Faculty Bibliography
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Pharmacological and non-pharmacological interventions for adults with ADHD: protocol for a systematic review and network meta-analysis
INTRODUCTION/BACKGROUND:It is unclear how pharmacological and non-pharmacological interventions compare with each other in terms of efficacy and tolerability for core symptoms and additional problems in adults with attention-deficit/hyperactivity disorder (ADHD). We aim to conduct the first network meta-analysis (NMA) comparing pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD. METHODS AND ANALYSIS/METHODS:We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMAs. We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished randomised controlled trials (RCTs) (parallel or cross-over) of medications (either licensed or unlicensed) and any non-pharmacological intervention in adults (≥18 years) with ADHD. Primary outcomes will be: (1) change in severity of ADHD core symptoms, and (2) acceptability (all-cause discontinuation). Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS. Pooled estimates of NMA will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool (which includes assessment of publication bias). We will conduct a series of sensitivity analyses to assess the robustness of the findings. ETHICS AND DISSEMINATION/BACKGROUND:As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-reviewed journals. PROSPERO REGISTRATION NUMBER/UNASSIGNED:CRD42021265576.
PMCID:8919448
PMID: 35277411
ISSN: 2044-6055
CID: 5183672
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.
PMID: 35027679
ISSN: 1476-5578
CID: 5119072
Association between autism spectrum disorder and diabetes: systematic review and meta-analysis
There is mixed evidence on the link between autism spectrum disorder (ASD) and diabetes. We conducted the first systematic review/meta-analysis on their association. Based on a pre-registered protocol (PROSPERO: CRD42021261114), we searched Pubmed, Ovid, and Web of Science databases up to 6 December 2021, with no language/type of document restrictions. We assessed study quality using the Newcastle-Ottawa Scale (NOS). We included 24 studies (total: 3,427,773 individuals; 237,529 with ASD and 92,832 with diabetes) in the systematic review and 20 in the meta-analysis (mean stars number on the NOS: 5.89/10). There was a significant association, albeit characterized by significant heterogeneity, when pooling unadjusted OR (1.535, 95%CI = 1.109-2.126), which remained significant when restricting the analysis to children and type 2 diabetes, but became non-significant when considering adjusted ORs (OR: 1.528, 95%CI = 0.954-2.448). No significant prospective association was found (n=2) on diabetes predicting ASD (HR: 1.232, 0.826-11.837). Therefore, the association between ASD and diabetes is likely confounded by demographic and clinical factors that should be systematically investigated in future studies.
PMID: 35217107
ISSN: 1873-7528
CID: 5172562
The collaborative outcomes study on health and functioning during infection times in adults (COH-FIT-Adults): Design and methods of an international online survey targeting physical and mental health effects of the COVID-19 pandemic
BACKGROUND:. High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed. METHODS:. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others. RESULTS:. Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive. LIMITATIONS:. Cross-sectional survey, preponderance of non-representative participants. CONCLUSIONS:. Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics.
PMCID:8288233
PMID: 34949568
ISSN: 1573-2517
CID: 5185182
Journal of the American Academy of Child & Adolescent Psychiatry. 2022:61(2):128-130.DOI: 10.1016/j.jaac.2021.07.004
Editorial: Second-Generation Antipsychotics for Bipolar Depression in Youth: The Best Evidence Synthesis is a Strong Call for Further Evidence [Editorial]
PMID: 34273494
ISSN: 1527-5418
CID: 4947702
Medical conditions and Attention-Deficit/Hyperactivity Disorder symptoms from early childhood to adolescence
The comorbidity between physical and mental health conditions is challenging and frequently goes unrecognized in practice. Associations between Attention-Deficit/Hyperactivity Disorder (ADHD) and physical conditions have been reported in youth. However, prior research failed to: (1) address the patterns of associations in early childhood, middle childhood, and adolescence within the same population sample; (2) consider a large set of physical disorders at the same time; (3) take confounders into account. Our goal was to assess the associations between ADHD symptoms and a broad set of physical conditions across developmental periods. This birth cohort study (n = 2057) is the first to explore the associations between ADHD and a wide range of medical conditions by encompassing the whole early development from 5 months to 17 years in the same sample and relying on innovative network analyses. We found significant associations between ADHD symptoms and several physical conditions, some of which were observed in early childhood, middle childhood, and adolescence (e.g., asthma, sleep problems) or were confounded by socioeconomic status or psychiatric comorbidities (e.g., body mass index, dental caries). The study calls for an effective integrated care model encompassing mental and general healthcare across the developmental period.
