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Use of Clonidine in children with autism spectrum disorders
Abstract
Children with autism spectrum disorders (ASD) often exhibit sleep and behavioral disorders. Treatment of sleep disorders can be difficult in these children. Clonidine, an alpha2-adrenergic receptor agonist, has been shown to be effective in reducing impulsivity, inattention, and hyperactivity, as well as in serving as a sedative for medial procedures. An open labeled retrospective study of clonidine in treatment of insomnia, and/or hyperactivity, inattention, mood disorder, and aggressive behaviors was conducted using parent reports of sleep initiation and maintenance, as well as behaviors prior and during clonidine treatment. Clonidine was effective in reducing sleep initiation latency and night awakening, to a less degree in improving attention deficits hyperactivity, mood instability and aggressiveness in this cohort of 19 children with ASD. The side effects were largely tolerable. Further evaluation with placebo-controlled double-blind clinical trial of clonidine use in ASD will provide more insight into the clinical efficacy and safety of the medicine in ASD.
... A first randomized double-blind study on ASD subjects aged 5-33 years old reported a 4-week clonidine treatment (dose 0.005 mg/kg/day) reducing hyperarousal behaviors and improving the social interactions in these patients [174]. Further studies highlighted a modest improvement in irritability and hyperactivity after treatment with clonidine [175] and important effects in reducing sleep onset latency, night waking, hyperactivity, and aggression in children with ASD [176]. No significant side effects were found in any of these studies [174,175]. ...
... Reducing hyperarousal behaviors and improving social interactions in ASD [174][175][176] Guanfacine Reduction of hyperactivity, impulsivity, and distractibility in ASD [177,179] Cholinesterase inhibitors and NMDA-receptor antagonists Memantine Improvements in memory, irritability, lethargy, stereotypies, hyperactivity, and language deficit in ASD [182][183][184] R-Baclofen improvement in irritability, social function, and communication in ASD [185] N-acetylcysteine Reduction in irritability, repetitive behaviors, and stereotypes [190] * Approved by the FDA. ...
Autism spectrum disorder (ASD) is a condition that is gaining increasing interest in research and clinical fields. Due to the improvement of screening programs and diagnostic procedures, an increasing number of cases are reaching clinical attention. Despite this, the available pharmacological options for treating ASD-related symptoms are still very limited, and while a wide number of studies are focused on children or adolescents, there is a need to increase research about the treatment of ASD in adult subjects. Given this framework, this work aims to review the available literature about pharmacological treatments for ASD, from older strategies to possible new therapeutic targets for this condition, which are often poorly responsive to available resources. The literature, besides confirming the efficacy of the approved drugs for ASD, shows a lack of adequate research for several psychopharmacological treatments despite possible promising results that need to be further investigated.
... Clonidine, an α 2 -adrenergic agonist, has been studied for sleep onset, and the long-acting preparation can be used for sleep maintenance [66]. Short-acting clonidine is effective in improving sleep onset. ...
... Short-acting clonidine is effective in improving sleep onset. The long-acting formulation however, has not been adequately studied and requires swallowing a pill whole [66]. For sleep onset, it is generally recommended to start with half of the short-acting clonidine 0.1 mg tablet (0.05 mg) 30 min before bedtime and increase the dose by half a pill every 3 to 5 days as tolerated. ...
Background
The prevalence of autism spectrum disorder (ASD) has surged, with an estimated 1 in 36 eight-year-olds in the United States meeting criteria for ASD in 2020. Autistic individuals face elevated rates of co-occurring medical, psychiatric, and behavioral conditions compared to non-autistic individuals. The rising ASD-patient demand is increasingly outpacing the capacity of ASD-specialty clinics, resulting in urgent need for autism-competent providers in general practice settings. This work aims to empower healthcare providers, especially primary care providers (PCPs), with guidelines for the recognition and safe pharmacologic management of common co-occurring psychiatric and behavioral conditions in ASD.
Methods
Lurie Center for Autism medical providers, who have extensive experience in ASD care, delineated approaches for recognition and pharmacological treatment of sleep disturbances, attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and irritability tailored to ASD patients. Pharmacological guidelines were iteratively refined until consensus was reached. Treatment differences relative to standard of care (SOC) of non-autistic individuals are noted. Key literature and clinical trial results were reviewed to supplement clinical experience.
Results
The pharmacological treatment pathways reflect how appropriate medication options for ASD patients can depend on many factors unique to the patient and can differ from established non-autistic SOC. Key takeaways include: For sleep disturbances in ASD, initial strategies align with non-autistic SOC, emphasizing sleep hygiene and melatonin use. First-line recommendations for treating ADHD, anxiety, and depression in ASD differ from non-autistic SOC; α2-adrenergic agonists are more suitable than stimulants for some ASD-ADHD patients, buspirone and mirtazapine are preferred to selective serotonin reuptake inhibitors (SSRIs) for anxiety, and duloxetine, mirtazapine, bupropion, and vortioxetine are recommended ahead of SSRIs for depression. Addressing irritability in ASD requires interdisciplinary evaluation of contributing factors, and guanfacine, risperidone, or aripiprazole may be appropriate, depending on severity.
Conclusions
Recognition and treatment of co-occurring psychiatric and behavioral conditions in autistic patients must account for differences in clinical presentation and medication effectiveness and tolerability. Drawing on evidence-based clinical insights, these guidelines seek to support PCPs in making informed decisions when prescribing medications for ASD patients with co-occurring psychiatric and behavioral conditions, ultimately enhancing access to timely, comprehensive care for all individuals with ASD.
... Alpha agonists are often prescribed by US physicians for the treatment of pediatric insomnia (Schnoes et al., 2006), although there is limited evidence for this indication. The strongest support lies with clonidine, but even here the research is limited to retrospective chart reviews and case studies and only among patients with ADHD (Wilens et al., 1994;Prince et al., 1996;Ming et al., 2008). Dosages of 0.05-0.1 mg at bedtime have been reported to reduce sleep latency and improve sleep efficiency (Ming et al., 2008). ...
... The strongest support lies with clonidine, but even here the research is limited to retrospective chart reviews and case studies and only among patients with ADHD (Wilens et al., 1994;Prince et al., 1996;Ming et al., 2008). Dosages of 0.05-0.1 mg at bedtime have been reported to reduce sleep latency and improve sleep efficiency (Ming et al., 2008). Fewer studies have assessed guanfacine for the treatment of pediatric insomnia, but among this research, there is no evidence of benefit. ...
Insomnia is the most commonly reported sleep disorder among children and adolescents, impacting their cognitive, emotional, behavioral, and physical development. The prevalence of insomnia generally increases with age, often persisting into adulthood if unaddressed. Insomnia is exceedingly common among those with developmental disabilities and is frequently comorbid with a great range of psychiatric diagnoses. The COVID-19 pandemic has only increased the prevalence of insomnia among children and adolescents. Health care providers are routinely called upon to treat insomnia in the pediatric population. Psychoeducation and behavioral interventions, especially cognitive behavioral therapy for insomnia (CBT-I), remain the first line treatments, given empirical evidence for their efficacy and success in relapse prevention. However, medications are frequently employed in clinical practice, despite the fact that no medications are approved by the Food and Drug Administration (FDA) for the treatment of pediatric insomnia. This review was designed to educate and support practitioners who are treating children and adolescents who struggle with insomnia. A thorough narrative review was completed to identify all published medication studies of pediatric insomnia; the identified studies are described and then graded into four categories according to the strength of the evidence supporting their use, side effect profiles, co-morbidities, and overall risk vs. benefit of each pharmacological treatment. This review will help practitioners in making clinical decisions for their pediatric patients who suffer with insomnia.
... Other medications studied included donepezil (Buckley et al., 2011), L-carnosine (Gringras et al., 2017), and clonidine (Ming et al., 2008). The use of donepezil did not result in significant change in night wakings; however, the study had a small sample size (n = 5) and therefore these results were deemed to have Very Low strength (Buckley et al., 2011). ...
... Taking L-carnosine also did not result in significant changes in night wakings, a result with Moderate strength evidence (Mehrazad-Saber et al., 2018). Clonidine showed some decrease in night wakings; however, the significance was not assessed and the sample size was small (n = 19), resulting in Very Low strength of evidence for this finding (Ming et al., 2008). ...
Children with autism spectrum disorder (ASD) report high rates of sleep problems. In 2012, the Autism Treatment Network/ Autism Intervention Research Network on Physical Health (ATN/AIR-P) Sleep Committee developed a pathway to address these concerns. Since its publication, ATN/AIR-P clinicians and parents have identified night wakings as a refractory problem unaddressed by the pathway. We reviewed the existing literature and identified 76 scholarly articles that provided data on night waking in children with ASD. Based on the available literature, we propose an updated practice pathway to identify and treat night wakings in children with ASD.
... Furthermore, dysregulation of the noradrenergic system has been shown to modulate attentional deficits in children with ASD (Bast et al., 2018). In particular, nighttime awakenings, delayed sleep onset, and insomnia were attenuated after clonidine administration (further described in section IV) indicating that heightened noradrenergic signaling may contribute to sleep problems in children with ASD (Ingrassia and Turk, 2005;Ming et al., 2008;Schnoes et al., 2006). Notably, a decrease in sleep spindle activity has been reported in ASD. ...
... Clonidine, an anti-hypertensive therapeutic, is the most used medication within this drug class for treating sleep disturbances, including children with ASD (Schnoes et al., 2006) (Table 2). Clonidine decreased the time to fall asleep and helped children with neurodevelopmental disorders, including ASD, pervasive developmental disorders (PDDs), and Asperger's syndrome (AS) to stay asleep (Ingrassia and Turk, 2005;Ming et al., 2008). Clonidine is generally well tolerated in children with few adverse side effects such as REM sleep suppression (Pelayo and The other α 2 -adrenergic agonist that has been shown to improve sleep in children with ASD is guanfacine (Politte et al., 2018;Posey et al., 2004;Propper, 2018). ...
