Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Premigration social adversity and autism spectrum disorder.

BACKGROUND: Several studies suggest significant relationships between migration and autism spectrum disorder (ASD) but there are discrepant results. Given that no studies to date have included a pathological control group, the specificity of the results in ASD can be questioned. AIMS: To compare the migration experience (premigration, migratory trip, postmigration) in ASD and non-ASD pathological control groups, and study the relationships between migration and autism severity. METHOD: Parents' and grandparents' migrant status was compared in 30 prepubertal boys with ASD and 30 prepubertal boys without ASD but with language disorders, using a questionnaire including Human Development Index (HDI)/Inequality-adjusted Human Development Index (IHDI) of native countries. Autism severity was assessed using the Child Autism Rating Scale, Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised scales. RESULTS: The parents' and grandparents' migrant status frequency did not differ between ASD and control groups and was not associated with autism severity. The HDI/IHDI values of native countries were significantly lower for parents and grandparents of children with ASD compared with the controls, especially for paternal grandparents. Furthermore, HDI/IDHI levels from the paternal line (father and especially paternal grandparents) were significantly negatively correlated with autism severity, particularly for social interaction impairments. CONCLUSIONS: In this study, parents' and/or grandparents' migrant status did not discriminate ASD and pathological control groups and did not contribute either to autism severity. However, the HDI/IHDI results suggest that social adversity-related stress experienced in native countries, especially by paternal grandparents, is potentially a traumatic experience that may play a role in ASD development. A 'premigration theory of autism' is then proposed.

Anxiety disorders in children with high intellectual potential.

BACKGROUND: Several studies have reported anxiety disorders in children with high intellectual potential (HIP). However, there are discrepant results possibly as a result of methodological biases (different/absent definitions of HIP, small sample sizes, non-validated/adapted/specific tools for assessing anxiety and a single observational source). AIMS: To examine more thoroughly the relationships between HIP and anxiety in large samples of children using clear definitions of HIP, different observational sources and specific assessments of anxiety. METHOD: Children with HIP (n = 211, total IQ ≥130) were compared with children without HIP (n = 397, total IQ <130) for anxiety using different observational sources (child psychiatric diagnosis, parental evaluation and child's self-evaluation). Intellectual functioning was assessed using the Wechsler Intelligence Scale. RESULTS: There were significantly more children with HIP who had anxiety disorders than children without HIP based on the child psychiatric diagnosis. Moreover, based on the child's self-evaluation, children with a high Verbal Comprehension Index (VCI ≥130) were significantly more anxious than children with a VCI <130, whereas children with a high Perceptual Reasoning Index (PRI ≥130) were significantly less anxious than children with a PRI <130. Finally, there was no significant relationship between levels of intellectual functioning and anxiety according to parental observation. CONCLUSIONS: The results highlight the importance of using multiple observational sources and conducting analyses on different dimensions of intellectual functioning (such as VCI and PRI), rather than only on the composite total IQ score. High verbal potential might be a factor of vulnerability for anxiety, whereas high perceptual reasoning might be a protective factor. Further studies are necessary to understand better the mechanisms underlying these results.

Relationships Between Self-Injurious Behaviors, Pain Reactivity, and ß-Endorphin in Children and Adolescents With Autism.

OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and ß-endorphin levels in autism. METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma ß-endorphin concentrations were measured in 57 participants using 2 different immunoassay methods. RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between ß-endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations. CONCLUSIONS: The absence of any observed relationships between ß-endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain.

Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives.

There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.

Altered circadian patterns of salivary cortisol in low-functioning children and adolescents with autism.

BACKGROUND: Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism. METHODS: The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured. RESULTS: The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups. CONCLUSION: Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety.

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives.

Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.

Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.

BACKGROUND: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized. METHODS: Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. RESULTS: The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. CONCLUSIONS: Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.

Biological and psychological rhythms: an integrative approach to rhythm disturbances in autistic disorder.

Biological rhythms are crucial phenomena that are perfect examples of the adaptation of organisms to their environment. A considerable amount of work has described different types of biological rhythms (from circadian to ultradian), individual differences in their patterns and the complexity of their regulation. In particular, the regulation and maturation of the sleep-wake cycle have been thoroughly studied. Its desynchronization, both endogenous and exogenous, is now well understood, as are its consequences for cognitive impairments and health problems. From a completely different perspective, psychoanalysts have shown a growing interest in the rhythms of psychic life. This interest extends beyond the original focus of psychoanalysis on dreams and the sleep-wake cycle, incorporating central theoretical and practical psychoanalytic issues related to the core functioning of the psychic life: the rhythmic structures of drive dynamics, intersubjective developmental processes and psychic containment functions. Psychopathological and biological approaches to the study of infantile autism reveal the importance of specific biological and psychological rhythmic disturbances in this disorder. Considering data and hypotheses from both perspectives, this paper proposes an integrative approach to the study of these rhythmic disturbances and offers an etiopathogenic hypothesis based on this integrative approach.

