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Group-based talking therapies shown to be most effective treatment for young people with anxiety disorders.
The lifetime accumulation of multimorbidity and its influence on dementia risk: a UK Biobank study.
The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients, making multimorbidity an important risk factor for dementia. However, we lack an understanding of the specific health conditions, and their age of onset, that drive the link between multimorbidity and dementia. Using data from 282 712 participants of the UK Biobank, we defined the sequential patterns of accumulation of 46 chronic conditions over the life course. By grouping individuals based on their life history of chronic illness, we show here that the risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity throughout the lifespan (cardiometabolic, mental health, neurovascular, peripheral vascular, eye diseases and low/no multimorbidity). We observed that the odds of developing dementia varied based on when these comorbidities were diagnosed. Until midlife (age 55), the accumulation of cardiometabolic conditions, such as coronary heart disease, atrial fibrillation, and diabetes, was most strongly associated with dementia risk. However, from 55 to 70 years, the accumulation of mental health conditions, such as anxiety and depression, as well as neurovascular conditions, such as stroke and transient ischaemic attack, was associated with an over 2-fold increase in dementia risk compared with low multimorbidity. Importantly, individuals who continuously and sequentially accumulate cardiometabolic, mental health, and neurovascular conditions were at greatest risk. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high- and low-risk groups and could inform targeted prevention strategies based on a person's prior history of chronic disease.
Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial.
BACKGROUND: Lithium and several atypical antipsychotics are the recommended first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. Consequently, there is little evidence-based guidance for clinicians when choosing an augmentation option for patients with treatment-resistant depression. OBJECTIVES: This trial examined whether it is more clinically and cost-effective to prescribe lithium or quetiapine augmentation therapy for patients with treatment-resistant depression over 12 months. DESIGN: This was a parallel group, multicentre, pragmatic, open-label superiority trial comparing the clinical and cost-effectiveness of lithium versus quetiapine augmentation of antidepressant medication in treatment-resistant depression. Participants were randomised 1 : 1 at baseline to the decision to prescribe either lithium or quetiapine. SETTING: Six National Health Service trusts in England. PARTICIPANTS: Eligible participants were aged ≥ 18 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for major depressive disorder, scored ≥ 14 on the 17-item Hamilton Depression Rating Scale and whose depression had had an inadequate response to at least two therapeutic antidepressant treatment trials in the current episode, with a current antidepressant treatment at or above the therapeutic dose for ≥ 6 weeks. Patients with a history of psychosis or bipolar disorder were excluded. Patients were judged suitable for either treatment. INTERVENTIONS: After randomisation, pre-prescribing safety checks were undertaken as per standard care and trial clinicians decided whether to proceed with prescribing the allocated medication. Trial clinicians received recommendations for titration and dosing in line with current clinical guidelines; however, dosing regimens could be altered according to tolerability and response. Participants were followed up using weekly self-report questionnaires and 8-, 26- and 52-week research visits. MAIN OUTCOME MEASURES: The co-primary outcome measures were depressive symptom severity over 52 weeks, measured weekly using the self-rated Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation of the trial medication. Economic analyses compared costs between the two treatment arms over 52 weeks, from a National Health Service and Personal Social Services perspective, and a societal perspective. RESULTS: Two hundred and twelve participants were randomised, 107 to quetiapine and 105 to lithium. The quetiapine arm showed a significantly greater reduction in depressive symptoms than the lithium arm over 52 weeks (quetiapine vs. lithium area under the differences curve = -68.36, 95% confidence interval: -129.95 to -6.76, p = 0.0296). Median days to discontinuation did not significantly differ between the two arms (quetiapine = 365.0, interquartile range = 57.0-365.0, lithium = 212.0, interquartile range = 21.0-365.0), p = 0.1196. Quetiapine was more cost effective than lithium. Thirty-two serious adverse events were recorded, only one of which was deemed possibly related to the intervention (lithium). LIMITATIONS: The trial was unblinded, therefore expectancies regarding the trial medications may have influenced the results. Further, there was substantial missing data for some of the secondary outcome measures. CONCLUSIONS: As well as being more cost-effective, quetiapine may be a more clinically effective augmentation option for treatment-resistant depression. FUTURE WORK: Examining predictors of treatment response, including clinical, sociodemographic and biological factors, will help establish whether there are additional factors to consider when choosing an augmentation treatment for treatment-resistant depression. TRIAL REGISTRATION: This trial is registered as ISRCTN16387615. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/222/02) and is published in full in Health Technology Assessment; Vol. 29, No. 12. See the NIHR Funding and Awards website for further award information.
Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis.
IMPORTANCE: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. OBJECTIVE: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. DATA SOURCES: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. STUDY SELECTION: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. DATA EXTRACTION AND SYNTHESIS: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. MAIN OUTCOMES AND MEASURES: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. RESULTS: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.
Yawning as Therapy? The Potential of the Conditioned Yawn Reflex as a Novel Treatment for Insomnia Disorder.
In 1986, Provine, the pioneer of yawning research wrote that 'Yawning may have the dubious distinction of being the least understood, common human behaviour' (p. 120); and so yawning remains some 40 years later, as something of a biological and social curiosity. However, this article examines contemporary scientific understanding of this age-old conundrum, proposing not only that yawning is a universal component of sleep's normal stimulus control paradigm, but that the conditioned yawn reflex might be harnessed to treat insomnia disorder. The core features of yawning as a ubiquitous, involuntary, periodic and conditionable behaviour; its associated actions on arousal, biofeedback and selective attention, as well as thermoregulation and airway patency; and its potential to signal and promote sleep engagement, lead to the proposition that the conditioned yawn reflex as therapy (CYRaT) is a feasible and potentially effective novel therapeutic for sleep-onset and sleep-maintenance insomnia disorder. Much research is required to test this hypothesis, but the article describes preliminary protocols for the administration and testing of CYRaT that might be utilised for this purpose.
Negative bias in encoding and recall memory in depressed patients with inadequate response to antidepressant medication.
RATIONALE: Cognitive theories propose that negative biases in emotional processing contribute to the maintenance of depressive states. Previous studies reported that acute antidepressant treatment in depressed patients reversed negative emotional biases. However, studies addressing the differences in emotional processing between healthy volunteers and clinically depressed patients with inadequate response to standard antidepressant treatments are limited. OBJECTIVES: To investigate the differences in emotional processing domains between depressed patients with inadequate response to current antidepressant treatment and healthy controls. METHODS: Fifty-four medicated patients with major depression and 45 age- and sex-equated healthy volunteers were tested using the Oxford Emotional Testing Battery. RESULTS: There was no difference between the two groups in the accuracy of recognising emotional facial expressions. However, there was a significant difference in the pattern of response times in an emotional categorisation task (F1,97 = 6.44, p = 0.013, partial η2 = 0.017) where healthy controls had faster responses towards positive than negative self-referent words (95%CI: -0.291 - -0.054, p = 0.005). In contrast, patients had no significant differences in reaction time for categorizing positive and negative self-referent descriptors. There was also a significant group interaction in an emotional memory task (F1,91 = 7.90, p = 0.006, partial η2 = 0.080) where healthy volunteers recalled significantly more positively valenced words than depressed patients (95%CI: -2.104 - -0.168, p = 0.022). CONCLUSIONS: Depressed patients with inadequate responses toward antidepressants had negative biases in emotional categorisation and emotional memory. These psychological abnormalities may represent targets for treatment in patients with difficult-to-treat depression.
Cost-effectiveness of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression: Economic evaluation of the PAX-BD randomised controlled trial.