PMID: 34703026
ISSN: 1476-5578
CID: 5042402
Structural gray matter differences in Problematic Usage of the Internet: a systematic review and meta-analysis
Problematic Usage of the Internet (PUI) has been linked to diverse structural gray matter changes in individual data studies. However, no quantitative synthesis across studies has been conducted. We aimed to identify gray matter regions showing significant spatial convergence across neuroimaging studies in PUI. We searched PubMed and PsycINFO up to 10/03/2021 and included original, cross-sectional comparative studies that examined structural gray matter imaging in PUI versus control groups; reported a whole-brain analysis; and provided peak coordinates for gray matter differences. From a total of 624 potentially relevant studies, 15 (including 355 individuals with PUI and 363 controls) were included in a meta-analysis of voxel-based morphometry studies. Anatomical likelihood estimation (ALE) meta-analysis was performed using extracted coordinates and identified significant spatial convergence in the medial/superior frontal gyri, the left anterior cingulate cortex/cingulate gyrus, and the left middle frontal/precentral gyri. Datasets contributing to these findings all indicated reduced gray matter in cases compared to controls. In conclusion, voxel-based morphometric studies indicate replicable gray matter reductions in the dorsolateral prefrontal cortex and anterior cingulate cortex in PUI, regions implicated in reward processing and top-down inhibitory control. Further studies are required to understand the nature of gray matter differences across PUI behaviors, as well as the contribution of particular mental health disorders, and the influence of variation in study and sample characteristics.
PMID: 34642454
ISSN: 1476-5578
CID: 5067972
Association between autism spectrum disorder and inflammatory bowel disease: A systematic review and meta-analysis
Children with autism spectrum disorder (ASD) are frequently diagnosed with co-occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random-effects meta-analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta-regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle-Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25-2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41-2.6, p < 0.001; Crohn's disease, OR = 1.47, 95%CI = 1.15-1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28-1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36-2.12, p < 0.001; Crohn's disease, OR = 1.37, 95%CI = 1.12-1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta-regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD.
PMID: 34939353
ISSN: 1939-3806
CID: 5100012
ssDefault mode network connectivity and attention-deficit/hyperactivity disorder in adolescence: Associations with delay aversion and temporal discounting, but not mind wandering
BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) has been associated with reduced resting state connectivity in the core subsystem of the default mode network (DMN; medial prefrontal cortex - posterior cingulate cortex). However, the neuropsychological consequences of this hypoconnectivity remain to be determined. Building on recent theoretical models of DMN function, we tested the association between DMN hypo-connectivity and three neuropsychological processes previously implicated in ADHD: (i) excessive task-unrelated spontaneous thought (i.e., mind-wandering); (ii) sub-optimal decision-making due to exaggerated temporal discounting; and (iii) delay aversion - a heightened emotional response to the imposition or experience of delay. METHODS:Twenty male adolescents with a clinical diagnosis of ADHD and 18 typically developing adolescents (all aged 11-16 years) underwent a resting-state fMRI scan to assess DMN connectivity. An experimental paradigm was used to assess temporal discounting and self-report questionnaires were used to measure mind wandering and delay aversion. RESULTS:ADHD was significantly associated with DMN hypo-connectivity specifically in the core subsystem, elevated levels of mind-wandering, delay aversion, and temporal discounting. Mediation analysis suggested that DMN hypoconnectivity mediated the link between ADHD and delay aversion. CONCLUSION/CONCLUSIONS:The results provide initial evidence that disturbances in the DMN may impair ability to regulate delay-related negative affect in adolescents with ADHD.
PMID: 35032471
ISSN: 1872-7697
CID: 5119212
The feasibility of a strategy for the remote recruitment, consenting and assessment of recent referrals: a protocol for phase 1 of the On-Line Parent Training for the Initial Management of ADHD referrals (OPTIMA)
BACKGROUND:In the UK, children with high levels of hyperactivity, impulsivity and inattention referred to clinical services with possible attention-deficit/hyperactivity disorder (ADHD) often wait a long time for specialist diagnostic assessment. Parent training (PT) has the potential to support parents during this difficult period, especially regarding the management of challenging and disruptive behaviours that often accompany ADHD. However, traditional face-to-face PT is costly and difficult to organise in a timely way. We have created a low-cost, easily accessible PT programme delivered via a phone app, Structured E-Parenting Support (STEPS), to address this problem. The overall OPTIMA programme will evaluate the efficacy and cost-effectiveness of STEPS as a way of helping parents manage their children behaviour while on the waitlist. To ensure the timely and efficient evaluation of STEPS in OPTIMA, we have worked with children's health services to implement a remote strategy for recruitment, screening and assessment of recently referred families. Part of this strategy is incorporated into routine clinical practice and part is OPTIMA specific. Here, we present the protocol for Phase 1 of OPTIMA-a study of the feasibility of this remote strategy, as a basis for a large-scale STEPS randomised controlled trial (RCT). METHODS:This is a single arm observational feasibility study. Participants will be parents of up to 100 children aged 5-11 years with high levels of hyperactivity/impulsivity, inattention and challenging behaviour who are waiting for assessment in one of five UK child and adolescent mental health or behavioural services. Recruitment, consenting and data collection will occur remotely. The primary outcome will be the rate at which the families, who meet inclusion criteria, agree in principle to take part in a full STEPS RCT. Secondary outcomes include acceptability of remote consenting and online data collection procedures; the feasibility of collecting teacher data remotely within the required timeframe, and technical difficulties with completing online questionnaires. All parents in the study will receive access to STEPS. DISCUSSION/CONCLUSIONS:Establishing the feasibility of our remote recruitment, consenting and assessment strategy is a pre-requisite for the full trial of OPTIMA. It can also provide a model for future trials conducted remotely.
PMCID:8720938
PMID: 34980279
ISSN: 2055-5784
CID: 5106902
