Prenatal Exposure to Opioids and Neurodevelopmental Disorders in Children: A Bayesian Mediation Analysis.

This study explores natural direct and joint natural indirect effects (JNIE) of prenatal opioid exposure on neurodevelopmental disorders (NDDs) in children mediated through pregnancy complications, major and minor congenital malformations, and adverse neonatal outcomes, using Medicaid claims linked to vital statistics in Rhode Island, United States, 2008-2018. A Bayesian mediation analysis with elastic net shrinkage prior was developed to estimate mean time to NDD diagnosis ratio using posterior mean and 95% credible intervals (CrIs) from Markov chain Monte Carlo algorithms. Simulation studies showed desirable model performance. Of 11,176 eligible pregnancies, 332 had ≥2 dispensations of prescription opioids anytime during pregnancy, including 200 (1.8%) having ≥1 dispensation in the first trimester (T1), 169 (1.5%) in the second (T2), and 153 (1.4%) in the third (T3). A significant JNIE of opioid exposure was observed in each trimester (T1, JNIE = 0.97, 95% CrI: 0.95, 0.99; T2, JNIE = 0.97, 95% CrI: 0.95, 0.99; T3, JNIE = 0.96, 95% CrI: 0.94, 0.99). The proportion of JNIE in each trimester was 17.9% (T1), 22.4% (T2), and 56.3% (T3). In conclusion, adverse pregnancy and birth outcomes jointly mediated the association between prenatal opioid exposure and accelerated time to NDD diagnosis. The proportion of JNIE increased as the timing of opioid exposure approached delivery.

Evidence for effect of l-serine, a novel therapy for GRIN2B-related neurodevelopmental disorder.

RATIONALE: To date, causal therapy is potentially available for GRIN2B-related neurodevelopmental disorder (NDD) due to loss-of-function (LoF) variants in GRIN2B, resulting in dysfunction of the GluN2B subunit-containing N-methyl-d-aspartate receptor (NMDAR). Recently, in vitro experiments showed that high doses of NMDAR co-agonist d-serine has the potential to boost the activity in GluN2B LoF variant-containing NMDARs. Initial reports of GRIN2B-NDD patients LoF variants, treated with l-serine using different regimens, showed varying effects on motor and cognitive performance, communication, behavior and EEG. Here, this novel treatment using a standardized protocol with an innovative developmental outcome measure is explored further in an open-label observational GRIN2B-NDD study. METHODS: Initially, in vitro studies were conducted in order to functionally stratify two de novo GRIN2B variants present in two female patients (18 months and 4 years old). Functional studies showed that both variants are LoF, and thus the patients were treated experimentally according to an approved protocol with oral l-serine (500 mg/kg/day in 4 doses) for a period of 12 months. Both patients showed a heterogeneous clinical phenotype, however overlapping symptoms were present: intellectual developmental disability (IDD), behavioral abnormalities and hypotonia. Outcome measures included laboratory tests, quality of life, sleep, irritability, stool, and performance skills, measured by, among others, the Perceive-Recall-Plan-Perform System of Task Analysis (PRPP-Assessment). RESULTS: Both patients tolerated l-serine without adverse effects. In one patient, improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months). In the most severe clinically affected patient no significant objective improvement in validated outcomes was observed. Caregivers of both patients reported subjective increase of alertness and improved communication skills. CONCLUSION: Our observational study confirms that l-serine supplementation is safe in patients with GRIN2B-NDD associated with LoF variants, and may accelerate psychomotor development and ameliorate cognitive performance in some but not all patients. The PRPP-Assessment, a promising instrument to evaluate everyday activities and enhance personalized and value-based care, was not performed in the severely affected patient, meaning that possible positive results may have been missed. To generate stronger evidence for effect of l-serine in GRIN2B-NDD, we will perform placebo-controlled n-of-1 trials.

Dual orexin receptor antagonists for insomnia in youth with neurodevelopmental disorders: a case series and review.

Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.

GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.

A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders.

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.

Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

BACKGROUND: Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoints. Here we publish the protocol of the post-trial access combined cohort study to confirm previous effects and stratification strategies in the trial cohorts and in new participants. METHOD/DESIGN: Participants of the three previous cohorts and a new cohort will be subjected to 6 months bumetanide treatment using multiple baseline Single Case Experimental Designs. The primary outcome is the change, relative to baseline, in a set of patient reported outcome measures focused on direct and indirect effects of sensory processing difficulties. Secondary outcome measures include the conventional questionnaires 'social responsiveness scale', 'repetitive behavior scale', 'sensory profile' and 'aberrant behavior scale'. Resting-state EEG measurements will be performed at several time-points including at Tmax after the first administration. Assessment of cognitive endpoints will be conducted using the novel Emma Tool box, an in-house designed battery of computerized tests to measure neurocognitive functions in children. DISCUSSION: This study aims to replicate previously shown effects of bumetanide in NDD subpopulations, validate a recently proposed treatment prediction effect methodology and refine endpoint measurements. TRIAL REGISTRATION: EudraCT: 2020-002196-35, registered 16 November 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002196-35/NL.

STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies.

Mutations in Munc18-1/STXBP1 (syntaxin-binding protein 1) are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders. Heterozygous mutations in the STXBP1 gene include missense, nonsense, frameshift, and splice site mutations, as well as intragenic deletions and duplications and whole-gene deletions. No genotype-phenotype correlation has been identified so far, and patients are treated by anti-epileptic drugs because of the lack of a specific disease-modifying therapy. The molecular disease mechanisms underlying STXBP1-linked disorders are yet to be fully understood, but both haploinsufficiency and dominant-negative mechanisms have been proposed. This review focuses on the current understanding of the phenotypic spectrum of STXBP1-linked disorders, as well as discusses disease mechanisms in the context of the numerous pathways in which STXBP1 functions in the brain. We additionally evaluate the available animal models to study these disorders and highlight potential therapeutic approaches for treating these devastating diseases.

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders.

BACKGROUND: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. METHODS: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. RESULTS: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). CONCLUSIONS: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

Diagnostic yield and treatment impact of whole-genome sequencing in paediatric neurological disorders.

AIM: To investigate the diagnostic yield and treatment impact of whole-genome sequencing (WGS) in patients with paediatric neurological disorders. METHOD: From January 2016 to December 2019, paediatric patients who had suspected genetic neurological disorders were assessed using WGS. The phenotypes of eligible patients were divided into four groups: patients with neurodevelopmental disorders; patients with epilepsy; patients with neuromuscular disorders; and patients with movement disorders. RESULTS: A total of 214 consecutive patients (128 males, 86 females) underwent WGS. The mean (SD) age of disease onset was 13.8 (27.6) months (range 1d-15y 5mo). The mean (SD) age at which WGS was performed was 71.7 (58.9) months (range 8d-18y). A molecular diagnosis was reported in 43.9% of patients. The highest diagnostic rate was achieved in 62.5% of patients with neuromuscular disorders, 47.5% of patients with epilepsy, 41.1% of patients with neurodevelopment disorders, and 15.4% of patients with movement disorders. All 94 patients with a WGS diagnosis were given access to genetic counselling and 23.4% of patients had immediate changes in treatment strategies after undergoing WGS. INTERPRETATION: WGS allows paediatric neurologists to integrate genomic data into their diagnosis and adjust management strategies for a range of clinical and genetically heterogeneous disease entities to improve the clinical outcomes of patients. In our cohort, the diagnosis of a significant proportion of patients was reached through WGS (43.9%). Clinicians could use these results to directly guide the management of their patients and improve their clinical outcomes (23.4%). What this paper adds For selected children in our cohort, the diagnostic yield of whole-genome sequencing (WGS) was 43.9%. WGS can be used to expand our knowledge of phenotype-genotype variations.

Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion.

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement.

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes.

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target.

Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future.

Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor.