Sleep is crucial for brain development. Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, these sleep problems are positively correlated with the severity of ASD core symptoms such as deficits in social skills and stereotypic behavior, indicating that sleep problems and the behavioral characteristics of ASD may be related. In this review, we will discuss sleep disturbances in children with ASD and highlight mouse models to study sleep disturbances and behavioral phenotypes in ASD. In addition, we will review neuromodulators controlling sleep and wakefulness and how these neuromodulatory systems are disrupted in animal models and patients with ASD. Lastly, we will address how the therapeutic interventions for patients with ASD improve various aspects of sleep. Together, gaining mechanistic insights into the neural mechanisms underlying sleep disturbances in children with ASD will help us to develop better therapeutic interventions.
... Another important and encouraging finding from this scoping review is that these drugs can be easily used at home, even for prolonged periods. Regarding clonidine, this finding is also supported by previous experience in the treatment of movement and sleep disorders, especially in children with attention-deficit/hyperactivity disorder (ADHD), developmental delays, autism spectrum disorders and genetic syndromes (35)(36)(37)(38). ...
Background
Children receiving palliative care often suffer from refractory neurological symptoms. In recent years, there has been a growing interest in the use of alpha-2 agonists as a second- or third-line therapy for severe dystonia and irritability.
Objectives
The aim of this review was to provide an overview of the scientific literature on the use of alpha-2 agonists for the treatment of refractory neurological symptoms in pediatric palliative care, evaluating the evidence available and identifying gaps related to their reported efficacy and safety.
Methods
A scoping review was performed according to the PRISMA extension. A systematic search was conducted in PubMed, Medline, EMBASE, Web of Science, CINAHL, and The Cochrane Library, using terms referring to alpha-2 agonists and neurological symptoms in pediatric palliative care.
Results
Seven articles were identified, including three case reports, two case series, one observational cohort study, and one retrospective analysis. Two drugs (dexmedetomidine, n = 4/7, and clonidine, n = 3/7) were investigated, encompassing a total of 44 patients aged between 7 months and 18 years. Most patients (95%) initiated treatment in an inpatient setting before transitioning to home care. All patients reported clinical improvement; however, 25% of children treated with clonidine discontinued its use due to ineffectiveness or side effects. No adverse effects were reported with dexmedetomidine use.
Conclusion
Alpha-2 agonists are increasingly being used to manage intractable neurological symptoms in pediatric palliative care. However, evidence regarding their safety profile and effectiveness remains limited, highlighting the need for further research in this area.
... del/+ mice took longer time to habituate to their sleep environment, and the degree of habituation may therefore significantly impact the amount and quality of sleep in mouse models of ASD. 16,17 Our findings further imply that blocking noradrenergic transmission can not only improve sleep in ASD patients, 69 but help them to more quickly habituate to new sleep environments. ...
Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine consolidate sleep. Furthermore, inhibiting LC-NE neurons restores memory. Finally, rabies-mediated screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory-regulatory regions in 16p11.2 deletion mice. Our findings identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.
... Clonidine may be an effective and low-cost pharmacological option for individuals with ASD and behavioral disturbances. Two small double-blind, placebocontrolled studies and one retrospective open-label study have examined clonidine for the treatment of hyperactivity and impulsivity in children and adolescents with ASD; both studies found clonidine to be at least modestly effective for symptoms of hyperactivity (31,32). Some of the studies found it to be helpful for other symptoms as well, such as social relationships, sensory responses, irritability, sleep, and aggression. ...
Background: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) are both neurodevelopmental disorders that affect children early in life. Both conditions have a complicated origin. Objectives: The aim of this study is to evaluate the neonatal complications linked with ASD and ADHD and to outline the utilization of psychotropic medications in the management of children and adolescents with ASD. Methods: This study was conducted from January to April 2022 in the National Center for Autism/Medical City Complex in Baghdad. It involved 120 children with neurodevelopmental disorders and 120 controls participants. A questionnaire was used to collect the data, which was then analyzed using SPSS 25. Results: There are five perinatal factors that have significant associations with child behavioral disorders, as indicated by a P-value of less than of 0.05. These factors are: Low birth weight (LBW), newborn complications, preterm-birth, being the last child and children delivered via a caesarean section. Additionally, the types of behavioral disorders have significant associations with the use of psychotropic medications. Around 50% of children with both ASD and ADHD, as well as children with ADHD alone, have used psychotropic medications. By comparison, only about 27% of children with ASD have used these medications. Conclusions: Neonatal risk factors may be linked to neurodevelopmental disorders. Medications are used to manage ASD and ADHD in children and youth.
... Clonidine may be an effective and low-cost pharmacological option for individuals with ASD and behavioral disturbances. Two small double-blind, placebocontrolled studies and one retrospective open-label study have examined clonidine for the treatment of hyperactivity and impulsivity in children and adolescents with ASD; both studies found clonidine to be at least modestly effective for symptoms of hyperactivity (31,32). Some of the studies found it to be helpful for other symptoms as well, such as social relationships, sensory responses, irritability, sleep, and aggression. ...
Background: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both neurodevelopmental disorders that affect children early in life. Both conditions have a complicated origin. Objectives: This study aims to evaluate the neonatal complications linked with ASD and ADHD and to outline the utilization of psychotropic medications in the management of children and adolescents with ASD. Methods: This study was conducted from January to April 2022 at the National Center for Autism/Medical City Complex in Baghdad. It involved 120 children with neurodevelopmental disorders and 120 control participants. A questionnaire was used to collect the data, which was then analyzed using SPSS 25. Results: Five perinatal factors have significant associations with child behavioral disorders, as indicated by a P-value of less than 0.05. These factors are Low birth weight (LBW), newborn complications, preterm birth, being the last child, and children delivered via a cesarean section. Additionally, the types of behavioral disorders have significant associations with the use of psychotropic medications. Around 50% of children with both ASD and ADHD, as well as children with ADHD alone, have used psychotropic medications. By comparison, only about 27% of children with ASD have used these medications. Conclusions: Neonatal risk factors may be linked to neurodevelopmental disorders. Medications are used to manage ASD and ADHD in children and youth.
... del/+ mice took longer time to habituate to their sleep environment, and the degree of habituation may therefore significantly impact the amount and quality of sleep in mouse models of ASD [16,17]. Our findings further imply that blocking noradrenergic transmission can not only improve sleep in ASD patients [43], but help them to more quickly habituate to new sleep environments. ...
Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.
... The conclusion was that these medications may improve hyperactivity, impulsivity, disinhibition, and inattention 62 . Clonidine was investigated by Ming et al. 63 , who reported decreased sleep latency and night awakening and improved attention deficits, mood instability, and aggressiveness. • Various other medications James et al. 64 were concerned with metabolic abnormalities, like transmethylation metabolites and glutathione redux status, and therefore they examined the effects of treatment with methylcobalamin and folinic acid for 3 months. ...
The numbers of cases of autism diagnosed are increasing every year. Approximately one in every 166 children is affected some aspect of the autism spectrum disorders. Various diagnostic methods are being developed along with treatments and therapies. Extensive research is going on worldwide to find underlying causes; the genetic cause is thought to be principle among them. This article intends to review the development occurred in this field in recent years.
... The conclusion was that these medications may improve hyperactivity, impulsivity, disinhibition, and inattention 62 . Clonidine was investigated by Ming et al. 63 , who reported decreased sleep latency and night awakening and improved attention deficits, mood instability, and aggressiveness. • Various other medications James et al. 64 were concerned with metabolic abnormalities, like transmethylation metabolites and glutathione redux status, and therefore they examined the effects of treatment with methylcobalamin and folinic acid for 3 months. ...
... showed that clonidine significantly reduced SoL and night waking, while its effectiveness in improving ADHD, mood instability, and aggression in this population has been limited. The adverse effects were generally tolerable [50]. ...
Sleep disorders are very common in children and adolescents with Autism Spectrum Disorder (ASD) and can negatively impact their lives, mental health, developmental processes, families' lives, and emotional well-being. It is essential to determine the specific sleep disorder and its underlying cause in treatment planning. Currently, nonpharmacological and pharmacological interventions are the main treatments for improving sleep disorders in children and adolescents with ASD. If nonpharmacological strategies are unsuccessful or difficult to implement, medications should be considered and used in conjunction with them. Melatonin, behavioral interventions, and parent education are the most effective treatments to improve sleep, relative to other pharmacological treatments. Medications used to treat sleep disorders in these children are used off-label. Melatonin appearing to be safe and effective may be an evidence-based and efficacious first-line treatment for treating insomnia symptoms in children and adolescents with ASD. Antipsychotics (e.g.low dose quetiapine), antidepressants with strong sedative effects such as trazodone and mirtazapine, antihistamines (e.g.diphenhydramine, niaprazine), alpha-adrenergic drugs (e.g. clonidine), benzodiazepines (e.g.clonazepam) and other hypnotic drugs, anticonvulsants (e.g. gabapentin), Alzheimer's drugs (e..g donepezil), superoxide and iron treatment are other drugs used in pharmacological treatment. Depending on the type of sleep disorders and the presence of comorbidities, the most effective pharmacological treatment should be selected on a case-by-case basis.
... del/+ mice took longer time to habituate to their sleep environment, and the degree of habituation may therefore significantly impact the amount and quality of sleep in mouse models of ASD (Angelakos et al., 2017;Lu et al., 2018). Our findings further imply that blocking noradrenergic transmission can not only improve sleep in ASD patients (Ming et al., 2008), but help them to more quickly habituate to new sleep environments. ...
Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further disrupts sleep in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation in 16p11.2 deletion mice. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings reveal that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.
... The shortened duration of use with nonstimulants could reflect issues with cost, efficacy or tolerability. Even though alpha-2 agonists are advised to be taken daily for optimal efficacy and tolerability, as needed dosing for sleep problems is not uncommon (Ming et al., 2008) and could also explain the relatively low rate of script refills for this medication class. Prior work has documented that therapy services for children with ADHD often end prematurely (Kazdin, 1996). ...
Objective
The aim of this study was to identify patterns of ADHD care, including factors that guide selection and sequencing of treatments in a large nationwide sample of preschool-aged youth over the past 6 years.
