Faculty Bibliography

BACKGROUND:Numerous interventions for irritability in autism spectrum disorder (ASD) have been investigated. We aimed to appraise the magnitude of pharmacological and non-pharmacological interventions for irritability in ASD without any restrictions in terms of eligible interventions. METHODS:We systematically searched PubMed/MEDLINE, Scopus, and Web of Science until April 15, 2023. We included randomized controlled trials (RCTs) with a parallel design that examined the efficacy of interventions for the treatment of irritability in patients of any age with ASD without any restrictions in terms of eligible interventions. We performed a random-effects meta-analysis by pooling effect sizes as Hedges' g. We classified assessed interventions as follows: pharmacological monotherapy, risperidone plus adjuvant therapy versus risperidone monotherapy, non-pharmacological intervention, and dietary intervention. We utilized the Cochrane tool to evaluate the risk of bias in each study and the GRADE approach to assess the certainty of evidence for each meta-analyzed intervention. RESULTS:Out of 5640 references, we identified 60 eligible articles with 45 different kinds of interventions, including 3531 participants, of which 80.9% were males (mean age [SD] = 8.79 [3.85]). For pharmacological monotherapy, risperidone (Hedges' g - 0.857, 95% CI - 1.263 to - 0.451, certainty of evidence: high) and aripiprazole (Hedges' g - 0.559, 95% CI - 0.767 to - 0.351, certainty of evidence: high) outperformed placebo. Among the non-pharmacological interventions, parent training (Hedges' g - 0.893, 95% CI - 1.184 to - 0.602, certainty of evidence: moderate) showed a significant result. None of the meta-analyzed interventions yielded significant effects among risperidone + adjuvant therapy and dietary supplementation. However, several novel molecules in augmentation to risperidone outperformed risperidone monotherapy, yet from one RCT each. LIMITATIONS/CONCLUSIONS:First, various tools have been utilized to measure the irritability in ASD, which may contribute to the heterogeneity of the outcomes. Second, meta-analyses for each intervention included only a small number of studies and participants. CONCLUSIONS:Only risperidone, aripiprazole among pharmacological interventions, and parent training among non-pharmacological interventions can be recommended for irritability in ASD. As an augmentation to risperidone, several novel treatments show promising effects, but further RCTs are needed to replicate findings. Trial registration PROSPERO, CRD42021243965.

The increasing administrative prevalence of Attention-Deficit Hyperactivity Disorder (ADHD) over recent years has correspondingly escalated the prescriptions of pharmacological treatments for ADHD, particularly methylphenidate (MPH), which remains the most extensively prescribed medication for this condition. In light of this trend, evaluating the long-term risks associated with using MPH is important. This article aims to present findings from studies concerning the long-term use of MPH, derived from a literature review of the past decade, primarily focusing on data sourced from PubMed to assess these risks. Our review has drawn on a diverse range of studies, including cohort studies, meta-analyses, and database reviews from various global regions, reflecting a comprehensive international perspective on the long-term safety of MPH. Our review highlights several key aspects. Initial worries about the adverse psychiatric effects of MPH did not find strong support in subsequent studies. Rather, the current body of literature suggests that MPH may have a protective effect against depression and substance use disorders. We found no significant increase in the likelihood of suicide or psychotic disorders among long-term users of MPH. In fact, studies indicate that MPH treatment might reduce the incidence of depression. Moreover, contrary to concerns that stimulant treatment might predispose individuals to SUDs, recent longitudinal studies have generally shown no increased risk of substance misuse. Some studies have even suggested a lower incidence of substance misuse among patients treated with MPH. The review also delved into cardiovascular risks, which have been a notable concern with long-term MPH usage. While short-term studies typically showed minimal cardiovascular risks, results on longer-term effects suggest potential increases in hypertension and other arterial diseases for a higher dosage, highlighting the necessity for careful cardiovascular monitoring in patients undergoing long-term treatment. No elevated risk was described concerning other cardiovascular diseases. Results regarding the impact on growth have been mixed. Some studies suggest a temporary reduction in growth velocity that normalizes over time. This pattern suggests a delayed, rather than permanently stunted, growth trajectory in children treated with MPH over the long term. Lastly, our review did not find any risk of testicular dysfunction in patients treated with MPH. The collective findings from the reviewed studies offer reassurance regarding several of the initial concerns about the long-term use of MPH. While there are concerns about potential hypertension and arterial disease risks and uncertainties regarding growth, it is important to regularly monitoring for patients using MPH. These findings should be communicated transparently to patients and their families, helping to inform shared decision-making about the initiation and continuation of MPH therapy for ADHD. As research continues to evolve, it is imperative to keep updating our understanding of the safety of MPH safety profile to optimize treatment strategies and ensure that patients receive the most effective and safe care possible.

