Efficacy of cannabinoids in neurodevelopmental and neuropsychiatric disorders among children and adolescents: a systematic review.

A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available.

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype.

Background: Oxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours. Method: We compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours. Results: While we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems. Conclusion: These findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

The characteristics of temper outbursts in Prader-Willi syndrome.

The purpose of this study was to develop a comprehensive understanding of temper outbursts in Prader-Willi syndrome (PWS). A survey was developed from interviews conducted with individuals with PWS and their caregivers. The survey was completed by 101 primary caregivers. The findings suggest that outburst frequency decreases with age while duration increases. Adolescents exhibited more severe behaviors than children or adults. No differences were found across gender or genetic subtype. Provocations fit into three themes: goal blockage, social injustice, and difficulty dealing with change. Distracting the person or giving them space to calm down were the only management strategies judged effective. Risperidone, sertraline, and fluoxetine were the most common medications prescribed for outbursts, though parents reported only minor effects.

A review of clinical trials of oxytocin in Prader-Willi syndrome.

PURPOSE OF REVIEW: PWS is a severe developmental disability for which there is no known treatment. The oxytocin system is currently a primary target for intervention. The aim of this article is to review the evidence for the efficacy of intranasal oxytocin in PWS. RECENT FINDINGS: To date, there have been five clinical trials of oxytocin in PWS. Four of these studies reported that oxytocin improved behaviors. However, each of these studies suffered important limitations that likely influenced the findings. For example, one study did not include a control group. Another study did not statistically analyze the effects of oxytocin on behavior. The final two studies used study-specific measures for which psychometric properties have not been assessed. SUMMARY: Because of these limitations, the most appropriate conclusion to draw from the existing studies is that there is currently no convincing evidence that intranasal oxytocin improves symptoms of PWS. However, this does not mean that oxytocin is not involved in PWS. Rather, it suggests that further work is needed to understand the nature of the PWS oxytocin abnormality.

Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study.

Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor imaging (DTI) enables in vivo investigation of the microstructural integrity of white matter pathways. To date, only one study has used DTI to examine white matter alterations in PWS. However, that study used selected regions of interest, rather than a whole brain analysis. In the present study, we used diffusion tensor and magnetic resonance (T 1-weighted) imaging to examine microstructural white matter changes in 15 individuals with PWS (17-30 years) and 15 age-and-gender-matched controls. Whole-brain voxel-wise statistical analysis of FA was carried out using tract-based spatial statistics (TBSS). Significantly decreased fractional anisotropy was found localized to the left hemisphere in individuals with PWS within the splenium of the corpus callosum, the internal capsule including the posterior thalamic radiation and the inferior frontal occipital fasciculus (IFOF). Reduced integrity of these white matter pathways in individuals with PWS may relate to orientating attention, emotion recognition, semantic processing, and sensorimotor dysfunction.

A cross-cultural exploration of the everyday social participation of individuals with autism spectrum disorders in Australia and Taiwan: An experience sampling study.

Individuals with an autism spectrum disorder commonly have limited social participation. This study aimed to examine the similarities and differences of everyday participation among males and females with autism spectrum disorder in Australia and Taiwan, using an experience sampling methodology. A total of 14 Australians (4 males, aged 16-43 years) and 16 Taiwanese (12 males, aged 19-45 years) with autism spectrum disorder who are cognitively able were asked to carry a device which prompted them seven times per day for 7 days, to record everyday participation: where they were, what they were doing, and who they were with. Multilevel analyses were used to identify the relationships between everyday participation and associated factors including gender, country of residence, clinical severity of autism spectrum disorder, and social anxiety. The results showed that Taiwanese participants were more likely to stay at home than Australian participants. However, female participants were more likely to engage in social situations than males. Furthermore, participants with fewer autism spectrum disorder symptoms and those with higher levels of social anxiety were less likely to engage in social interactions. This study sheds light on ways that culture and gender affect social participation and highlights the relationship of social anxiety to social participation. The findings have implications for interventions for social participation.

Young People with Intellectual Disability Transitioning to Adulthood: Do Behaviour Trajectories Differ in Those with and without Down Syndrome?