Method
A retrospective cohort study utilizing a large electronic health record (TriNetX) of nearly 24,000 children ages 3 to 6 diagnosed with ADHD.
Results
One in three preschoolers with ADHD were prescribed psychotropic medication, most commonly methylphenidate and guanfacine. One in 10 had at least one psychotherapy billing code during the entire assessment with most youth starting medication before psychotherapy. Rates of most treatments, including polypharmacy, increased with comorbid psychiatric disorders or sleep problems and over the course of the coronavirus pandemic.
Conclusion
Rates of treatment have increased over time but are still largely inconsistent with published care guidelines that advise therapy before medication. Clinicians appear to prioritize psychiatric comorbidity and sleep problems when selecting treatments.
... One salient manifestation of this dysregulation in ASD is the prevalence of sleep disturbances [59]. Nighttime awakenings, delayed sleep onset, and insomnia were notably reduced following the administration of clonidine-a drug known to modulate noradrenergic signaling-indicating that heightened noradrenergic activity may contribute to these sleep challenges in ASD children [61][62][63]. Such findings underscore the potential involvement of the LC's noradrenergic system in the regulation of sleep problems and associated symptoms both in children with ASD [56] and animal models mimicking the disorder [64]. ...
... Many side effects are reported, especially on the cardiovascular system, sometimes even serious (e.g., dysrhythmias, hypotension, and conduction abnormalities). The short half-life (a few hours, determining the need for six daily transdermal administrations) and the appearance of tolerance after a few months of therapy limit its clinical utility [584][585][586][587]. ...
Unlabelled:
AUTISM: spectrum disorders (ASD) often remain undiagnosed until adulthood. The aim of this study is to report differential diagnoses (DDX) and comorbidities of adults without intellectual impairment suspected of having an ASD and to test the self-assessment questionnaire Autism Quotient (AQ) for its suitability for screening.
Methods:
DDX and comorbidities were recorded with standardized scales in an autism outpatient clinic in 106 individuals. The AQ was tested against the expert judgment of an interdisciplinary case conference using ROC analysis.
Results:
Affective disorders were common in both groups (48%); other DDX were phobias (33%) and personality disorders (22%). The AQ showed an AUC of 0,527 with sensitivity/specificity of 70%/35%.
Conclusions:
Adults suspected of having autism are highly burdened by DDX and comorbidities. An interdisciplinary diagnostic procedure based on standardized scales is useful, whereas the AQ hardly differentiates between persons with and without ASD.
... As previously mentioned, KYNA is anti-inflammatory, and this increase is similar to the effect of SSRIs shown by Halaris et al. (2015). Clonidine is an α2 adrenergic agonist and primarily used as an anti-hypertensive agent; however, it is also effective in treating ADHD and behavioral disturbances in neurodevelopmental disorders (Ming et al., 2008;Kollins et al., 2011). Studies investigating the biological effects of clonidine in humans in the context of ADHD are limited. ...
Mental health and neurodevelopmental disorders are extremely common across the lifespan and are characterized by a complicated range of symptoms that affect wellbeing. There are relatively few drugs available that target disease mechanisms for any of these disorders. Instead, therapeutics are focused on symptoms and syndromes, largely driven by neurotransmitter hypotheses, such as serotonin or dopamine hypotheses of depression. Emerging evidence suggests that maternal inflammation during pregnancy plays a key role in neurodevelopmental disorders, and inflammation can influence mental health expression across the lifespan. It is now recognized that commonly used psychiatric drugs (anti-depressants, anti-psychotics, and mood stabilizers) have anti-inflammatory properties. In this review, we bring together the human evidence regarding the anti-inflammatory mechanisms for these main classes of psychiatric drugs across a broad range of mental health disorders. All three classes of drugs showed evidence of decreasing levels of pro-inflammatory cytokines, particularly IL-6 and TNF-α, while increasing the levels of the anti-inflammatory cytokine, IL-10. Some studies also showed evidence of reduced inflammatory signaling via nuclear factor- (NF-)κB and signal transducer and activator of transcription (STAT) pathways. As researchers, clinicians, and patients become increasingly aware of the role of inflammation in brain health, it is reassuring that these psychiatric drugs may also abrogate this inflammation, in addition to their effects on neurotransmission. Further studies are required to determine whether inflammation is a driver of disease pathogenesis, and therefore should be a therapeutic target in future clinical trials.
... Genetic variants in this enzyme have been associated with the response to treatment in ADHD patients. 24,25 Several studies have reported that CES 1 variants may affect the metabolism and induce adverse events of MPH and other drugs metabolized by CES1, [26][27][28][29][30][31][32] although these findings have not been universally replicated. 31 However, there is a lack of evidence of NET1 and CES1 genetic variants' role in the response to MPH in ASD subjects. ...
Purpose
Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40–70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety.
Patients and Methods
A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype.
Results
Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05).
Conclusion
CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.
... Further investigations should also address the potential interest of the other members of this family, such as ADRA1D among the most downregulated genes in the prefrontal cortex of patients [11]. Administration of clonidine, a non-selective and approved drug targeting -adrenoceptors improves hyperarousal, hyperactivity and social relationships in individuals with ASD [424][425][426][427][428]. Moreover, carriers of two highly frequent mutations, Ser49Gly and Trp64Arg in ADRB1 and ADRB3 genes respectively [12,13], may alter receptor functions. ...
Changes in genetic and/or environmental factors to developing neural circuits and subsequent synaptic functions are known to be a causative underlying the varied socio-emotional behavioural patterns associated with autism spectrum disorders (ASD). Seven transmembrane G protein-coupled receptors (GPCRs) comprising the largest family of cell-surface receptors, mediate the transfer of extracellular signals to downstream cellular responses. Disruption of GPCR and their signalling have been implicated as a convergent pathologic mechanism of ASD. Here, we aim to review the literature about the 23 GPCRs that are genetically associated to ASD pathology according to Simons Foundation Autism Research Initiative (SFARI) database such as oxytocin (OXTR) and vasopressin (V1A, V1B) receptors, metabotropic glutamate (mGlu5, mGlu7) and gamma-aminobutyric acid (GABAB) receptors, dopamine (D1, D2), serotoninergic (5-HT1B and additionally included the 5-HT2A, 5-HT7 receptors for their strong relevance to ASD), adrenergic (2) and cholinergic (M3) receptors, adenosine (A2A, A3) receptors, angiotensin (AT2) receptors, cannabinoid (CB1) receptors, chemokine (CX3CR1) receptors, orphan (GPR37, GPR85) and olfactory (OR1C1, OR2M4, OR2T10, OR52M1) receptors. We discussed the genetic variants, relation to core ASD behavioural deficits and update on pharmacological compounds targeting these 23 GPCRs. Of these OTR, V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 serve as the best therapeutic targets and have potential towards core domains of ASD pathology. With a functional crosstalk between different GPCRs and converging pharmacological responses, there is an urge to develop novel therapeutic strategies based on multiple GPCRs to reduce the socioeconomic burden associated with ASD and we strongly emphasize the need to prioritize the increased clinical trials targeting the multiple GPCRs.
... These results are consistent with those of previous studies showing that clonidine reduced sleep latency. Ming et al. 22 showed that clonidine was effective in reducing sleep latency and night awakening in children with ASD. Ingrassia and Turk 23 described the benefit of clonidine on sleep initiation, night-time wakening and early morning awakening in 6 children with intellectual disabilities. ...
Objective:
We aimed to investigate the improvement in sleep quantity and quality when clonidine was used in children and adolescents with insomnia. We also examined how sociodemographic characteristics such as age, sex, underlying psychological problems, and levels of depression and anxiety affected the effect of clonidine.
Methods:
We retrospectively reviewed outpatients aged 6 to 24 who took clonidine due to insomnia from September 2019 to September 2021 at the Department of Psychiatry at Eunpyeong St. Mary's Hospital of Catholic University. We used the Pittsburgh Sleep Quality Index (PSQI), Children's Depression Inventory (CDI), and State-Trait Anxiety Inventory (STAI) for our study.
Results:
A total of 62 participants were included in our study (34 females, mean age 13.94±4.94 years). After using clonidine, there was a significant decrease in PSQI components 1, 2, and 5, especially PSQI component 2. There was a greater decrease in sleep latency when clonidine was used in females, those aged between 13 and 24, those with mood/anxiety disorder or attention-deficit/hyperactivity disorder, those whose sleep latency exceeded 60 minutes at baseline, and those who used clonidine for more than 14 days. Those with higher STAI-Trait scores and CDI scores at baseline showed less improvement in total PSQI scores.
Conclusion:
Considering that there are currently no Food and Drug Administration-approved sleep drugs for children and adolescents and no apparent difference in efficacy and safety among sleep drugs, we demonstrated that treatment with clonidine might be a good approach to improve sleep quality and quantity for children and adolescents.
... Many side effects are reported, especially on the cardiovascular system, sometimes even serious (e.g., dysrhythmias, hypotension, and conduction abnormalities). The short half-life (a few hours, determining the need for six daily transdermal administrations) and the appearance of tolerance after a few months of therapy limit its clinical utility [584][585][586][587]. ...
... Drugs that are prescribed or compounds under clinical trials are antipsychotics such as risperidone and clozapine (Fung et al. 2016;LeClerc and Easley 2015;Doyle and McDougle 2012;Wink et al. 2010), psychostimulants (clonidine) (Wink et al. 2010;Doyle and McDougle 2012;LeClerc and Easley 2015), antidepressants (Clomipramine and Nortriptyline) (Campbell et al. 1971;Gordon et al. 1993;Kurtis 1966), anticonvulsants (Levetiracetam and Lamotrigine) (Rugino and Samsock 2002;Uvebrant and Bauzienè 1994), glutamate antagonists (Memantine and Amantadine) (Chez et al. 2007a, b;King et al. 2001;Owley et al. 2006), Naltrexone (endorphin and encephalins) (Bouvard et al. 1995;Elchaar et al. 2006;Kolmen et al. 1995), Clonidine (Ming et al. 2008;Boellner et al. 2007), Methylphenidate (Di Martino et al. 2004;Tsujii et al. 2021), and Acetylcholinesterase inhibitors (rivastigmine and donepezil) (Chez et al. 2004;Hardan and Handen 2002). These drugs are proven to be effective in symptoms associated with such as insomnia, anxiety, epilepsy, aggression, and repetitive behaviour. ...
Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2–3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.
... Given the limited pharmacological interventions available to aid the management of challenging ASD-related behavioral symptoms, off-label clonidine showed to improve sleep disturbances, aggression, and self-injurious behavior [84]. The most commonly reported adverse effects included drowsiness, sedation, fatigue, hypotension, and lethargy, particularly during the initial treatment period, but usually self-resolved during the first 2 weeks of clonidine treatment [84,99,100]. Further studies suggested the efficacy of guanfacine, a second alpha-2 agonist, on aggressive behavior in patients with a diagnosis of ASD and comorbid ADHD [101][102][103]. ...
Acute agitation is common in youths presenting to emergency departments, and, in some cases, may escalate into aggression and violence. Therefore, acute agitation in youths should be immediately and appropriately recognized and treated to avoid the consequences of its escalation. Agitation is widespread in youths, being reported in around 7% of all youths admitted to emergency departments due to psychiatric reasons. Overall, the most frequent causes of youth acute agitation include the exacerbation of neurodevelopmental disorders such as ADHD, autism, or intellectual disabilities, or the onset of mood and psychotic disorders. Substance abuse is also common in adolescents and young adults with acute agitation. Management of agitation should be individualized, multidisciplinary, and collaborative. Along with a diagnostic assessment, the needs of the young patients should be understood and addressed, and de-escalation strategies should be immediately prompted. Rapid recognition and management are warranted, in order to assure the safety of the patient and healthcare staff jeopardized by the acute crisis. Firstly, environmental and de-escalation strategies should be acted with the aim to reduce agitation and, if possible, avoid the use of physical restraint. In case these strategies fail to succeed, pharmacological treatment should be rapidly implemented. Although youth agitation and aggression is trans-diagnostic, prior diagnosis of psychiatric disorder should guide the choice of the tranquilizing medication whenever possible. This review will examine these aspects in detail and provide guidance on how to recognize, manage, treat and resolve acute agitation in youths.
Despite the paucity of Food and Drug Administration-approved treatments, symptoms of irritability, hyperactivity, disruptive, and repetitive behaviors are common in youth with autism spectrum disorder (ASD). In North America and Europe, about half of youth with ASD receive pharmacologic treatment for psychiatric symptoms and co-occurring diagnoses. Moreover, the most commonly used medications in youth with ASD are antipsychotics, antidepressants, and ADHD medications. The selective serotonin reuptake inhibitor class of antidepressants is among the most commonly used psychotropic in this patient population, despite having limited evidence for their use, which we will explore further in this chapter. Polypharmacy is also common for children with ASD: per a study of Medicaid-eligible 8-year-olds, 41% with an ASD diagnosis were prescribed more than one psychotropic medication. For these reasons, and more, we find it important to summarize the evidence-based pharmacotherapies for youth with ASD and co-occurring psychiatric and behavioral disturbances.
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability (ID), limited expressive language, epilepsy, motor impairment, and a behavioral profile notable for strong social affinity and excitability. It is caused by insufficient expression of ubiquitin-protein ligase E3A from the UBE3A gene on the maternal copy of chromosome 15. Common clinical concerns include epilepsy, disordered sleep, and behavioral challenges such as hypermotoric behavior, aggression, and self-injury. This chapter reviews the evidence for interfering behaviors across the lifespan in patients with AS and the approach to evaluation, treatment including pharmacology, and school-based accommodations. Research supporting the efficacy of these interventions is presented when available.
Among children with autism spectrum disorders (ASDs), many co-occurring disorders occur at greater frequency compared to children without a neurodevelopmental condition. Gastrointestinal problems, epilepsy, cerebral palsy, disorders of hearing and vision, motor coordination disorders, tic disorders and Tourette’s, sleep disorders, and migraines all occur at higher frequencies than their neurotypical peers and can worsen the core neurobehavioral symptoms of ASDs. Understanding the increased risk for each of these disorders, how to screen and diagnose them in this population, and initiate treatment or referral for the optimal treatment approach is essential to decreasing the disease burden on our patients and their families with ASDs.
Assessing sleep as a vital sign is particularly important for persons with developmental disabilities, as up to a third of persons with intellectual disability experience sleep problems. This chapter reviews classification systems for sleep disorders, including the Diagnostic and Statistical Manual of the American Psychiatric Association, International Classification of Diseases, International Classification of Sleep Disorders, Diagnostic Manual-Intellectual Disability: A Textbook of Diagnosis of Mental Disorders in Persons with Intellectual Disability, and the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood. The Five Finger and Palm Approach to the assessment of sleep–wake complaints is introduced—detailing a novel and clinically useful assessment approach.
This analysis is a systematic literature review assessing efficacy and adverse effects of three alpha-2 agonists for the symptomatic management of autism spectrum disorder (ASD).
The present investigation involved an extensive systematic search for eligible studies in PubMed, Embase, Cochrane Library, and Google Scholar. Nine studies, collectively incorporating 226 patients, were assessed.
The results demonstrated promising indications for use of alpha-2 agonists in the symptomatic management of autism spectrum disorders, including improvement of hyperactivity, impulsivity, attention deficit symptoms, irritability, and stereotypies in many of the participants studied.
The present investigation encourages physicians to consider treatment outcomes of clonidine, guanfacine, and lofexidine to determine the most effective management of ASD-related symptoms and to minimize adverse effects. However, our review cannot provide definitive treatment protocols related to various study limitations.
Sleep is a brain-derived homeostatic process. Neurodevelopmental milestones typically parallel the natural ontogeny of sleep observed in humans. In fact, an early indicator of neurodivergence is commonly abnormal sleep, which may manifest as reduced duration, impaired quality, or inappropriate timing of sleep. Typically, sleep evolves with predictable changes in duration of sleep required in 24 h, progression toward consolidation of nocturnal sleep, entrainment of circadian rhythms, and maturation of ultradian patterns, as a function of age and brain development. Genetically based neurodevelopmental disorders (NDDs) are providing initial insights to further understanding the relationship between sleep and neurodevelopmental trajectories and how genetics guide these neurodivergent pathways. Recognition and intervention of sleep-wake disorders may benefit developmental trajectories, especially in these high-risk populations.
Approximately 70% of individuals diagnosed with autism spectrum disorder (ASD) receive at least one psychotropic medication to treat comorbidities. However, the response to treatment with these drugs is far from satisfactory, with 30-50% of treated patients not responding adequately or developing severe and long-lasting side effects. There is strong evidence of the clinical utility of pharmacogenetics for the personalization of antipsychotic and antidepressant treatments in adult populations. However, the use of pharmacogenetic interventions for the personalization of treatment in ASD populations is minimal. The aim of this review is to summarize the findings of pharmacogenetic studies conducted in subjects with ASD and illustrate their utility in the personalization of treatment with psychoactive drugs in this population group.
Background:
Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs).
Objectives:
To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD.
Search methods:
We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies.
Selection criteria:
We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control.
Data collection and analysis:
We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome.
Main results:
We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias.
Authors' conclusions:
Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs.
Clonidine has been widely used in child and adolescent psychiatry, especially in attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), which are recently categorized under neurodevelopmental disorders. However, it is not recommended as a first-line medication for treatment, and current data on the use of clonidine are limited. Herein, we present 3 cases with ADHD and ASD comorbidity, if any, as well as other neurodevelopmental disorders, including intellectual disability and Tourette’s disorder, treated with clonidine. At the second-month follow-up, substantial improvements were observed in subscale scores of Conners’s Parent Rating Scale–Revised Long Form, and Autism Behavior Checklist. Our case report indicated that clonidine is well tolerated, safe, and effective in improving both ADHD- and ASD-related symptoms as well as disruptive, aggressive behaviors and tics in children with multiple neurodevelopmental disorders.
Autism spectrum disorders (ASDs) are diagnosed in 1/100 children worldwide, based on two core symptoms: deficits in social interaction and communication, and stereotyped behaviours. G protein‐coupled receptors (GPCRs) are the largest family of cell‐surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR; vasopressin V1A and V1B; metabotropic glutamate mGlu5 and mGlu7; GABAB2; dopamine D1, D2 and D3; serotoninergic 5‐HT1B; β2‐adrenoceptor; cholinergic M3; adenosine A2A and A3; angiotensin AT2; cannabinoid CB1; chemokine CX3CR1; orphan GPR37 and GPR85; and olfactory OR1C1, OR2M4, OR2T10 and OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, as well as 5‐HT2A and 5‐HT7, for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopoeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight D2, 5‐HT2A, CB1, OTR and V1A as the more promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.
LINKED ARTICLES
This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc
Autism spectrum disorders are developmental disabilities that occur in early childhood and are characterized with a persistent deficit of social interaction. Treatment of this disease is often multimodal and may include early intensive behavioral therapy (applied behavioral analysis), speech therapy, occupational and physiotherapy, social skills training, special education and training. Modern options for drug treatment of the autism spectrum remain limited. There is no evidence that any of the known drugs have a significant effect on social exclusion, which is one of the characteristic symptoms of this disorder. However, there are potential effects on its other disorders; in particular, risperidone and aripiprazole have the highest level of evidence for the irritability treatment. Memantine, riluzole, amantadine, and buspirone reduced irritability in children with autism spectrum disorders when administered in combination with risperidone. One of the common manifestations of the autism spectrum in children is a symptom of attention deficit / hyperactivity disorder. Methylphenidate has been reported to be effective in treating hyperactivity, but its efficacy in children with autism spectrum disorders is usually lower than in those developing physiologically. The efficacy of prolonged−release guanfacine and clonidine has been demonstrated. Stereotyped and repetitive behaviors in autism spectrum disorders are difficult to treat. Antidepressants have been shown to be ineffective in children with these disorders. Moreover, children with autism spectrum disorders develop more severe side effects when taking these drugs. Cannabidiol is likely to be a promising substance for the treatment of autism spectrum disorders, but there are still insufficient convincing clinical data on the efficacy and safety of cannabinoid therapy. Key words: autism spectrum disorders, comorbid conditions, treatment.