Temporality, trauma and care of repeat adolescent offenders.

In recent years the matter of repeat young offenders has raised questions for and bewildered the institutions caring for them. The temporality of these youngsters is ingrained in the current and urgent moment, and in the repetition of acts of delinquency, which preclude them from having a linear perception of time. This study reflects on the different temporalities with which institutions need to work and on how the judicial, educational, and psychological times can, by building bridges between the present and the past, help piece together the story of adolescents' lives. The personal history of each young offender contributes to explain his/her misbehavior. Acting out can symbolize childhood abuse. Thus, repetitive acts of delinquency should not be considered and treated as isolated acts of violence, which each time cause a rupture, but should be seen and as a whole. Repetition of acts of delinquency should prompt questioning about the past of young offenders-a past which is buried and which distorts their perception of present time, preventing them from projecting themselves into and making plans for the future.

Prognostic value of early therapeutic alliance in weight recovery: a prospective cohort of 108 adolescents with anorexia nervosa.

PURPOSE: To determine whether patients' perception of early therapeutic alliance (TA) could predict time to achieve a target weight among adolescents undergoing treatment for anorexia nervosa. METHOD: TA was assessed in a prospective cohort recruited from both inpatient and outpatient settings by self-administered and validated questionnaires. Kaplan-Meier survival curves were compared by log rank test, and Cox regression was used to test whether patients' perception of early TA predicted time to achieve a target weight. RESULTS: In total, 108 patients were included, and 79.6% achieved a target weight. Better patient perception of early TA increased the hazard ratio (HR) of achieving a target weight (HR = 2.7, 95% confidence interval: 1.7-4.4, p < .001) such as being in the inpatient setting by 6.7. Being very severely underweight at admission decreased the HR of achieving the target weight. CONCLUSION: Patients' perception of early TA is a good predictor of achieving a target weight. Because TA is a modifiable construct, it could be a target for intervention.

Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder.

BACKGROUND: Several reports indicate that nocturnal production of melatonin is reduced in autism. Our objective was to examine whether melatonin production is decreased during the whole 24-h cycle, whether the melatonin circadian rhythm is inverted, and whether the reduction in melatonin production is related to the severity of autistic behavioral impairments. METHOD: Day and nighttime urinary excretion of 6-sulphatoxymelatonin (6-SM) was examined during a 24-h period in post-pubertal individuals with autism (N=43) and typically developing controls (N=26) matched for age, sex and pubertal stage. RESULTS: Low 6-SM excretion (mean ± SEM) was observed in autism, both at daytime (0.16 ± 0.03 vs. 0.36 ± 0.05 µg/h, p<0.01), nighttime (0.52 ± 0.07 vs. 1.14 ± 0.23 µg/h, p<0.05), and during 24h (8.26 ± 1.27 vs. 18.00 ± 3.43 µg/24-h collection, p<0.001). Intra-individual nighttime-daytime differences (delta values) in 6-SM excretion were smaller in individuals with autism than in controls (0.36 ± 0.07 vs. 0.79 ± 0.23 µg/h, p<0.05). Nocturnal excretion of 6-SM was negatively correlated with autism severity in the overall level of verbal language (Spearman ρ=-0.30, p<0.05), imitative social play (Spearman ρ=-0.42, p<0.05), and repetitive use of objects (Spearman ρ=-0.36, p<0.05). CONCLUSION: A deficit in melatonin production is present both at daytime and at nighttime in individuals with autism, particularly in the most severely affected individuals. These results highlight interest in potential therapeutic uses of melatonin in autistic disorder, especially in individuals with severe autistic impairment and/or low urinary 6-SM excretion.

Are impairments of time perception in schizophrenia a neglected phenomenon?

Based on clinical, phenomenological and neurobiological observations, psychiatrists often report a deficit in time estimation in patients with schizophrenia. Cognitive models of time estimation in healthy subjects have been proposed and developed for approximately 30 years. The current theory in the field of time perception, which is supported by a connectionist model, postulates that temporal judgement is based upon a pacemaker-counter device that depends mostly upon memory and attentional resources. The pacemaker emits pulses that are accumulated in a counter, and the number of pulses determines the perceived length of an interval. Patients with schizophrenia are known to display attentional and memory dysfunctions. Moreover, dopamine regulation mechanisms are involved in both the temporal perception processes and schizophrenia. Thus, it is still unclear if temporal impairments in schizophrenia are related to a specific disturbance in central temporal processes or are due to certain cognitive problems, such as attentional and memory dysfunctions, or biological abnormalities. The authors present a critical literature review on time perception in schizophrenia that covers topics from psychopathology to neuroscience. Temporal perception appears to play a key role in schizophrenia and to be partially neglected in the current literature. Future research is required to better ascertain the underlying mechanisms of time perception impairments in schizophrenia.