BACKGROUND: Young people with intellectual disability exhibit substantial and persistent problem behaviours compared with their non-disabled peers. The aim of this study was to compare changes in emotional and behavioural problems for young people with intellectual disability with and without Down syndrome as they transition into adulthood in two different Australian cohorts. METHODS: Emotional and behavioural problems were measured over three time points using the Developmental Behaviour Checklist (DBC) for those with Down syndrome (n = 323 at wave one) and compared to those with intellectual disability of another cause (n = 466 at wave one). Outcome scores were modelled using random effects regression as linear functions of age, Down syndrome status, ability to speak and gender. RESULTS: DBC scores of those with Down syndrome were lower than those of people without Down syndrome indicating fewer behavioural problems on all scales except communication disturbance. For both groups disruptive, communication disturbance, anxiety and self-absorbed DBC subscales all declined on average over time. There were two important differences between changes in behaviours for these two cohorts. Depressive symptoms did not significantly decline for those with Down syndrome compared to those without Down syndrome. The trajectory of the social relating behaviours subscale differed between these two cohorts, where those with Down syndrome remained relatively steady and, for those with intellectual disability from another cause, the behaviours increased over time. CONCLUSIONS: These results have implications for needed supports and opportunities for engagement in society to buffer against these emotional and behavioural challenges.

Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, hypogonadism, small hands and feet, distinct facial features and usually intellectual impairment. The disorder is associated with severe behavioral disturbances which include hyperphagia leading to morbid obesity, temper outbursts, skin-picking, and compulsive behaviors. While the brain mechanisms that underpin these disturbances are unknown these behaviors suggest a lack of inhibition and thus gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter may be implicated. In the present study, we investigated in vivo brain GABA and its relationship with emotion and behavior in individuals with PWS. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed on 15 individuals with PWS and 15 age- and gender-matched typically developing controls. GABA levels were measured in the parieto-occipital lobe. All other metabolite levels (N-acetyl aspartate, myo-Inositol, glutathione, glutamate, and glutamine + glutamate) were measured in the anterior cingulate cortex (ACC). GABA levels were significantly lower in the participants with PWS who had clinically significant emotional and behavioral problems relative to typically developing control participants and participants with PWS who did not have emotional and behavioral problems within the clinically significant range. GABA levels were negatively correlated with total behavioral problem scores as well as temper outbursts, skin-picking, depression, social relating difficulties, and a tendency to be self-absorbed. Our data suggests that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS. Pathological mechanism found in PWS may be relevant to understanding the control of similar behaviors in the general population. © 2016 Wiley Periodicals, Inc.

The Developmental Trajectory of Self-Injurious Behaviours in Individuals with Prader Willi Syndrome, Autism Spectrum Disorder and Intellectual Disability.

In the present study we examined the nature and developmental trajectory of self-injurious behaviour in Prader Willi syndrome (PWS) and autism spectrum disorder (ASD). The development of interventions is greatly aided by understanding gene to behaviour pathways, and this requires an accurate description of the behaviour phenotype, that is, which types and natural history of self-injurious behaviour are more common in PWS and ASD and which are shared with other forms of developmental disability. Self-injury displayed by individuals with PWS and individuals with ASD was compared with that reported in a group of individuals with intellectual disability due to mixed aetiology (ID group). Three self-injurious behaviours (head banging, skin-picking and hitting and/or biting self) were measured on five occasions over 18 years using the Developmental Behaviour Checklist (DBC) a well-validated caregiver report measure. Rates of skin picking were higher in individuals with PWS and hitting and/or biting self was higher in individuals with ASD compared to the ID group. Rates of head banging were similar across the three groups. Over time, skin-picking and head banging increased with age for individuals with ASD and hitting and/or biting self increased for the PWS group. In the PWS and mixed ID groups head banging decreased with age. These findings suggest that the typology and developmental trajectories of self-injurious behaviours differ between those with PWS and ASD.

Motivation for everyday social participation in cognitively able individuals with autism spectrum disorder.

OBJECTIVE: The purpose of the present study was to examine motivation for the contextual nature of motivations for social participation in cognitively able adolescents and adults with autism spectrum disorder, using self-determination theory as a theoretical framework. METHODS: Fourteen Australians and 16 Taiwanese (aged 16-45 years) with Asperger's syndrome and high functioning autism were asked to carry a device which prompted them seven times/day for 7 days, to record what they were doing, with whom, perceived difficulty and social reciprocity, and the reasons for engaging in a situation, which were then coded into degree of self-determination. RESULTS: Multilevel analyses showed that participants were more likely to be self-determined while engaging in "solitary/parallel leisure" and "social activities" than in other types of activities. Interactions with "family members" and "casual/intimate friends" were also positively associated with self-determined motivation. Further, participants were more likely to perceive higher levels of being listened to during interaction with casual/intimate friends than in interaction with other people. Global social anxiety served as a moderator for their perceptions of difficulty and social reciprocity during social engagement. CONCLUSION: The findings highlight the context-dependent motivations for social engagement of cognitively able individuals with autism spectrum disorder.

Patterns of depressive symptoms and social relating behaviors differ over time from other behavioral domains for young people with Down syndrome.