Background
Sleep disorders in autism spectrum disorders (ASD/SD) are distinct, broad, and highly variable clinical entities that ubiquitously affect core symptomatology, development of comorbid disorders, and overall quality of life for affected children and families. High genetic predisposition and the presence of co-occurring disorders present significant challenges in assessment and appropriate interventions.
Objective
The study aimed to review the best available evidence and address the clinical gaps in the knowledge about sleep disorders in children and adolescents with autism spectrum disorders.
Methods
The review provides a comprehensive literature search of 1622 articles and summarizes 110 selected for empirical evidence to methodically consider critical aspects of sleep disorders in ASD for informing clinicians of useful information.
Results
Clinicians have insufficient guidance and support to effectively manage sleep disruptions in ASD youth in practice. Prevalence of sleep disruption in ASD, close to 80%, is characterized by unique subtypes, including but not limited to obstructive sleep apnea, circadian rhythm disorders, and sleep-related movement disorders. Greater awareness of sleep disruption, its neurodevelopmental basis, scope, and impact allows for improved treatment and prevention efforts of these conditions, and is critical for clinical practice and future research. The bidirectional nature of disruptive sleep and ASD is considered a major area requiring further clarification.
Conclusion
Clinician-friendly screening tools are needed for everyday office practice to identify ASD/SD conditions and interventions, and mitigate harmful effects. Psychoeducational and cognitive-behavioral approaches for improving and supporting healthy sleep hygiene, considered the first line of treatment, are detailed. The weak database for the use of psychopharmacologic agents is summarized, and the strength of prescribing prolonged-release melatonin for optimal results is described. The promise of other medications is discussed.
In general, poor sleep is common in children with a neurodevelopmental disorder (Esbensen AJ, Schwichtenberg AJ. Sleep in neurodevelopmental disorders. Int Rev Res Dev Disabil. 2016;51:153–91. Schreck KA, Richdale AL. Sleep problems, behavior, and psychopathology in autism: inter-relationships across the lifespan. Curr Opin Psychol. 2020;34:105–11) and is related to additional difficulties for these children, such as increased daytime behaviour problems, poorer adaptive behaviour, and worsened academic functioning. Furthermore, sleep problems in children with neurodevelopmental disorders have a negative impact on families, particularly parents including increased parenting stress and poorer parent mental health(Cotton S, Richdale A. Brief report: parental descriptions of sleep problems in children with autism, Down syndrome, and Prader–Willi syndrome. Res Dev Disabil. 2006;27(2):151–61. Richdale AL, Baker EK. Sleep in individuals with an intellectual or developmental disability: recent research reports. Curr Dev Disord Rep. 2014;1(2):74–85. Martin CA, Papadopoulos N, Chellew T, Rinehart NJ, Sciberras E. Associations between parenting stress, parent mental health and child sleep problems for children with ADHD and ASD: systematic review. Res Dev Disabil. 2019;93:103463). This chapter examines sleep problems in the two most common neurodevelopmental disorders, Autism Spectrum Disorder (autism) and Attention-Deficit/Hyperactivity Disorder (ADHD). Additionally, as examples of sleep difficulties that commonly co-occur in a range of genetically determined neurodevelopmental disorders associated with developmental delay and intellectual disability (ID), we describe sleep in the X-linked disorders (Fragile X syndrome [FXS] and Rett syndrome), and the chromosome 15 imprinting disorders (Prader-Willi syndrome [PWS] and Angelman syndrome [AS]).
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication, along with restricted interests and repetitive behaviors. It is a lifelong condition that can profoundly impact the individual, their family, and the community. Given that the etiology of ASD is multifactorial, and the rise in ASD prevalence internationally, establishing evidencebased clinical guidelines is critical. The UAE offers a range of services for children and adolescents with ASD with the aim to improve the quality of services within a comprehensive system of care. The Dubai Clinical Practice Guidelines for Autism Spectrum Disorder (ASD) in Children and Adolescents (from Birth to 18 Years of Age), Version 1 aims to provide clinical guidance to healthcare professionals involved in managing ASD based on the best available local and international evidence. ASD management approaches are ranked in these guidelines based on their strength and availability of empirical evidence to support them. The clinical guidelines shall be read in conjunction with any new empirical evidence that arises.
Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder which has strong genetic basis. Despite the rapidly rising incidence of autism, little is known about its aetiology, risk factors, and disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism. Over the last two decades, there have been remarkable advances in genetics, with hundreds of genes identified and validated as being associated with a high risk for autism. The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism. Efforts have been devoted to exploring the behavioural functions, key pathological mechanisms and potential treatments of autism. Here, as we highlight in this review, emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription, translation, synaptic transmission, epigenetics and immunoinflammatory responses. This involvement has important implications for the discovery of precise molecular targets for autism. Moreover, we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular, cellular, neural circuit, and neurobehavioural aspects. Finally, the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.
A pilot comparison of the safety and efficacy of methylphenidate (MPH) combined with clonidine, clonidine monotherapy, or MPH monotherapy in 6to 16-year-old children diagnosed with attention deficit hyperactivity disorder (ADHD) and comorbid aggressive oppositional defiant disorder or conduct disorder was completed. Study design was a 3-month, randomized, blinded, group comparison with eight subjects per group. No placebo comparison was used. All three treatment groups showed significant improvements in attention deficits, impulsivity, oppositional, and conduct disordered symptoms as assessed by parent and teacher rating scales and laboratory measures. Significant differences among treatment groups were found only on a few measures. Only the clonidine monotherapy group showed significantly decreased fine motor speed. These results suggest the safety and efficacy of clonidine alone or in combination with MPH for the treatment of ADHD and aggressive oppositional and conduct disorders.
Data on sleep behavior were gathered on 100 children with pervasive developmental disorders (PDD), ages 2-11 years, using sleep diaries, the Children's Sleep Habits Questionnaire (CSHQ), and the Parenting Events Questionnaire. Two time periods were sampled to assess short-term stability of sleep-wake patterns. Before data collection, slightly more than half of the parents, when queried, reported a sleep problem in their child. Subsequent diary and CSHQ reports confirmed more fragmented sleep in those children who were described by their parents as having a sleep problem compared to those without a designated problem. Interestingly, regardless of parental perception of problematic sleep, all children with PDD exhibited longer sleep onset times and greater fragmentation of sleep than that reported for age-matched community norms. The results demonstrate that sleep problems identified by the parent, as well as fragmentation of sleep patterns obtained from sleep diary and CSHQ data, exist in a significant proportion of children with PDD.
Asperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders. Both children and adults with AS have subjective impairment in the initiation and continuity of sleep, and studies using objective assessment are sparse. Twenty young AS adults with frequent complaints of low sleep quality were compared to 10 age-, gender- and education-matched controls without sleep complaints using polysomnography and spectral power analysis of slow-wave sleep. AS subjects displayed a similar polysomnographic profile as compared with controls. In spectral power analysis, a statistically nonsignificant trend towards decreased relative delta power and increased theta power in slow-wave sleep was found in the AS group. It seems that nonorganic insomnia, due to anxiety inherent in AS, is responsible for the low sleep quality in these subjects.
A growing body of evidence indicates that people with autism frequently experience sleep disorders and exhibit atypical sleep architecture. In order to establish whether sleep disorders truly belong to the autism spectrum disorder (ASD) phenotype, we conducted a subjective and objective study of sleep in a group of high-functioning adults with ASD but without sleep complaints, psychiatric disorders or neurological comorbidity. We compared the subjective data of 27 ASD participants with those of 78 healthy controls matched for chronological age and gender. Subjective measures of sleep in the clinical group were compatible with insomnia and/or a tolerable phase advance of the sleep-wake cycle. Subjective data were confirmed by objective laboratory sleep recordings in a subset of 16 patients and 16 controls. Persons with autism presented with a longer sleep latency (P < 0.04), more frequent nocturnal awakenings (P < 0.03), lower sleep efficiency (P < 0.03), increased duration of stage 1 sleep (P < 0.02), decreased non-REM sleep (stages 2 + 3 + 4, P < 0.04) and slow-wave sleep (stages 3 + 4, P < 0.05), fewer stage 2 EEG sleep spindles (P < 0.004), and a lower number of rapid eye movements during REM sleep (P < 0.006) than did control participants. On clinical scales, the scores of persons with ASD on the Beck Depression Inventory were similar to those of persons without, but their trait anxiety scores on the Spielberger Anxiety Scale were higher (P < 0.02). The state anxiety scores of the Spielberger scale and cortisol levels were the same in the two groups. Objective total sleep time correlated negatively with the Social (-0.52, P < 0.05) and Communication (-0.54, P < 0.02) scales of the Autism Diagnostic Interview-Revised. The sleep of clinical subgroups (10 with high-functioning autism, six with Asperger syndrome) did not differ, except for the presence of fewer EEG sleep spindles in the Asperger syndrome subgroup (P < 0.05). In conclusion, these findings indicate that atypicalities of sleep constitute a salient feature of the adult ASD phenotype and this should be further investigated in younger patients. Moreover, the results are consistent with an atypical organization of neural networks subserving the macro- and microstructure of sleep in ASD. We are furthering this research with quantified analysis of sleep EEG.
This paper reports on the use of clonidine for the treatment of severe sleep problems associated with behavioural difficulties in children with neurodevelopmental disabilities. Data were obtained from reviewing the case notes of a series of six children with neurodevelopmental disorders of different nature and severity, presenting with problematic sleep. All children in this group showed maintained improvements in their sleep pattern following the use of clonidine with only mild side-effects reported.
To examine whether 2 sympatholytic medications decrease sleep bruxism and prevent the rise in sympathetic activity preceding the onset of sleep bruxism: propranolol, a nonselective adrenergic beta-blocker, and clonidine, a selective alpha2-agonist.