BACKGROUND: People with bipolar disorders (BD) frequently experience depressive symptoms that do not respond to available treatment options. The resulting burden for people with BD and society is substantial. This study sought to explore the cost-effectiveness of pramipexole in combination with mood stabilisers for people with treatment-resistant bipolar disorder (TRBD). METHODS: We calculated mean incremental cost ratios (ICER) of pramipexole compared to placebo over 12 and 48 weeks from health and social care (NHS + PSS) and societal perspectives for 36 participants with TRBD. Quality-adjusted life years (QALY) were captured with the EQ-5D-5L as the primary outcome measure. We used capability well-being measures (ICECAP-A, OxCAP-MH) to assess the robustness of the results and multiple imputation and bootstrapping to address missing data and small sample size. RESULTS: We found that pramipexole is more effective and cost-saving from the NHS + PSS perspective. The probability of being cost-effective at £30,000/QALY gained was 70 % (12 weeks) and 90 % (48 weeks). From the societal perspective, pramipexole was more effective but also more expensive with lower probability of cost-effectiveness (33 % at 12 weeks and 47 % at 48 weeks). Uncertainty around the mean ICERs was substantial due to the small sample size. LIMITATIONS: The PAX-BD trial was conducted during the COVID-19 pandemic and terminated early, resulting in a limited generalizability of resource use outside the pandemic context and a small sample size. CONCLUSIONS: Pramipexole is a cost-effective treatment option for TRBD from the NHS + PSS perspective, with statistically significant increases in health-related quality of life and capability well-being over extended periods.
Sleep disruption and its psychological treatment in young people at risk of psychosis: A peer methods qualitative evaluation.
OBJECTIVES: A recent randomized controlled feasibility trial showed that sleep problems in young people at risk of psychosis can be successfully treated with psychological therapy and that this may bring additional benefits such as reducing depression, anxiety and paranoia. Here we report participants' qualitative experience of sleep problems and therapy. DESIGN: A peer-methods qualitative study employing reflexive thematic analysis. METHODS: Semi-structured interviews, co-facilitated by peer researchers, were conducted with 16 young patients at risk of psychosis and having sleep problems who participated in the SleepWell Trial (ISRCTN85601537). Ten interviewees had received the 12-week sleep therapy. RESULTS: Four themes were generated: (1) the challenge to access mental health treatment ('bouncing between services'), (2) sleep problems and mental health difficulties are intertwined ('an obvious link'), (3) flexibility in therapy provision matters ('tailored to me as a person') and (4) improving sleep leads to wider benefits ('fixing the sleep helped everything else'). Participants described a frustrating journey to access mental health treatment, marked by rejection and invalidation, which resulted in hopelessness and often resignation. The interaction between sleep disruption and other mental health difficulties was seen as obvious. Treatment for sleep problems was highly valued. The clear focus, therapeutic style and flexible delivery of the treatment was seen to create patient ownership, active engagement and hope. Participants described transformative changes: better sleep, fewer voices and fears and improved mood and confidence. Improving sleep made a difference to everyday life. CONCLUSIONS: Treating sleep problems in people at risk of psychosis is highly valued and often brings rapid and widespread improvements across a range of domains.
Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study.
Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms - fatigue, post-exertional malaise and cognitive dysfunction - are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism. 24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups. The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and 'brain fog', and earlier animal studies showing that choline might prevent intravascular coagulation. Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.
Transdiagnostic early warning score for psychiatric hospitalisation: development and evaluation of a prediction model.