People with intellectual disabilities are at a higher risk for experiencing behavioral, emotional, and psychiatric problems in comparison with the general population. People with Down syndrome have been reported as experiencing fewer behavioral problems than others with intellectual disability, although still at a greater level than the non-intellectually disabled population, except for depression and Alzheimer disease. The aim of this study was to describe the trajectories of subscales of behavior, including depressive symptoms, communication disturbance, anxiety, disruptiveness, and social relating abilities, for young adults with Down syndrome.Families of young adults with Down syndrome living in Perth, Western Australia, participated in a questionnaire study over 8 years, 2004 (n = 255), 2009 (n = 191), and 2011 (n = 188). Questionnaires collected information about young person characteristics and family functioning. The parent-completed Developmental Behavior Checklist-Adult (DBC-A) and Developmental Behavior Checklist-Primary Carer Version (DBC-P) were used to measure emotional and behavioral problems. These measures include the following subscales: disruptive, communication and anxiety disturbances, self-absorbed, antisocial, depressive, and social relating.DBC score declined from 2004 to 2011 reflecting an improvement in behavior in the self-absorbed (coeff -0.011, 95% confidence interval (CI) -0.031, -0.008), anxiety (coef -0.009 95%CI -0.129, -0.006), communication disturbances (coeff -0.008, 95% CI -0.012, -0.005) and disruptive/antisocial behavior (coeff -0.013, 95% CI -0.016, -0.009) subscales. Subscales for depressive symptoms and social relating problems decreased less (coeff -0.003, 95% CI -0.007, -0.0001) (coeff -0.003 95% CI -0.007, 0.001). Young people who were lower functioning were reported as exhibiting significantly more behavioral problems across every subscale when compared with those who were higher functioning.Behavior of young adults with Down syndrome improves over time but depressive symptoms and social relating behavior problems persist into adulthood. It is possible that those with persistent depressive symptoms are at a high risk for developing depressive illness in adulthood. Identifying young people with Down syndrome who are at risk for developing depression in adult life has implications for prevention and early treatment.

The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome.

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood.

Cognitive and behavioural aspects of Prader-Willi syndrome.

PURPOSE OF REVIEW: To provide a review of the recent advances in the diagnosis and treatment of psychiatric disorders in Prader-Willi syndrome (PWS). RECENT FINDINGS: Research in the last 12 months has provided a descriptive prognosis of psychosis in PWS and highlighted the possible genes associated with the increased risk of psychosis for those with maternal uniparental disomy (mUPD). Several studies investigating social and communication skills have shown people with PWS to have difficulty with core, receptive and expressive language skills, interpreting emotional valence in faces, playing with children of their own age, understanding personal space and a developmental delay in the theory of mind. These social and communication deficits are often more pronounced in those with mUPD. Two recent clinical trials of oxytocin provide mixed results and highlight the need for an improved understanding of the neurobiological characteristics of the PWS brain. A recent pilot study suggests N-acetylcysteine may be a viable treatment for skin picking. SUMMARY: Recent advances have contributed to our understanding of the emotional and behavioural problems associated with PWS, and provided directions for further research.

The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial.

BACKGROUND: There is increasing interest in oxytocin as a therapeutic to treat social deficits in autism spectrum disorders (ASD). The aim of this study was to investigate the efficacy of a course of oxytocin nasal spray to improve social behavior in youth with ASD. METHODS: In a double-blind, placebo-controlled trial across two Australian university sites between February 2009 and January 2012, 50 male participants aged between 12 and 18 years, with Autistic or Asperger's Disorder, were randomized to receive either oxytocin (n = 26) or placebo (n = 24) nasal sprays (either 18 or 24 International Units), administered twice-daily for 8 weeks. Participants were assessed at baseline, after 4- and 8-weeks of treatment, and at 3-month follow-up. Primary outcomes were change in total scores on the caregiver-completed Social Responsiveness Scale and clinician-ratings on the Clinical Global Impressions-Improvement scale. Secondary assessments included caregiver reports of repetitive and other developmental behaviors and social cognition. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry www.anzctr.org.au ACTRN12609000513213. RESULTS: Participants who received oxytocin showed no benefit following treatment on primary or secondary outcomes. However, caregivers who believed their children received oxytocin reported greater improvements compared to caregivers who believed their child received placebo. Nasal sprays were well tolerated and there was no evidence of increased side effects resulting from oxytocin administration. CONCLUSIONS: This is the first evaluation of the efficacy for a course of oxytocin treatment for youth with ASD. Although results did not suggest clinical efficacy, further research is needed to explore alternative delivery methods, earlier age of intervention, and the influence of caregiver expectation on treatment response.

