Faculty Bibliography

The coexistence of mental and physical health illnesses could be accounted for by an underlying general disease factor (termed d-factor), reflecting theoretical underpinnings based on possible genetic and pathophysiological overlapping mechanisms. This study evaluated whether the d-factor underlies mental and physical health illnesses in adolescents. A series of confirmatory factor analyses were conducted using data from 1120 adolescents. The proposed common underlying factor, we believe is the d-factor, was consistently present across different modeling approaches, including unidimensional, correlated-factor, and bifactor models. The best model fit was achieved with the bifactor model represented by mental, neurological, and psychical conditions tested. The first compelling evidence was provided supporting the existence of the transdiagnostic d-factor in youth, opening the door to innovative research of comorbid mental and physical health conditions.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24-2.12) or depression (1.65 [1.34-2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19-1.90]); and (3) major congenital malformation (1.24 [1.09-1.40]) or cardiac malformations (1.28 [1.11-1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.

Systematic reviews and meta-analyses have become crucial for evidence-based decision-making in recent decades. However, it is common for the results of multiple reviews on the same topic to be inconsistent, and it is widely recognised that the results of the reviews are not always effectively communicated to healthcare professionals and the lay public. This manuscript proposes a strategy to summarise and communicate the findings of previous systematic reviews and meta-analyses to wider audiences. The proposed approach couples the findings of umbrella reviews with the creation of open-access online platforms that present the results of these umbrella reviews in an accessible way to various stakeholders. The key potential methodological avenues of this approach are presented, and specific examples from the author's own works and those from other teams are provided. An accompanying website (https://u-reach.org/) has been designed to present this Umbrella-Review, Evaluation, Analysis, and Communication Hub (U-REACH) approach and to overcome the technical challenges associated with this type of project (by sharing the code used to build existing U-REACH projects). The present document is intended to serve as a methodological and technical guide for the creation of large-scale projects designed to synthesise and disseminate scientific information to a broad audience.

BACKGROUND:Clinical guidelines remain unclear on which medications for gambling disorder are to be preferred in terms of efficacy and tolerability. We aimed to compare pharmacological treatments for gambling disorder in terms of efficacy and tolerability, using network meta-analysis (NMA). METHODS:Based on our pre-registered protocol [CRD42022329520], a structured search was conducted across broad range of databases, for double-blind randomized controlled trials (RCTs) of medications for gambling disorder. Data were independently extracted by two researchers. We used standardized mean differences (SMD) using Hedges' g to measure the efficacy outcomes, and for the effect for tolerability we used dropout rate due to medication side effects, expressed as odds ratio (OR). Confidence in the network estimates was assessed using the CINeMA framework. We followed the PRISMA-NMA guidelines for this work. Outcomes were gambling symptom severity and quality of life (for efficacy), and tolerability. FINDINGS/RESULTS:We included 22 RCTs in the systematic review and 16 RCTs (n = 977 participants) in the NMA. Compared with placebo, moderate confidence evidence indicated that nalmefene [Standardized Mean Difference (SMD): -0.86; 95 % confidence interval (CI: -1.32,-0.41)] reduced gambling severity, followed by naltrexone (SMD: -0.42; 95 %CI: (-0.85,0.01)). Naltrexone (SMD: -0.50; 95 %CI: (-0.85,-0.14)) and nalmefene (SMD: -0.36; 95 %CI: (-0.72,-0.01) were also more beneficial than placebo in terms of quality of life. Olanzapine and topiramate were not more efficacious than placebo. Nalmefene [Odds Ratio (OR): 7.55; 95 %CI: (2.24-25.41)] and naltrexone (OR: 7.82; 95 %CI: (1.26-48.70)) had significantly higher dropout due to side effects (lower tolerability) compared with placebo. INTERPRETATION/CONCLUSIONS:Based on NMA, nalmefene and naltrexone currently have the most supportive evidence for the pharmacological treatment of gambling disorder. Further clinical trials of novel compounds, and analysis of individual participant data are needed, to strengthen the evidence base, and help tailor treatments at the individual patient level.

