Systematic review and meta-analysis: Season of birth and schizophrenia risk.

OBJECTIVE: Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months. METHODS: We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere. RESULTS: Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births. CONCLUSIONS: Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association.

The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis.

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose-response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose-response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

Cannabis-based medicine in treatment of patients with Gilles de la Tourette syndrome.

INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a childhood onset disorder characterised by the presence of motor and vocal tics. The guidelines of both the American Academy of Neurology (AAN) as well as the European Society for the Study of Tourette Syndrome (ESSTS) recommend behavioural therapy and pharmacotherapy, mainly with antipsychotics, as first line treatments for tics. In spite of these well-established therapeutic approaches, a significant number of patients are dissatisfied because of insufficient tic reduction or intolerable side effects. Previous studies have suggested that cannabis-based medicine (CBM) might be an alternative treatment in these patients. MATERIAL AND METHODS: Two reviewers (KS, NS) searched the electronic database of PubMed on 1 July, 2021 for relevant studies using the search terms: ('Tourette syndrome' [MeSH Terms] OR 'Gilles de la Tourette syndrome' [MeSH Terms] OR 'tic disorders' [MeSH Terms] OR 'tics' [MeSH Terms] OR 'tic disorders'[Title/Abstract]) AND ('cannabis-based medicine' [Title/Abstract] OR 'cannabis' [Title/Abstract] OR 'dronabinol' [Title/Abstract] OR 'nabiximols' [Title/Abstract] OR 'tetrahydrocannabinol' [Title/Abstract] OR 'THC' [Title/Abstract] OR 'cannabidiol' [Title/Abstract], limit: 'humans'. These studies were further reviewed for additional relevant citations. The titles and abstracts of the studies obtained through this search were examined by two reviewers (KS, NS) in order to determine article inclusion. Discrepancies were addressed by the reviewers through discussion and eventually conversation with the senior reviewer (KMV). RESULTS: Although the amount of evidence supporting the use of CBM in GTS is growing, the majority of studies are still limited to case reports, case series, and open uncontrolled studies. To date, only two small randomised controlled trials (RCTs) using tetrahydrocannabinol (THC, dronabinol) have been published demonstrating the safety and efficacy of this intervention in the treatment of tics in patients with GTS. On the other hand, another RCT with Lu AG06466 (formerly known as ABX-1431), a modulator of endocannabinoid neurotransmission, has failed to prove effective in the therapy of GTS. Accordingly, under the guidelines of both the ESSTS and the AAN, treatment with CBM is categorised as an experimental intervention that should be applied to patients who are otherwise treatment-resistant. CONCLUSIONS: Increasing evidence suggests that CBM is efficacious in the treatment of tics and psychiatric comorbidities in patients with GTS. The results of ongoing larger RCTs, such as CANNA-TICS (ClinicalTrials.gov Identifier: NCT03087201), will further clarify the role of CBM in the treatment of patients with GTS.

Genomics of Obsessive-Compulsive Disorder-Toward Personalized Medicine in the Era of Big Data.

Pathogenesis of obsessive-compulsive disorder (OCD) mainly involves dysregulation of serotonergic neurotransmission, but a number of other factors are involved. Genetic underprints of OCD fall under the category of "common disease common variant hypothesis," that suggests that if a disease that is heritable is common in the population (a prevalence >1-5%), then the genetic contributors-specific variations in the genetic code-will also be common in the population. Therefore, the genetic contribution in OCD is believed to come from multiple genes simultaneously and it is considered a polygenic disorder. Genomics offers a number of advanced tools to determine causal relationship between the exposure and the outcome of interest. Particularly, methods such as polygenic risk score (PRS) or Mendelian Randomization (MR) enable investigation of new pathways involved in OCD pathogenesis. This premise is also facilitated by the existence of publicly available databases that include vast study samples. Examples include population-based studies such as UK Biobank, China Kadoorie Biobank, Qatar Biobank, All of US Program sponsored by National Institute of Health or Generations launched by Yale University, as well as disease-specific databases, that include patients with OCD and co-existing pathologies, with the following examples: Psychiatric Genomics Consortium (PGC), ENIGMA OCD, The International OCD Foundation Genetics Collaborative (IOCDF-GC) or OCD Collaborative Genetic Association Study. The aim of this review is to present a comprehensive overview of the available Big Data resources for the study of OCD pathogenesis in the context of genomics and demonstrate that OCD should be considered a disorder which requires the approaches offered by personalized medicine.

Parental Age and the Risk for Alzheimer's Disease in Offspring: Systematic Review and Meta-Analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, accounting for 50-75% of all cases. While older maternal and paternal age at childbirth are established risk factors for Down syndrome which is associated with later AD, it is still not entirely clear whether parental age is a risk factor for AD. Previous studies have suggested contradictory findings. OBJECTIVES: We conducted a systematic review and meta-analysis to examine whether parental (maternal and paternal) age at birth was associated with AD and whether individuals born to younger or older parents were at an increased risk for AD. METHODS: Two reviewers searched the electronic database of PubMed for relevant studies. Eligibility for the meta-analysis was based on the following criteria: (1) studies involving patients with AD and an adequate control group, (2) case control or cohort studies, (3) studies investigating parental age. All statistical analyses were completed in STATA/IC version 16. RESULTS: Eleven studies involving 4,371 participants were included in the systematic review and meta-analysis. Meta-analysis demonstrated no significant association between maternal (weighted mean difference [WMD] 0.49, 95% CI -0.52 to 1.49, p = 0.34) and paternal age and AD (WMD 1.00, 95% CI -0.55 to 2.56, p = 0.21). Similarly, individuals born to younger (<25 years) or older parents (>35 years) did not demonstrate a differential risk for AD. CONCLUSIONS: Overall, this meta-analysis did not demonstrate an association between parental age and the risk of AD in offspring. These findings should be interpreted with caution given the limited power of the overall meta-analysis and the methodological limitations of the underlying studies as in many cases no adjustment for potential confounders was included.

Refractory Gilles de la Tourette Syndrome-Many Pieces That Define the Puzzle.

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.

Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration.

Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.