The Autism Psychodynamic Evaluation of Changes (APEC) scale: a reliability and validity study on a newly developed standardized psychodynamic assessment for youth with Pervasive Developmental Disorders.

The present study was designed to examine the reliability and validity of the Autism Psychodynamic Evaluation of Changes (APEC) scale, developed to assess the evolution in individuals with autism under treatment. The APEC scale focuses on the key role of impairment in body image construction, which requires cross-modal sensory integration through emotional communication with motor representations. Thus, the body image construction is associated simultaneously with spatial and temporal organization and allows the emergence of self- and others-representations. The use of the APEC scale, with its seven domains (expression of emotion in relationships, eye contact, body image, graphic productions, exploration of space and objects, time perception, and verbal language), underlines the importance in autistic disorder of anxieties related to body and spatial representations, and of impairment in the body ego construction which is closely linked to the emergence of individuation/separation processes. This study was conducted on 73 children and adolescents with autistic disorder. They were recruited in day care facilities where two caregivers independently gave their ratings based on their clinical observation on a daily basis during the same month. Analyses included assessing construct validity through correspondence analyses and inter-rater reliability using kappa coefficients. The APEC scale offers a reliable and validated psychodynamic assessment of interest for professionals (such as child psychiatrists, caregivers, therapists or teachers) and researchers working with children, adolescents and adults with autistic disorder, especially in the follow-up of their evolution. The APEC scale provides an approach at the interface of psychoanalysis and neuroscience, and is also of interest for clinical and developmental psychology. Using the APEC scale in a range of different practical and research settings will foster links between psychoanalytic perspectives and educational training for children with autistic disorder, and will contribute to the dialogue between psychoanalysis, neuroscience and psychology.

Adolescent brain development, risk-taking and vulnerability to addiction.

Adolescents (12-18 years old) and young adults (18-25 years old), are more likely than older adults to drive-or agree to be driven-recklessly or while intoxicated, to use illicit or dangerous substances and to engage in both minor and more serious antisocial behaviour. Numerous factors during adolescence may lead to or favour initiation of drug use, such as sensation-seeking, gregariousness and social conformity. These aspects, however, cannot be dissociated from the increased sex drive and quest for an integrated self. In the separation-individuation process, relationships with peers play many different roles: a field for experimentation, emotional support, a place for "projection" and "identification", and the possibility of finding a partner. Unsurprisingly, therefore, drug use generally takes place in a group setting. Despite evidence of heightened real-world risk-taking, laboratory studies have yet to yield consistent evidence that adolescents, when on their own, are more inclined towards risky behaviour than their elders. Moreover, their comprehension and reasoning abilities in risky decision-making situations are roughly equivalent to those of adults. Structural and functional neuroimaging studies have shown that neural circuitry undergoes major reorganization during adolescence, particularly in those regions of the brain relating to executive functions, the self and social cognition, and that the "emotional brain" may play a role in that reorganization. Age-related decreases in gray matter volume mainly reflect a reduction in the number of synapses and the complexity of axonal ramifications. By 18-20 years old, most of the subcortical white matter and association pathways have reached a plateau. Risk-taking behavior and novelty-seeking may provide, with an appropriate feed back, a mechanism to optimize brain development in adolescence.

French adaptation and validation of the helping alliance questionnaires for child, parents, and therapist.

OBJECTIVES: To adapt the Helping Alliance Questionnaires for Child and Parents (HAQ-CP) into French and to assess their validity and reproducibility for use with the child, parent, and therapist. METHOD: First, the 3 US versions of the questionnaires were translated into French by 3 French-English bilingual translators (who were native speakers), and the translations were then discussed by an expert committee to ensure that the concept explored within the French context was efficiently targeted. Second, the psychometric properties of the French version were investigated in a cross-sectional, multicentre study. The questionnaires were completed by 148 children and adolescents, aged 9 years or older and with various conditions, who were followed in 3 university hospital outpatient clinics and 2 ambulatory psychiatry units, and also by their parents and therapists. RESULTS: The instruments were quick and easy to administer, and acceptability was good. All 3 versions proved unidimensional in factorial analysis (80% of variance was explained) with high internal construct validity (Cronbach's alpha = 0.8). Reproducibility was satisfactory (intraclass correlation coefficients were as follows: child, 0.84; parent, 0.84; and therapist, 0.87). Concordance of the 3 alliance assessments was moderate. CONCLUSION: This work provides child psychiatrists with a valid measure of the therapeutic alliance. Its predictive value, while recognized in adults, remains to be demonstrated in children.