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty individuals with PWS aged 12-30 years participated in an 18-week randomized double-blind placebo-controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2-week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13-15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13-15 years. Measures used to assess changes were standardized well-accepted measures, including the Developmental Behavior Checklist-Monitor, Parent, Teacher, and Adult; The Yale-Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading The Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin.

Adult outcomes in autism: community inclusion and living skills.

Longitudinal research has demonstrated that social outcomes for adults with autism are restricted, particularly in terms of employment and living arrangements. However, understanding of individual and environmental factors that influence these outcomes is far from complete. This longitudinal study followed a community sample of children and adolescents with autism into adulthood. Social outcomes in relation to community inclusion and living skills were examined, including the predictive role of a range of individual factors and the environment (socio-economic disadvantage). Overall, the degree of community inclusion and living skills was restricted for the majority, and while childhood IQ was an important determinant of these outcomes, it was not the sole predictor. The implications of these findings in relation to interventions are discussed.

The association between behavioural and emotional problems and age in adults with Down syndrome without dementia: Examining a wide spectrum of behavioural and emotional problems.

The literature on the association between behavioural and emotional problems and ageing in adults with Down syndrome (DS) without dementia is limited and has generally not reported on a wide range of behavioural and emotional problems. This research aimed to extend the field by examining the associations between age and a wide spectrum of behavioural and emotional problems in adults with DS without dementia. A preliminary analysis of the association between potential covariates and behavioural and emotional problems was also undertaken. Parents and caregivers completed a questionnaire on behavioural and emotional problems for 53 adults with DS aged between 16 and 56 years. Twenty-eight adults with DS and their caregivers were part of a longitudinal sample, which provided two time points of data approximately four years apart. Additionally, 25 participants with DS and their caregivers were from a cross sectional sample, which provided one time point of data. Random effects regression analyses were used to examine the patterns in item scores for behavioural and emotional problems associated with age. No significant associations between age and the range or severity of any behavioural and emotional items were found. This suggested a more positive pattern for ageing adults with DS than has been previously described. Given that behavioural and emotional problems were not associated with age, investigation into other factors that may be associated with the behavioural and emotional difficulties for adults with DS is discussed.

Validation of the emotion regulation and social skills questionnaire for young people with autism spectrum disorders.

The current study aims to evaluate the psychometric properties of the Emotion Regulation and Social Skills Questionnaire (ERSSQ), a rating scale designed specifically to assess the social skills of young people with Autism Spectrum Disorder (ASD). The participants were 84 children and young adolescents with ASD, aged between 7.97 and 14.16 years with a mean IQ score of 90.21 (SD = 18.82). The results provide evidence for the concurrent and criterion validity of the ERSSQ Parent form, and the concurrent validity of the ERSSQ Teacher form. The clinical and theoretical implications are discussed, including the necessity of ratings across multiple contexts and the potential use of the ERSSQ in identifying individuals most in need of intervention and for planning and assessing the outcomes of social skills interventions.

Prevention and early intervention for behaviour problems in children with developmental disabilities.

PURPOSE OF REVIEW: To review the recent evidence regarding early intervention and prevention studies for children with developmental disabilities and behaviour problems from 2011 to 2013. Recent advances in the field are discussed and important areas for future research are highlighted. RECENT FINDINGS: Recent reviews and studies highlight the utility of antecedent interventions and skills training interventions for reducing behaviour problems. There is preliminary evidence for the effectiveness of parent training interventions when delivered in minimally sufficient formats or in clinical settings. Two recent studies have demonstrated the utility of behavioural interventions for children with genetic causes of disability. SUMMARY: Various forms of behavioural and parent training interventions are effective at reducing the behaviour problems in children with developmental disabilities. However, research on prevention and early intervention continues to be relatively scarce. Further large-scale dissemination studies and effectiveness studies in clinical or applied settings are needed.

Interventions provided by parents for children with intellectual disabilities in low and middle income countries.

BACKGROUND: In low- and middle-income (LAMI) countries, there is a lack of well-trained therapists to provide specialist interventions for children with intellectual disabilities and their families. We sought to identify strategies deliverable by families or non-specialist workers. MATERIALS AND METHODS: After searches of appropriate scientific databases, we applied GRADE methodology to rate the quality of evidence for these interventions. RESULTS: We identified small-scale interventions trialled in LAMI countries with limited evidence of effectiveness in supporting development, adaptive behaviour and/or community participation. In high-income countries, the Stepping Stones Triple P program for adaptive behaviour and the Portage program for child development have the most extensive evidence base and may be applicable in LAMI countries. CONCLUSIONS: There is reason to hope that, when combined with community development strategies, the welfare of children with intellectual disabilities in LAMI countries can be advanced within those countries' economic means.