OBJECTIVE:It is unclear how the functional brain hierarchy is organized in preschool-aged children, and whether alterations in the brain organization are linked to mental health in this age group. Here, we assessed whether preschool-aged children exhibit a brain organizational structure similar to that of older children, how this structure might change over time, and whether it might reflect mental health. METHOD/METHODS:This study derived functional gradients using diffusion embedding from resting state functional magnetic resonance imaging data of 4.5-year-old children (N = 100, 42 male participants) and 6.0-year-old children (N = 133, 62 male participants) from the longitudinal Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We then conducted partial least-squares correlation analyses to identify the association between the impairment ratings of different mental disorders and network gradient values. RESULTS:The main organizing axis of functional connectivity (ie, principal gradient) separated the visual and somatomotor regions (ie, unimodal) in preschool-aged children, whereas the second axis delineated the unimodal-transmodal gradient. This pattern of organization was stable from 4.5 to 6 years of age. The second gradient separating the high- and low-order networks exhibited a diverging pattern across mental health severity, differentiating dimensions related to attention-deficit/hyperactivity disorder and phobic disorders. CONCLUSION/CONCLUSIONS:This study characterized, for the first time, the functional brain hierarchy in preschool-aged children. A divergence in functional gradient pattern across different disease dimensions was found, highlighting how perturbations in functional brain organization can relate to the severity of different mental health disorders.

BACKGROUND:Evidence that autism often manifests differently between males and females is growing, particularly in terms of social interaction and communication, but it is unclear if there are sex differences in restricted and repetitive behaviours and interests (RRBIs) when rigorously focusing on the narrow construct level (i.e., stereotyped behaviour, restricted interests, insistence on sameness, and/or sensory experiences). METHODS:We conducted a systematic review and four random effects meta-analyses investigating sex differences in narrow construct measures of RRBIs in autistic children, adolescents, and adults (Prospero registration ID: CRD42021254221). Study quality was appraised using the Newcastle-Ottawa Quality Assessment Scale. RESULTS:Forty-six studies were narratively synthesised and 25 of these were included in four random effects meta-analyses. Results found that autistic males had significantly higher levels of stereotyped behaviours (SMD = 0.21, 95% confidence interval (CI) [0.09, 0.33], p < .001) and restricted interests (SMD = 0.18, 95% CI [0.07, 0.29], p < .001) compared to autistic females. In contrast, there were no significant sex differences for sensory experiences (SMD = -0.09, 95% CI [-0.27, 0.09], p = .32) and insistence on sameness (SMD = 0.01, 95% CI [-0.03, 0.05], p = .68). The findings from the narrative synthesis were generally consistent with those from the meta-analyses and also found qualitative sex differences in the way RRBIs manifest. CONCLUSIONS:Our findings show significant differences in narrowly defined RRBIs in males and females. Practitioners need to be aware of such differences, which could be contributing to the under-recognition of autism in females and may not be captured by current diagnostic instruments.

This systematic review aimed to establish the extent to which each Attention Deficit/Hyperactivity Disorder (ADHD) symptom criterion is being assessed without being influenced (biased) by factors such as informant, sex/gender, and age. Measurement invariance (MI) testing using confirmatory factor analysis (CFA) is the prime statistical method to ascertain how these factors may affect the measurement and colour the perception or interpretation of symptom criteria. Such effects (non-invariance) can be operationalised in the form of altered association of a symptom criterion with the measured trait (expressed via variations in CFA loadings which represent the weight of each symptom criterion) due to the factor(s) and/or artificially alter the probability of endorsement of a particular symptom criterion (expressed via variations in the CFA threshold(s) representing how mild or severe a given symptom is). Based on a pre-registered protocol (CRD42022276105), we searched PubMed, Global Health, Embase and PsycInfo up to 21-02-23 for studies that included MI assessments on specific ADHD symptom criteria in individuals aged 0-18 years old, using parental and/or teacher report. Self-reports were excluded, given the poor reliability of self-report in ADHD. All included studies met specific COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria. Results were synthesised in tabular form, grouping results by factors (e.g. informant) from 44 studies retained. Most comparisons indicated both metric (same loadings) and scalar invariance (same thresholds) with regard to informant, gender, age, temporal (repeated assessments) and co-morbidity. Therefore, the available evidence supports the current diagnostic criteria. However, findings could have been improved by systematic reporting of the direction of bias and its effect size. There appears to be a bias towards reporting MI instead of non-invariance. More studies in the literature are needed where the amalgamation of information provided by different informs and the association of specific symptoms with comorbidity are analysed.