Experimental randomized controlled crossover studies with placebo and active treatments (propranolol 120 mg; clonidine 0.3 mg).
Hospital-based sleep research laboratory.
Twenty-five subjects with a history and diagnosis of SLEEP BRUXISM (11 men, 14 women; age range, 21 to 31 years).
Polygraphic study.
Polygraphic sleep laboratory recordings were done for 4 nights: the first night was habituation, the second, sleep bruxism diagnosis; and 3 and 4 were study nights. The sleep bruxism index was estimated using masseter muscle activity. Heart rate variability was estimated with spectral analysis of RR intervals. Sleep and sleep bruxism variables were not significantly influenced by propranolol. A reduction of the mean RR intervals and of the sympathetic dominance (p < .05) was seen. Under clonidine, duration of sleep stage 2 was prolonged, whereas REM sleep was suppressed in 14 of 16 subjects with sleep bruxism. The sleep bruxism index was reduced by 61% (p < .05). Under clonidine, a reduction in heart rate and sympathetic dominance was observed in stable sleep and in the minute preceding the onset of sleep bruxism (p < .05).
Although propranolol did not affect sleep bruxism, clonidine decreased sympathetic tone in the minute preceding the onset of sleep bruxism, thus reducing sleep bruxism by preventing the sequence of autonomic to motor activation of sleep bruxism. This further supports the role of sympathetic activity in the pathophysiology of sleep bruxism. Because morning hypotension was seen in 19% of patients, further dose-dependant research is required to assess the safety of clonidine for the management of sleep bruxism.
The prescription rates of clonidine have risen dramatically and the extent to which these increases can be attributed to treatment of sleep disturbance is unknown. Surveys were mailed to 800 pediatricians across four geographically diverse states to assess prescribing practices specific to sleep disturbance. Ninety-six percent of the respondents treated sleep disturbance. More than one third of the sample reported using clonidine specifically for sleep disturbance including sleep onset, sleep schedule, nighttime awakening, and early morning awakening problems and parasomnias. Clonidine ranked second only to antihistamines as the most commonly used medication for treating sleep disturbance.
To explore inattentive, hyperactive, and impulsive behaviours in teenagers with intellectual disabilities (ID), with and without autism.
We identified teenagers with ID, with and without autism, in a single geographic area. Those with autism were matched for age, sex, and nonverbal IQ to those with ID only. We compared inattentive, hyperactive, and impulsive (IHI) behaviours in the 2 groups, along with adaptive functioning and medical circumstances. We further subdivided the autism group into those with IHI behaviours (autism IHI) and those without (autism non-IHI) and explored similarities and differences between autism subgroups.
As a group, those with autism and ID had more IHI behaviours than those with ID alone. More in the autism group met criteria for attention-deficit hyperactivity disorder and hyperkinetic syndrome. Lifetime exposure to psychotropic medication was greater in the autism group, with stimulant and antipsychotic medications predominating. However, just under one-half of those in the autism group showed no IHI behaviours. Comparison of autism IHI and autism non-IHI groups showed that those with IHI behaviours were significantly more likely to have past (but not current) exposure to stimulant medication.
One in 2 teenagers with ID and coexisting autism displayed clinically significant inattentive, hyperactive, and (or) impulsive behaviours, compared with 1 in 7 of those with ID alone. Most of the remaining teenagers with autism displayed no IHI behaviours. Our results support the need for further investigation into the prevalence and etiology of these IHI behaviours in individuals with autism.
Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.
Before discussing the issue of early symptoms in autism, one must try and make clear what is implied by the word “early”. In this connection, I will mostly be concerned with symptoms and developmental problems in the under 3 years age group. However, Í am aware of the possibility that autism can appear to present later and indeed occasionally does have its onset after age 3 years — but the main focus of this overview will be on the very young in an attempt to pinpoint practical guidelines for those concerned with trying to diagnose autism already in the first few years of life.
Researchers have been placing an increased importance on discovering what variables contribute to better prognosis during behavioral interventions for children with autism. This article preliminarily identifies sleep problems that may exacerbate symptoms of autism; thus, possibly influencing effectiveness of daytime interventions. A data-base of parent report of sleep problems of children with autism ( N =55), ranging from 5 to 12 years of age ( M =8.2 years) was evaluated. Results suggested that fewer hours of sleep per night predicted overall autism scores and social skills deficits. Similarly, stereotypic behavior was predicted by fewer hours of sleep per night and screaming during the night. Increased sensitivity to environmental stimuli in the bedroom and screaming at night predicted communication problems. Finally, sensitivity to environmental stimuli in the bedroom also predicted fewer developmental sequence disturbances. The results indicate that sleep problems and the diagnostic characteristics of autism may be related. However, future research must be completed to determine the specific relationship.
Background:
The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)--the most commonly used drug to treat ADHD--has been reported to worsen tics and because clonidine (CLON)--the most commonly prescribed alternative--has unproven efficacy.
Methods:
The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 x 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy).
Results:
Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire--Teacher), significant improvement occurred for subjects assigned to CLON (p < 0.002) and those assigned to MPH (p < 0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p < 0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity.
Conclusions:
Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.
Objective:
Children and adolescents with attention-deficit hyperactivity disorder (ADHD), with or without psychostimulant treatment, frequently suffer from sleep disturbances. This report evaluates the use of clonidine in the treatment of sleep disturbances associated with ADHD.
Method:
A systematic search of a computerized database in an outpatient pediatric psychopharmacology unit of patients treated with clonidine for ADHD-associated sleep disturbances (N = 62; 42 children and 20 adolescents) was performed. Patients were rated retrospectively about the type and severity of sleep disturbances at baseline and after treatment with clonidine.
Results:
A majority of patients (85%) treated with clonidine for ADHD-associated sleep disturbances were considered to be much to very much improved by the National Institute of Mental Health global assessment of improvement (sleep). Nighttime clonidine doses ranged from 50 to 800 micrograms (mean +/- SEM; 157 +/- 14 micrograms), and subjects received clonidine for 35.5 +/- 3.5 months. There was no association between response and age group, gender, comorbidity, or concurrent pharmacotherapy. Children and adolescents with ADHD with baseline, medicine-induced, or medicine-exacerbated sleep disturbances responded equally well to clonidine treatment. Mild adverse effects were reported in 19 subjects (31%).
Conclusions:
These findings suggest that clonidine may be an effective agent for sleep disturbances associated with ADHD, or its treatment, and warrant further controlled investigations.
Many autistic children have associated problems of inattention, impulsivity, and hyperactivity that limit the effectiveness of educational and behavioral interventions. Few controlled psychopharmacologic trials have been conducted in autistic children to determine which agents may be effective for these associated features. Eight male children (8.1 +/- 2.8 years) with autistic disorder, diagnosed by DSM-III-R criteria, completed a placebo-controlled, double-blind crossover trial of clonidine. Subjects were included in the study if they had inattention, impulsivity, and hyperactivity that was excessive for their developmental level. Subjects had not tolerated or responded to other psychopharmacologic treatments (neuroleptics, methylphenidate, or desipramine). Teacher ratings on the Aberrant Behavior Checklist irritability, stereotypy, hyperactivity, and inappropriate speech factors were lower during treatment with clonidine than during treatment with placebo. Attention deficit disorder with hyperactivity: Comprehensive Teacher's Rating Scale ratings were not significantly improved during the study, except for oppositional behavior. Parent Conners Abbreviated Parent-Teacher Questionnaire ratings significantly improved during clonidine treatment. Clonidine led to increased ratings of the side effects of drowsiness and decreased activity. Clinician ratings (Children's Psychiatric Rating Scale Autism, Hyperactivity, Anger and Speech Deviance factors; Children's Global Assessment Scale; Clinical Global Impressions efficacy) of videotaped sessions were not significantly different between clonidine and placebo. Clonidine was modestly effective in the short-term treatment of irritability and hyperactivity in some children with autistic disorder.
Autistic individuals often exhibit hyperarousal behaviors (e.g., stereotyped body movements, self-stimulation, hypervigilance, and hyperactivity). Clonidine, an alpha 2-adrenergic receptor agonist, has been shown to be effective in reducing impulsivity, inattention, and hyperactivity associated with attention deficit disorder with hyperactivity. This study investigated the efficacy and safety of transdermal clonidine in reducing hyperarousal behaviors associated with autism.
A double-blind, placebo-crossover study with transdermal clonidine was performed in nine autistic males (aged 5 to 33 years). Subjects received either clonidine (approximately 0.005 mg/kg/day) or placebo by a weekly transdermal patch. Each trial lasted 4 weeks with a 2-week washout period between treatment phases. Subjects were evaluated every 2 weeks by clinician raters and weekly by parents.
The clonidine treatment showed a significant difference from placebo treatment on three subscales of the Ritvo-Freeman Real Life Rating Scale (i.e., social relationship to people, affectual responses, and sensory responses). The Clinical Global Impressions scale indicated that clonidine produced a significant improvement on severity of illness, global improvement, and efficacy index for therapeutic effect of the drug. A patient global rating scale showed clonidine treatment resulted in significant improvement in comparison with placebo. Adverse effects included sedation and fatigue during the first 2 weeks of clonidine treatment.
Results from this preliminary study show that clonidine was effective in reducing several hyperarousal behaviors and improved social relationships in some autistic subjects. Further studies are needed in a larger autistic population to determine the dose-response relationship of clonidine.