BACKGROUND: The lack of an early warning score for psychiatric hospitalisation means that the decision to initiate preventative interventions is based solely on clinical judgement, which is prone to bias. OBJECTIVE: The objective is to develop and externally validate a transdiagnostic score that predicts psychiatric hospitalisation. METHODS: In this retrospective cohort study using deidentified electronic health records from 20 healthcare organisations in the NeuroBlu Data, we identified all patients with any of seven major psychiatric disorders with at least five Clinical Global Impressions of Severity and five Global Assessment of Functioning measured over a period of 6 consecutive months before any hospitalisation. From these measurements, metrics of clinical severity and instability and functional severity and instability were derived and incorporated into a score predicting the 6-month risk of incident psychiatric hospitalisation. Discrimination and calibration of this score were validated in an external sample. The transdiagnostic validity of the score was evaluated and its performance was compared between white and non-white people. FINDINGS: Altogether, 37 049 individuals (531 incident hospitalisations) were included. The predictive model showed good discrimination in the training (optimism-adjusted c-index: 0.74, 95% CI 0.72 to 0.76) and external validation (c-index: 0.80, 95% CI 0.78 to 0.82) samples, with adequate calibration. Discrimination improved with adjustment for organisation-level hospitalisation rates (c-index: 0.80, 95% CI 0.78 to 0.82 and 0.84, 95% CI 0.82 to 0.86 in the derivation and validation samples). Good discrimination was also achieved for each diagnostic category (c-index: 0.71-0.82 and 0.64-0.75 with/without adjustment for organisation-level hospitalisation rates, respectively). There was no significant difference in model performance between white and non-white people. DISCUSSION: A transdiagnostic early warning system based on simple longitudinal measurements can reliably and robustly predict psychiatric hospitalisation. It will help target preventative interventions to individuals most at risk.
Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel.
Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.
Automated quality control of T1-weighted brain MRI scans for clinical research: methods comparison and design of a quality prediction classifier
T1-weighted (T1w) MRI is widely used in clinical neuroimaging for studying brain structure and its changes, including those related to neurodegenerative diseases, and as anatomical reference for analysing other modalities. Ensuring high-quality T1w scans is vital as image quality affects reliability of outcome measures. However, visual inspection can be subjective and time-consuming, especially with large datasets. The effectiveness of automated quality control (QC) tools for clinical cohorts remains uncertain. In this study, we used T1w scans from elderly participants within ageing and clinical populations to test the accuracy of existing QC tools with respect to visual QC and to establish a new quality prediction framework for clinical research use. Four datasets acquired from multiple scanners and sites were used (N = 2438, 11 sites, 39 scanner manufacturer models, 3 field strengths – 1.5T, 3T, 2.9T, patients and controls, average age 71 ± 8 years). All structural T1w scans were processed with two standard automated QC pipelines (MRIQC and CAT12). The agreement of the accept-reject ratings was compared between the automated pipelines and with visual QC. We then designed a quality prediction framework that combines the QC measures from the existing automated tools and is trained on clinical research datasets. We tested the classifier performance using cross-validation on data from all sites together, also examining the performance across diagnostic groups. We then tested the generalisability of our approach when leaving one site out and explored how well our approach generalises to data from a different scanner manufacturer and/or field strength from those used for training, as well as on an unseen new dataset of healthy young participants with movement related artefacts. Our results show significant agreement between automated QC tools and visual QC (Kappa=0.30 with MRIQC predictions; Kappa=0.28 with CAT12’s rating) when considering the entire dataset, but the agreement was highly variable across datasets. Our proposed robust undersampling boost (RUS) classifier achieved 87.7% balanced accuracy on the test data combined from different sites (with 86.6% and 88.3% balanced accuracy on scans from patients and controls respectively). This classifier was also found to be generalisable on different combinations of training and test datasets (average balanced accuracy of leave-one-site-out = 78.2%; exploratory models on field strengths and manufacturers = 77.7%; movement related artefact dataset when including 1% scans in the training = 88.5%). While existing QC tools may not be robustly applicable to datasets comprised of older adults, they produce quality metrics that can be leveraged to train a more robust quality control classifiers for ageing and clinical cohorts.
Call up the (cognitive) reserves: how adult socialisation and education influences cognition in the UK Biobank.