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT7R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT7R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT7R/G12 signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT7R could be a potential therapeutic target for the treatment of NDDs.

MicroRNAs and Child Neuropsychiatric Disorders: A Brief Review.

MicroRNAs (miRNAs) are short, endogenous, noncoding RNAs that regulate gene expression through posttranscriptional mechanisms via degradation or inhibition of specific mRNAs targets. In recent years, abundant studies have illustrated the relevance of miRNAs in human psychopathology. In this current review, neuropsychiatric disorders with moderate to high prevalence among children and adolescents such as Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, Dyslexia, Epilepsy, Schizophrenia and Tourette Syndrome were discussed focusing on the functional consequence of altered miRNA expression during the development of such diseases. The insight about the roles that miRNAs play in central nervous systems development such as cell proliferation and differentiation, synaptogenesis, synaptic plasticity, and apoptosis might be the key to explicate novel biomarkers for diagnosis and prognosis of these disorders, as well as the finding of new targets for drug development for therapeutic approaches.

Melatonin Use in Psychiatry-Quo Vadis?

Melatonin use in clinical psychiatry is currently rife, and the trend of utilization is on the rise. Efficacy coupled with safety and lack of abuse potential render melatonin an attractive therapeutic option. Data from neuroscience accrue speaking to the idea of a pluripotent molecule beyond a mere sleeping aid. Here, authors would shed some light on melatonin use in psychiatry while examining the extant evidence.

Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders.

BACKGROUND: Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. METHODS: We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. RESULTS: Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan-74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], - 36.7 ± 46.1 min; 95% confidence interval [CI], - 45.9 to - 27.5; P <  0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P <  0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P <  0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. CONCLUSIONS: Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being. TRIAL REGISTRATION: ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.

Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder.

CCCTC-binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow-up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.

Pediatric sleep disturbances and treatment with melatonin.

BACKGROUND: There are no guidelines concerning the best approach to improving sleep, but it has been shown that it can benefit the affected children and their entire families. The aim of this review is to analyse the efficacy and safety of melatonin in treating pediatric insomnia and sleep disturbances. MAIN BODY: Sleep disturbances are highly prevalent in children and, without appropriate treatment, can become chronic and last for many years; however, distinguishing sleep disturbances from normal age-related changes can be a challenge for physicians and may delay treatment. Some published studies have shown that melatonin can be safe and effective not only in the case of primary sleep disorders, but also for sleep disorders associated with various neurological conditions. However, there is still uncertainty concerning dosing regimens and a lack of other data. The dose of melatonin should therefore be individualised on the basis of multiple factors, including the severity and type of sleep problem and the associated neurological pathology. CONCLUSIONS: Melatonin can be safe and effective in treating both primary sleep disorders and the sleep disorders associated with various neurological conditions. However, there is a need for further studies aimed at identifying the sleep disordered infants and children who will benefit most from melatonin treatment, and determining appropriate doses based on the severity and type of disorder.

Post-weaning social isolation of mice: A putative animal model of developmental disorders.

Post-weaning social isolation of laboratory animals is known to induce many behavioural and neurochemical abnormalities, which resemble neuropsychiatric disorders such as depression and anxiety. Therefore, they can help provide a suitable animal model to investigate the pathophysiology of neuropsychiatric symptoms and explore potential drugs for the treatment of neuropsychiatric diseases. Our recent studies have demonstrated that post-weaning social isolation of mice for no less than one week causes behaviour changes such as reduced attention, impaired social affiliation behaviour, and impaired conditional fear memories. Our neuropharmacological analyses have revealed that these behavioural features are modulated by different neuronal mechanisms, suggesting that post-weaning social isolation of mice can help provide an animal model with comorbid symptoms of patients with developmental disorders, including attention-deficit hyperactivity disorder, autism spectrum disorder, and specific learning disability. In this review, we discuss the neuropharmacological features of developmental disorder-like behaviour induced by post-weaning social isolation in mice to offer new insights into the pathophysiology of developmental disorders and possible therapeutic strategies.