Autism is one of the behaviorally defined developmental disorders of brain function. It has a variety of genetic and nongenetic etiologies, with etiology being unknown in the majority of children. Boys are more frequently affected than girls. Manifest in the preschool years, autism always affects sociability, communication, and the child's repertoire of activities and interests. Autism encompasses children with a broad range of severities and a variety of other signs of brain dysfunction. These include motor signs, notably stereotypies; abnormal responses to a variety of sensory stimuli; and disorders of affect and attention. A significant proportion of autistic children experience epileptic seizures and have abnormal EEGs. Neuroimaging, preferably magnetic resonance imaging, discloses abnormalities of brain development in a minority of autistic persons. The level of intelligence may range from profound mental deficiency to giftedness. The pattern of cognitive skills is likely to be uneven, typically with better nonverbal than verbal skills. In the preschool years, all autistic children have a developmental language disorder. Verbal expression may range from total lack of language to verbosity with echolalia; comprehension and language use are invariably impaired. While there is no specific pharmacologic agent to mitigate the fundamental disorder, children may benefit from drugs to treat specific symptoms such as attention disorder and seizures. Although autistic behaviors are the consequence of a static disorder of brain function, their character changes with maturation and appropriate intervention. Communication skills and sociability remain deficient but improve in all but the most severely affected children. Outcome is a function of both innate cognitive competence and the effectiveness of early intervention focused on the development of appropriate social skills and meaningful communication. Intelligent autistic adults may be educable, employable, and able to live independently, while more severely handicapped ones require a lifelong protected environment.
The current treatment of choice for obstructive sleep apnea is continuous positive airway pressure. However, not all patients tolerate this form of therapy. We evaluated the effect of clonidine hydrochloride, an alpha 2-adrenergic agonist with REM-suppressant activity, in eight male patients with obstructive sleep apnea. In each patient, sleep-stage distribution and breathing pattern in two all-night sleep studies performed during a 10-day course of clonidine were compared with those of two control and two placebo nights. A dose of 0.2 mg of clonidine administered orally at bedtime totally suppressed REM sleep in two patients. In the other six patients, the same dose decreased percent time spent in REM sleep from a control of 13.4 +/- 1.0 to 8.6 +/- 1.4% (mean +/- SEM, p less than 0.05). The latency to REM sleep increased in the latter group from a control of 129 +/- 9 to 308 +/- 24 min (p less than 0.001). Clonidine had no effect on the frequency and duration of non-REM breathing abnormalities. Under clonidine, the level of nocturnal hypoxemia improved in six patients. This was due to a total suppression of REM and the consequent lack of REM apneas in two patients. In four patients, upper airway obstruction disappeared during period of unsuppressed REM sleep, and SaO2 remained above 90% throughout this sleep stage. Clonidine transformed the pattern of sleep-disordered breathing during unsuppressed REM in the other two patients from that of repetitive obstructive hypopneas associated with persistent hypoxemia to occlusive apneas and cyclical hypoxemia. These results were observed consistently in all patients during both clonidine-sleep studies.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper reports on a longitudinal study of sleep problems in 200 children with severe mental handicap. Sleep problems were extremely common: 51% of children had settling problems, 67% of children had waking problems, and 32% of parents said they rarely got enough sleep. Sleep problems were also very persistent: between a half and two-thirds of children who exhibited sleep problems at Time 1 still had them 3 years later. Sleep problems were associated with a number of child characteristics: poor communication skills, poor academic skills, poor self-help skills, incontinence, daytime behaviour problems and epilepsy. There were no relationships with family variables such as social class, income, family composition or housing tenure. However, maternal stress, maternal irritability and perceived impact on the family were related to sleep problems. A Sleep Index was constructed, and path analysis was used to trace the main causal pathways of the child, family and social characteristics. Ten variables explained 50% of the variance in the Sleep Problems Index. Communication skills played a pivotal role. The implications of the findings for intervention strategies are discussed.
Abstract— Data are reported from an exploratory study looking at the prevalence of sleep problems (broken sleep and limited hours of sleep) in a population of handicapped children. Some degree of difficulty occurred in over a third of the population. There were strong associations with age, a range of serious daytime behavioural difficulties and indices of family stress. Some support for distinct subgroups (night waking, limited hours) was obtained. The implications of these findings are discussed.
This retrospective study examined the clinical course of 18 prepubertal boys (aged 6 to 12) who had dual diagnoses of attention deficit hyperactivity disorder and conduct disorder and who received clonidine on an inpatient basis after failed trials of conventional drug therapy, consisting predominantly of psychostimulants. The effects of clonidine were assessed during inpatient treatment and after discharge at intervals of 1 to 2 months. Eleven (61%) of the children had marked improvement as measured by clinical impression. Transient sedation lasting 2 to 3 days occurred after initial administration or dosage increase; otherwise, clonidine was well tolerated. Our findings suggest that clonidine may prove to be an alternative treatment of comorbid attention deficit hyperactivity disorder and conduct disorder.
Clonidine has been suggested as an alternative pharmacotherapy for patients with attention-deficit hyperactivity disorder (ADHD) and comorbid tic disorders. To examine the efficacy of clonidine in this population of children, the use of clonidine in the treatment of children with ADHD with and without comorbid tic disorders was examined in a retrospective chart review of 54 children over a 4-year period.
Treatment was administered openly to these patients in a Pediatric Psychopharmacology Clinic, and response was assessed using clinical global improvement measures.
Clonidine treatment resulted in improvement in both the ADHD (39/54; 72%) and tic symptoms (18/24; 75%) groups. The findings suggested that the children with ADHD with comorbid tic disorders (23/24; 96%) have a more frequent positive behavioral response to clonidine than children with ADHD without comorbid tic disorders (16/30; 53%).
This report provides further support of a role for clonidine in the treatment of children with ADHD, particularly for those with comorbid tic disorders.
Unlabelled:
Children on the adenotonsillectomy waiting list aged 6 years or more were screened by questionnaire and overnight sleep monitoring to identify 12 with a moderate sleep and breathing disorder (SBD) group. They were matched by age and sex with 11 children who had a similar history of snoring and sleep disturbance but without an obvious sleep and breathing problem when monitored (snorer group) and also with a group of ten children most of whom were refered for an unrelated surgical procedure (control group). All children were studied before and 3-6 months after surgery. Pre-operatively the SBD and snorer groups both had significantly more restless sleep than the control group. The SBD group also had significantly more (> 4%) dips in oxygen saturation than the other two groups. After surgery there were no longer any significant differences between the three groups. After adenotonsillectomy the SBD group showed a significant reduction in aggression, inattention and hyperactivity on the parent Conners scale, and an improvement in vigilance on the Continuous Performance Test. The snorer group also improved showing less hyperactive behaviour than pre-operatively and better vigilance. The control groups's behaviour and performance did not change significantly. There were no significant changes in the performance of the Matching Familiar Figures Test in any of the groups.
Conclusion:
Relief of mild to moderate sleep and breathing disorders in children is associated with improved behaviour and functioning. We confirm previous work which suggests that the relation between sleep disordered breathing and daytime problems in children is a causal one.
The sleep patterns of two groups of children with autism, one with moderate to severe intellectual handicap, and one with mild handicap to normal IQ level, were compared with those of children without autism. Parents completed 14 day sleep diaries and questionnaires. Results suggested that at some stage during childhood, particularly under 8 years of age, the majority of children with autism will experience sleep problems. These problems are likely to be severe in many cases and will generally include one or more of: extreme sleep latencies; lengthy periods of night waking, shortened night sleep; and early morning waking. Such problems may have some specificity for autism as they appear to be rare in non-handicapped children and in children with mild degrees of intellectual handicap. It is likely that sleep problems in early childhood are related to the severe social difficulties present in autism and the consequent inability of these children to use social cues to synchronize their sleep/wake cycle. Continued sleep difficulties at older ages and with higher IQ may also be related to arousal and anxiety factors.
Eighty-eight children with autism, living in a suburb of Tokyo, were examined by questionnaire from 21 July to 31 August. Experienced sleep disorders were observed in 56 children; 44 of whom had sleep disorders before 3 years old. The average age when sleep disorders were seen to have stopped was 5 years old. The most common problem was difficulty falling sleep (n=23), followed by frequent awakening during sleep time (n=19), then early morning awakening (n=11). Bed-wetting was observed in 22 children.
The aim of the study was to investigate the specificity of sleep problems in children with autism and further explore the currently unclear association between sleep problems and daytime behaviour.
The Pervasive Developmental Disorder (PDD) group consisted of 31 children with autism and 7 children with Asperger's Disorder ranging in age from 44 to 152 months. The control group consisted of 36 children ranging in age from 63 to 171 months. The children were matched on age and gender, and group-matched on IQ level. A sleep diary was completed by parents over a 2-week period, in addition to several behaviour questionnaires.
Results showed that children in the PDD group exhibited qualitatively and quantitatively different sleep patterns to nonautistic control children.
The findings were discussed in light of current literature concerning circadian rhythm dysfunction, social difficulties, and abnormal melatonin levels in children with autism.
We studied the usefulness of melatonin for sleep disorders and emotional/behavior disturbances of patients with developmental disorders. The efficacy and side effects of melatonin at bedtime were evaluated in 50 children and young adults with sleep disorders (3-28 years old, 41 males and 9 females, autism [AU] in 27 patients, mentally retardation [MR] in 20 patients, and severe motor and intellectual disability [SMID] in 3 patients). The sleep disorders consisted of various types of insomnia in 44 patients and of circadian rhythm sleep disorders in 6 patients. Thirty nine of the insomnia patients and 3 of the circadian rhythm sleep disorder patients experienced improvement in response to melatonin. In some cases, the efficacies were diminished after the daily medication of melatonin. With the emotional/behavior disturbances, excitabilities were often improved in cases whose sleep disorders were also improved. There was almost no change in contrariness, stereotyped behavior and in school/workshop refusal. Melatonin at bedtime was efficacious in 42 of the 50 patients with sleep disorders. In 17 patients, there were side effects (residual drowsiness on the next morning, awakening in the middle of sleep, excitement after awakening and before going to sleep, etc.). But these side effects were not serious. The effects of melatonin were influenced by the type of sleep disturbances, the factors of the environment and the mental conditions. Taking side effects into account, we judged melatonin to be useful in 34 patients.
A 12-week, double-blind, randomized, placebo-controlled trial of oral clonidine in three fixed doses (4, 6, and 8 mcg/kg/day) using a crossover design was conducted with 10 children who had hyperkinetic disorder (mean age 7.6 years +/-.54). All had comorbid mental retardation. Both parents' ratings on the Parent Symptom Questionnaire and clinicians' ratings on the Hillside Behaviour Rating Scale showed a marked dose-related response to clonidine in hyperactivity, impulsivity, and inattention. Drowsiness was a common side effect of clonidine. It wore off by the 2nd to 4th week in most cases. Thus, clonidine is a safe and effective medication in young hyperkinetic children with comorbid mental retardation.
