Disorders

Comparing the symptoms, diagnostic criteria for both disorders, prevalence and causes, treatment options.

Most people have heard of narcissistic personality disorder and borderline personality disorder , but there are actually a wide range—and three different types—of personality disorders as described by the DSM-5-TR (the most recent version of the Diagnostic and Statistical Manual of Mental Disorders).

Two of those personality disorders—belonging to “Cluster A” disorders—are schizoid personality disorder and schizotypal personality disorder. Read on to learn more about these personality disorders and how to recognize them.

“Cluster A” personality disorders include paranoid, schizoid, and schizotypal personality disorders.

These disorders are characterized by difficulty forming close personal relationships and odd or eccentric behavior.

Schizoid and schizotypal have, at first glance, some overlapping signs and symptoms, but they are in fact very different.

Schizoid Personality Disorder

Someone with  schizoid personality disorder  is not interested in and may be unable to form close relationships with others, either romantic or friendship-based, although they may possess a rich internal fantasy world. It’s also very difficult for people with schizoid personality to exhibit a wide array of emotions. Their affect—the way they express emotions—is  blunted  and can cause them to come off as aloof, disengaged, and distant.

One easy way to remember the difference between schizoid and schizotypal is that “schizoid” rhymes with “devoid”—as in, devoid of emotion.

This lack of expression makes it appear as though people with schizoid personality disorder do not care about other people or about what is happening to them and around them.

While schizoid personality disorder can sometimes mimic what are known as “negative symptoms” in schizophrenia —specifically, a blunted affect and difficulty connecting with others—people with this disorder do not experience hallucinations or delusions.

They are able to express their thoughts to others in a clear and cogent way, as opposed to experiencing the disorganized thought process that is common with psychotic disorders.

Schizotypal Personality Disorder

While those with schizotypal personality disorder also experience social difficulties, schizotypal is characterized by a pattern of extreme discomfort with social interactions and close relationships, rather than the disinterested inability to form them.

People with schizotypal personality disorder also consistently hold distorted views of reality, tend to be extremely superstitious, and display unusual behaviors related to delusional thinking such as magical beliefs (think: never stepping on a sidewalk crack because you are absolutely convinced that it will actually break your mother’s back).

These superstitions and behaviors are often expressed with what most people would consider odd speech, making those with schizotypal personality disorder appear affected and strange to people who aren’t familiar with the condition.

One of the defining aspects of schizotypal personality disorder is that the person experiencing it might not realize that their behavior, speech, or beliefs are unusual, and often cannot recognize when their actions may be problematic.

Although there are some overlapping qualities between schizoid and schizotypal personality disorders, they are in fact quite different.

Both disorders are characterized by issues with relationships. However, while people with schizoid personality disorder display a chronic disinterest in forming and maintaining relationships, those with schizotypal personality disorder are intensely uncomfortable with relationships.

The relationship with reality is also vastly different between these two disorders.

While those with schizoid personality disorder experience no overt psychotic symptoms such as distorted thinking, delusions, or  paranoia , schizotypal is characterized by superstition, suspiciousness, odd thinking, and unusual behavior.

As far as these disorders’ connections to schizophrenia go, they are both different here as well. Schizoid personality disorder is not related to and does not lead to schizophrenia. The development of schizotypal personality disorder, on the other hand, might lead to full-blown schizophrenia (both conditions usually appear in early adulthood).

Schizotypal personality disorder is actually considered by some to be on the “schizophrenia spectrum” —as in, it is a milder version of schizophrenia.

However, there are notable differences between schizophrenia and schizotypal personality disorder. Those with the latter might experience odd distorted thinking, the former is characterized by more persistent hallucinations and delusions.

No interest in relationships

Indifferent to praise or criticism

Lack of affect/range of emotions

No psychotic symptoms

Acute discomfort with and reduced capacity for relationships

Affect/emotions might be restricted or inappropriate

Unusual behavior, odd thinking, superstition

Suspiciousness or paranoia may be present

According to the DSM-5, the following factors must be present to be diagnosed with schizoid personality disorder:

• Disinterest and detachment from social connections and relationships
• Limited and restricted range of expression in interpersonal or social situations
• Symptoms that appear by early adulthood
• Four or more of the following factors:
• Does not desire or enjoy close relationships, including family relationships
• Almost always chooses solitary activities
• No or very little interest in sexual activities or experiences
• Has no close friends other than immediate family
• Appears indifferent to others’ responses to them, including criticism or praise
• Shows emotional coldness, detachment, or flattened affectivity