INTRODUCTION: Dementia involves the loss of memory and degradation of cognitive function. Crucially, the onset of dementia may be prevented by identifying and modifying relevant risk factors years before disease onset in midlife. Commonly described modifiable risk factors include social isolation and educational attainment. Here, we aim to understand the relationships between adult activities and their effects on cognition related to mid-life aging in terms of where and how people live. METHODS: We analysed data from the UK Biobank (N = 502,165, Mage = 56.53, SDage = 8.09, 54.40% female). In particular, our path analysis investigated the associations between years of education in childhood, education later in life, social activities in adulthood, built environment (i.e., coastal distance and percentage of greenspace), socioeconomic status (i.e., Townsend deprivation index), and cognitive functions (i.e., memory, executive function, and abstract reasoning). RESULTS: Adult education and social activities predict better cognition. Being deprived predicts attendance in adult education classes, but fewer social activities and poorer cognition. Moreover, living in areas with less greenspace and being further away from coastlines predict attendance in adult education classes; however, only greenspace predicts participation in social activities. Finally, less greenspace and further coastal distance support abstract reasoning, whereas further coastal distance predicts poorer executive function. CONCLUSION: We demonstrate the potential utility of adult education and social activities which may offset the detrimental effects of deprivation. Accordingly, we argue for improved access to adult social programs in deprived/underserviced areas in the United Kingdom.
Engagement and attrition in digital mental health: current challenges and potential solutions.
In digital mental health engagement rates are consistently low, which may limit its effects. Using an international multidisciplinary consensus method, including lived experience expertise and a systematic review, we identified three key challenges: (i) lack of agreed metrics for engagement; (ii) lack of evidence on how better engagement improves outcomes; (iii) lack of standards for user involvement. Three potential solutions encompassed: (i) standardisation of frameworks for reporting engagement metrics and optimal doses of digital tools, (ii) measuring engagement with more precise reporting of outcomes, including potential harms; (iii) defining standards of user involvement (including appropriate diversity, and clinician as well as user input). Digital interventions have real potential in meeting the shortfall in service provision for mental health, but this will require focus on high quality research studies of the underlying mechanisms of engagement and optimal outcomes. Our findings identify and highlight the next best steps in this process.
Economic evaluation of caregiver interventions for children with developmental disabilities: A scoping review.
Globally, families with children with developmental disabilities (DDs) experience challenges, including social isolation, stigma, and poverty, especially in low-income settings in Africa. Most children with DDs in Africa remain unidentified and receive no formal support. Caregiver interventions focusing on education and training for the carers/parents have been shown to be adaptable and low intensity in implementation, although the economic evidence is limited. This review aimed to describe the evidence and methodological aspects of economic evaluations for caregiver interventions for DDs. The Arksey and O'Malley framework was applied. Seven electronic databases, grey literature and cited references were systematically searched to identify eligible studies. published from 1993 to 2023. We assessed the quality of the included studies using the Drummond checklist. Data were systematically extracted, tabulated, and qualitatively synthesised using inductive thematic analysis. From 7811 articles, twenty studies all in high-income countries were included, and focused on caregiver interventions for autism spectrum disorder (n = 7), attention deficit hyperactivity disorder (ADHD) (n = 6), disruptive behaviour and behaviour problems with ADHD (n = 5), intellectual disabilities (n = 1) and language delay (n = 1). Economic evaluation analyses included cost effectiveness (n = 11), costing (n = 3), cost utility (n = 2), cost consequence (n = 1) cost benefit (n = 1), and combined analyses (n = 2). Nine studies reported the interventions as cost effective and five studies reported the intervention to be cost saving. The main methodological challenges were related to costing, outcome measurement in children and the appropriate time horizon for modelling. Caregiver interventions demonstrate cost-effectiveness, with the available evidence supporting the adoption of the interventions as a promising avenue to strengthen access and reduce the associated healthcare costs. The identified key methodological challenges highlighted further research areas. Prioritizing more economic evaluation studies in this area would inform decision-making on efficient resource allocation, promote inclusivity and equitable access to services for children with DDs.