We performed nocturnal polysomnography on 11 children with autism who had symptoms of disrupted sleep and nocturnal awakenings. We identified rapid eye movement (REM) sleep behavior disorder in 5 of these 11 patients. Since REM sleep behavior disorder typically affects elderly males with neurodegenerative diseases, the identification of this phenomenon in autistic children could have profound implications for our understanding of the neurochemical and neurophysiologic bases of autism. Further, accurate diagnosis of REM sleep behavior disorder would enable specific treatment with clonazepam and help the family and the child consolidate sleep and improve daytime performance.
Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.
Researchers have been placing an increased importance on discovering what variables contribute to better prognosis during behavioral interventions for children with autism. This article preliminarily identifies sleep problems that may exacerbate symptoms of autism; thus, possibly influencing effectiveness of daytime interventions. A data-base of parent report of sleep problems of children with autism (N=55), ranging from 5 to 12 years of age (M=8.2 years) was evaluated. Results suggested that fewer hours of sleep per night predicted overall autism scores and social skills deficits. Similarly, stereotypic behavior was predicted by fewer hours of sleep per night and screaming during the night. Increased sensitivity to environmental stimuli in the bedroom and screaming at night predicted communication problems. Finally, sensitivity to environmental stimuli in the bedroom also predicted fewer developmental sequence disturbances. The results indicate that sleep problems and the diagnostic characteristics of autism may be related. However, future research must be completed to determine the specific relationship.
The present study sought to describe the profile of sleep disturbance reported in children with autistic spectrum disorders (ASDs) and to document any sleep disorders underlying reports of sleeplessness. Sixty-nine children aged 5 to 16 years (mean 9 years 4 months, SD 2 years 7 months; 14 females) with an ASD were assessed by detailed sleep histories taken from parents, the Simonds and Parraga Sleep Questionnaire, a 2-week sleep diary, and actigraphs worn by the child for five nights. Parent-reported sleeplessness featured prominently (64%). Sleep disorders underlying the sleeplessness were most commonly behavioural (i.e. to do with inappropriate sleep-related behaviours), although sleep-wake cycle disorders and anxiety-related problems were also seen. In addition, the sleeplessness patterns of a large minority of children could not be classified by conventional diagnostic criteria. Sleep patterns measured objectively did not differ between those children with or without reported sleeplessness, but the sleep quality of all children seemed to be compromised compared with normal values.
Autism is a developmental disability characterized by severe deficits in social interaction and communication, and the presence of repetitive-ritualistic behaviors. Sleep problems are frequently reported by parents of children with autism with prevalence estimates of 44-83% for sleep disorders in this population. To better understand sleep in autism, we surveyed sleep problems in 210 children with autism using a Likert-based questionnaire for parent report. The most frequently reported sleep problems included difficulty in falling asleep, restless sleep, not falling asleep in own bed, and frequent wakenings. Least frequently reported sleep problems were sleep walking, morning headaches, crying during sleep, apnea, and nightmares. When surveys were divided into mental retardation (MR)/not MR categories, no significant differences were identified in frequencies of reported sleep problems except for waking at night which occurred much more frequently in the MR group. There was also no difference in sleep problems related to age of the child other than nocturnal enuresis. An association was noted between certain medical problems and sleep problems. Vision problems, upper respiratory problems, and runny nose were associated with decreased nighttime sleep. Vision problems, poor appetite, and poor growth were associated with increased nighttime waking. Poor appetite and poor growth were associated with decreased willingness to fall asleep. This study confirms a high prevalence of sleep problems reported by parents of children with autism and points to the need for more systematic research as an initial step in developing treatment strategies.
This study compares parents' perceptions of the prevalence, severity, and pattern of sleep problems in children of normal intelligence with pervasive developmental disorders (PDDs) with a normative comparison group of children.
A survey including the Children's Sleep Habits Questionnaire was mailed to a sample of parents of children (age range 5-12 years) with PDDs (diagnosed by the Autism Diagnostic Interview-Revised) obtained by chart review of the past 7 years and to parents of comparison children matched on age, gender, and postal code.
The response rate in the PDD group was 82.2% (37/45) and 55.8% (43/77) in the comparison group. By individually matching, 23 pairs were obtained. The prevalence of sleep problems in the PDD group was reported by parents as being significantly higher than in the comparison group (78% and 26%, respectively; p < .002), as was the severity (mean score 48.2 and 39.0, respectively; p < .001). Values for four of eight sleep subscales including sleep onset delay, sleep duration, sleep anxiety, and parasomnias were significantly higher in the PDD group.
Parents report that sleep problems are significantly more prevalent and severe in children of normal intelligence with PDDs compared with normally developing children, and the pattern appears diverse. Sleep problems in children with PDDs require further research and clinical attention.
Patients with sleep apnea often present with cardiac diseases and breathing difficulties, with a high risk of postoperative respiratory depression. We conducted a randomized, double-blind, prospective study in 30 adult patients with obstructive sleep apnea, undergoing elective ear-nose-throat surgery. The patients were randomly assigned to receive placebo or clonidine (2 microg/kg oral) the night before and the next morning 2 h before surgery. Spo2, heart rate, mean arterial blood pressure, snoring, and oronasal airflow were monitored for 36 h. A standard anesthesia was used consisting of propofol and remifentanil. Anesthetic drug consumption, postoperative analgesics, and pain score were recorded. In the clonidine group, mean arterial blood pressures were significantly lower during induction, operation, and emergence from anesthesia. Both propofol dose required for induction (190 +/- 32.2 mg) and anesthesia (6.3 +/- 1.3 mg . kg(-1).h(-1)) during surgery were significantly reduced in the clonidine group compared with the placebo group (induction 218 +/- 32.4, anesthesia 7.70 +/- 1.5; P < 0.05). Piritramide consumption (7.4 +/- 5.1 versus 14.2 +/- 8.5 mg; P < 0.05) and analgesia scores were significantly reduced in the clonidine group. Apnea and desaturation index were not different between the groups, whereas the minimal postoperative oxygen saturation on the day of surgery was significantly lower in the placebo than in the clonidine group (76.7% +/- 8.0% versus 82.4% +/- 5.8%; P < 0.05). We conclude that oral clonidine premedication stabilizes hemodynamic variables during induction, maintenance, and emergence from anesthesia and reduces the amount of intraoperative anesthetics and postoperative opioids without deterioration of ventilation.
The cuffed endotracheal tube and laryngeal mask airway are very useful in the airway management of children. Safely anesthetizing and recovering a child with obstructive sleep apnea requires an understanding of both the altered anatomy and physiology of the patient. The addition of clonidine in caudal blocks prolongs pain relief.
Previous studies have suggested different patterns of associations between psychiatric symptoms and problem behaviours in people with intellectual disabilities (ID). The aim of this study was to investigate which problem behaviours are associated with specific psychiatric symptoms and the relative strength of these specific associations.
A cross sectional survey using the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist and the Disability Assessment Schedule was carried out in a sample of 214 adults with ID.
Self-injurious and, to a lesser extent, aggressive problem behaviours were most associated with affective type symptoms. Screaming and destructive behaviours tended to be more associated with autism-related social impairment rather than conventional psychiatric symptoms.
This study gives further evidence of associations between psychiatric symptoms and specific problem behaviours in people with ID. It may be particularly useful to consider the diagnosis of affective disorders if a person with ID shows self-injurious or aggressive behaviours.
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
The Kiddie Schedule for Affective Disorders and Schizophrenia was modified for use in children and adolescents with autism by developing additional screening questions and coding options that reflect the presentation of psychiatric disorders in autism spectrum disorders. The modified instrument, the Autism Comorbidity Interview-Present and Lifetime Version (ACI-PL), was piloted and frequently diagnosed disorders, depression, ADHD, and OCD, were tested for reliability and validity. The ACI-PL provides reliable DSM diagnoses that are valid based on clinical psychiatric diagnosis and treatment history. The sample demonstrated a high prevalence of specific phobia, obsessive compulsive disorder, and ADHD. The rates of psychiatric disorder in autism are high and are associated with functional impairment.
The purpose of this study was to determine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of children with autism. A previous open-label study in autistic children treated with levetiracetam demonstrated effectiveness in hyperactivity, impulsivity/aggression, and mood lability. Twenty patients with autism ranging from 5 to 17 years of age were entered into a 10-week, placebo-controlled, double-blind trial of levetiracetam versus placebo. The mean maximum dosage for levetiracetam was 862.50+/-279.19 mg/day. We evaluated global improvement of autism with the Clinical Global Impression-Improvement (CGI-I) Scale and aggression and affective instability with the Aberrant Behavior Checklist (ABC) parent and teacher ratings. We measured repetitive behaviors using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score and impulsivity and hyperactivity with the Conners' Rating Scale-Revised: Long Version for parent and teacher. No significant difference was found between levetiracetam and placebo groups comparing the change in CGI-I (t=0.350, d.f.=13.621, P=0.765), nor on change in ABC, CY-BOCS or Conners' scales. These findings suggest that levetiracetam does not improve behavioral disturbances of autism, but are limited by the small sample size and lack of stratification of the autistic sample at baseline.
Problems of inattention and hyperactivity affect one half of individuals with autistic disorder. Care must be taken to ensure that inattention and hyperactivity are not manifestations of other behavioural pathology seen in association with autistic disorder, as this will affect treatment decisions. The prescribing of psychotropic agents to individuals with autistic disorder is increasing but the evidence base is limited, with some exceptions, to uncontrolled studies. Substantial benefit in reducing inattention and hyperactivity is seen with atypical antipsychotics such as risperidone and quetiapine, although weight gain and sedation are common side effects. Moderate benefit is derived from methylphenidate, atomoxetine, some anticonvulsant medications, guanfacine and donepezil. Data show dexamphetamine, clonidine, clomipramine, mirtazapine, and fluoxetine are of unlikely benefit.