With schizotypal personality disorder, the following factors must be present:

• Acute discomfort with and reduced capacity for close relationships
• Cognitive or perceptual distortions
• Odd behavior that can’t be explained by cultural norms (as in, the behavior can’t be attributed to cultural practices)
• Five or more of the following factors:
• Ideas of reference (interpretation of random or irrelevant situations or occurrences in the world relate directly to one as an individual)
• Excessive social anxiety that is not resolved with familiarity and tends to be based on paranoia rather than negative self-judgment
• Odd or unusual thought processes (e.g., superstitiousness, belief in clairvoyance, telepathy, or “sixth sense;” in children and adolescents bizarre fantasies or preoccupations)
• Unusual perceptual experiences, including bodily illusions
• Odd or eccentric behavior or appearance
• Lack of close friends or confidants
• Odd thinking and speech (e.g., vague, circumstantial, metaphorical, overelaborate, or stereotyped)
• Inappropriate or constricted affect (the expression of emotions that is not appropriate for the situation or the inability to experience the full range of human emotions)
• Suspiciousness or paranoia

For both conditions, these symptoms cannot be attributed to another medical condition, and these symptoms cannot occur in the setting or context of schizophrenia, bipolar disorder, depressive disorder with psychotic features, another psychotic disorder or an autism spectrum disorder.

Both schizoid personality disorder and schizotypal personality disorder are relatively uncommon. By some estimates the prevalence of schizoid personality disorder (how many people are living with this condition) is 3.1%. whereas being slightly more prominent in men, whereas the prevalence of schizotypal personality disorder in some studies is about 3.9%.

The causes of both schizoid and schizotypal personality disorders are unknown, but it is generally felt that hereditary and genetics play a significant role along with environmental factors. Some researchers believe there might be a connection between schizoid personality disorder and autism spectrum disorder.

With schizotypal personality disorder, changes in brain function during development, environmental factors (such as where you grew up and with whom and other early exposures), and learned behaviors might play a part.

In addition, the risk of developing schizotypal personality disorder might be higher if you have a relative with a psychotic disorder like schizophrenia.

People with schizoid or schizotypal personality disorder might only seek treatment at the behest of friends or family; or, they might seek treatment for a co-occurring condition, such as depression or anxiety, rather than for the personality disorder itself. In these cases, they might be prescribed antidepressants, antipsychotics or other medication to treat their symptoms.

There are no medications with a specific indication for schizoid or schizotypal personality disorder. 

Those with schizoid personality disorder can benefit from  talk therapy  in both individual and group settings. Talk therapy modalities like  cognitive behavioral therapy  and psychodynamic psychotherapy can help those with schizoid examine their emotional responses and approach to relationships, while group therapy can help them learn and practice social skills.

People with schizotypal personality disorder may benefit from some of the same treatment approaches as those for schizophrenia—talk therapy and antipsychotic medication. How effective medication may be can vary and should be considered and prescribed on a case-by-case basis.

If you or a loved one are dealing either schizoid or schizotypal personality disorder, talk to a doctor to find out which treatment options may be worth exploring.

Schultze-Lutter F, Nenadic I, Grant P. Psychosis and Schizophrenia-Spectrum Personality Disorders Require Early Detection on Different Symptom Dimensions . Front Psychiatry. 2019 Jul 11;10:476. doi: 10.3389/fpsyt.2019.00476. PMID: 31354543; PMCID: PMC6637034.

Fariba, K. A. (2022, June 9). Schizoid personality disorder. StatPearls [Internet].  https://www.ncbi.nlm.nih.gov/books/NBK559234/

Moini, J., Koenitzer, J., & LoGalbo, A. (2021, May 21). Personality disorders. Global Emergency of Mental Disorders.  https://www.sciencedirect.com/science/article/abs/pii/B9780323858373000017

Koch J, Modesitt T, Palmer M, Ward S, Martin B, Wyatt R, Thomas C. Review of pharmacologic treatment in cluster A personality disorders. Ment Health Clin. 2016 Mar 8;6(2):75-81. doi: 10.9740/mhc.2016.03.75. PMID: 29955451; PMCID: PMC6007578.

By Hannah Owens, LMSW Hannah Owens is the Mental Health/General Health Editor for Dotdash Meredith. She is a licensed social worker with clinical experience in community mental health.