Around 5% of the children and teenagers worldwide are affected by Attention-Deficit/Hyperactivity Disorder [ADHD], making it a major public health concern. Recently, demand for assessments has substantially increased, putting strain on healthcare and waiting lists. There is concern that pressure to clear service bottlenecks is leading to variable quality and reliability of ADHD assessments in this population. The ADHD Assessment Quality Assurance Standard for Children and Teenagers [CAAQAS] aims to address this by proposing a quality framework for ADHD assessments in this population. CAAQAS is intended to complement formal training, provide support to clinicians, inform commissioners, and empower children, teenagers, and caregivers on what to expect from an assessment and assessment report. Our goal is to promote evidence-based high-quality assessments, improve diagnostic accuracy, and reduce the risks of overdiagnosis, misdiagnosis, and underdiagnosis. Seven key topics were identified by authors which guided the development of this expert consensus statement. It was agreed that a high-quality diagnostic assessment of ADHD in this population commences with advance preparation to facilitate engagement of the child or teenager and caregivers. The consensus agreed that the minimum/essential standards for assessing and diagnosing ADHD adopt a systematic approach from pre-assessment through assessment to post-diagnostic stage, enabling ADHD to be disentangled from differential diagnoses. The process applies multi-source information to inform an assessment of development history and early risk factors, history of physical, mental health and other neurodevelopmental conditions, family, educational, and social histories. Assessment of core ADHD symptoms should include specific developmentally appropriate examples of associated difficulties and impairments. Neuropsychiatric and physical comorbidities should be assessed and identified. Recommendations for report writing are intended to facilitate effective communication between ADHD specialists and other services, and we highlight the importance of linking the diagnosis to an appropriate post-diagnostic discussion. Further, we discuss core competencies required to conduct a diagnostic assessment of ADHD in children and teenagers.

Prior studies reported mixed effects of the COVID-19 pandemic on the mental health of children and adolescents with ADHD, but they were mainly cross-sectional and without controls. To clarify the impact, we searched Web of Science, EMBASE, Medline, and PsychINFO until 18/11/2023 and conducted a systematic review of controlled longitudinal cohort studies (Prospero: CRD42022308166). The Newcastle-Ottawa scale was used to assess quality. We identified 6 studies. Worsening of mental health symptoms was more evident in ADHD or control group according to symptom considered and context. However, those with ADHD had more persistent elevated symptoms and remained an at-risk population. Sleep problems deteriorated more significantly in those with ADHD. Lower pre-COVID emotion regulation skills and greater rumination were associated with worse mental health outcomes, and longer screen time with poorer sleep. Quality was rated as low in most studies, mainly due to self-report outcome measures and no information on attrition rates. Despite these limitations, results suggest a predominantly negative impact on youths with ADHD and may guide clinical practice and policy.

Schizophrenia substantially contributes to the burden of mental disorders. Schizophrenia's burden and epidemiological estimates in some countries have been published, but updated estimates of prevalence, incidence, and schizophrenia-related disability at the global level are lacking. Here, we present the data from and critically discuss the Global Burden of Diseases, Injuries, and Risk Factors Study data, focusing on temporal changes in schizophrenia's prevalence, incidence, and disability-adjusted life years (DALYs) globally. From 1990 to 2019, schizophrenia raw prevalence (14.2 to 23.6 million), incidence (941,000 to 1.3 million), and DALYs (9.1 to 15.1 million) increased by over 65%, 37%, and 65% respectively, while age-standardized estimates remained stable globally. In countries with high socio-demographic index (SDI), both prevalence and DALYs increased, while in those with low SDI, the age-standardized incidence decreased and DALYs remained stable. The male/female ratio of burden of schizophrenia has remained stable in the overall population over the past 30 years (i.e., M/F = 1.1), yet decreasing from younger to older age groups (raw prevalence in females higher than males after age 65, with males having earlier age of onset, and females longer life expectancy). Results of this work suggest that schizophrenia's raw prevalence, incidence, and burden have been increasing since 1990. Age-adjusted estimates did not reduce. Schizophrenia detection in low SDI countries is suboptimal, and its prevention/treatment in high SDI countries should be improved, considering its increasing prevalence. Schizophrenia sex ratio inverts throughout the lifespan, suggesting different age of onset and survival by sex. However, prevalence and burden estimates for schizophrenia are probably underestimated. GBD does not account for mortality from schizophrenia (and other mental disorders, apart from anorexia nervosa).

BACKGROUND:Intimate partner violence (IPV) and sexual violence (SV) are significant problems world-wide, and they affect women disproportionally. Whether individuals with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of being involved in these types of violence is unclear. METHODS:We carried out a systematic review and meta-analysis (PROSPERO registration CRD42022348165) of the associations between ADHD and being the victim or perpetrator of IPV and SV. Ratios of occurrence of violence were pooled in random-effects models and study risk of bias was evaluated using the Newcastle-Ottawa Scale. RESULTS:A search on multiple databases, carried out on 7 October 2022, yielded 14 eligible studies (1 111 557 individuals). Analyses showed a higher risk of ADHD individuals being involved in IPV as perpetrators (six studies, OR 2.5, 95% CI 1.51-4.15) or victims (four studies, OR 1.78, 95% CI 1.06-3.0). Likewise, individuals with ADHD were at increased risk of being perpetrators (three studies, OR 2.73, 95% CI 1.35-5.51) or victims of SV (six studies, OR 1.84, 95% CI 1.51-2.24). Results were overall robust to different analytical choices. CONCLUSIONS:Individuals with ADHD are at an increased risk of being involved in cases of violence, namely IPV and SV, either as victims or perpetrators. Although the causal path or mediating variables for these results are still unclear, this increased risk should inform evidence-based psychoeducation with individuals with ADHD, their families, and partners about romantic relationships and sexuality.