OBJECTIVE:Sleep problems are highly prevalent and impairing in adolescents with ADHD. However, their relation with co-occurring mental health problems is still unclear. This study assessed whether adolescents with ADHD, with and without self-reported sleep problems, differ from each other in co-occurring mental health problems, and whether they differ from adolescents without ADHD. Furthermore, we examined whether the adolescents with ADHD and self-reported sleep problems do indeed have more disturbed sleep than the other two groups and lastly, whether these sleep differences are moderated by co-occurring mental health problems. METHOD/METHODS:Three groups of adolescents (13-17 years): 1) with ADHD and comorbid self-reported sleep problems (N = 56), 2) with ADHD but without self-reported sleep problems (N = 25), and 3) without ADHD (N = 56) were assessed. Group comparisons were done for symptoms of co-occurring mental health problems, self- and parent-reported sleep problems, and objective and subjective sleep parameters. Exploratively, moderating effects of co-occurring mental health problems on sleep differences between groups are examined. RESULTS:Compared to those without self-reported sleep problems, adolescents with ADHD and comorbid self-reported sleep problems experienced significantly more co-occurring symptoms of mental health problems, especially depression. They also scored higher on all sleep problems, and had a longer sleep onset latency and lower sleep efficiency based on subjective and objective sleep measures. Depression and anxiety moderated objectively measured sleep differences. CONCLUSION/CONCLUSIONS:Co-occurring mental health problems, especially depressive symptoms, are more prevalent in adolescents with ADHD and sleep problems and partially moderate the relation with sleep. This indicates that when adolescents with ADHD present with sleep problems in clinical practice, it is essential to also assess symptoms and other mental health problems and vice-versa.

INTRODUCTION/BACKGROUND:ADHD has been linked to an increased risk of completed suicide. The aim of this study was to assess the relationship between ADHD medication use and completed suicide. METHODS:This nested case-control study included individuals aged 12-49 in Quebec, Canada, diagnosed with ADHD and/or dispensed ADHD medication. Suicide cases (n = 472) between 2000 and 2021 were matched with 5 controls each (n = 2360) on date of birth, sex, and continuous public drug insurance coverage for at least 365 days before suicide death (index date). Multivariable conditional logistic regression was used to estimate the association between ADHD medication use and completed suicide. The association between specific ADHD medication types and completed suicide was also assessed. RESULTS:After controlling for potential confounders, no significant association was found between ADHD medication use and completed suicide in the overall sample, in individuals aged 12-24 and 25 to 49 years, and those with a prior ADHD physician diagnosis. No significant differences were found when comparing the use of non-stimulants only (aOR 1.27; 95 % CI: 0.62, 2.63), stimulants and non-stimulants (aOR 1.01; 95 % CI: 0.33, 3.08), and ADHD consultation without medication (aOR 0.94; 95 % CI: 0.69, 1.28) against stimulant-only use. CONCLUSION/CONCLUSIONS:Both stimulants and non-stimulants were not associated with the risk of completed suicide. These findings can inform clinical decision-making.

There have been increasing efforts to develop prediction models supporting personalised detection, prediction, or treatment of ADHD. We overviewed the current status of prediction science in ADHD by: (1) systematically reviewing and appraising available prediction models; (2) quantitatively assessing factors impacting the performance of published models. We did a PRISMA/CHARMS/TRIPOD-compliant systematic review (PROSPERO: CRD42023387502), searching, until 20/12/2023, studies reporting internally and/or externally validated diagnostic/prognostic/treatment-response prediction models in ADHD. Using meta-regressions, we explored the impact of factors affecting the area under the curve (AUC) of the models. We assessed the study risk of bias with the Prediction Model Risk of Bias Assessment Tool (PROBAST). From 7764 identified records, 100 prediction models were included (88% diagnostic, 5% prognostic, and 7% treatment-response). Of these, 96% and 7% were internally and externally validated, respectively. None was implemented in clinical practice. Only 8% of the models were deemed at low risk of bias; 67% were considered at high risk of bias. Clinical, neuroimaging, and cognitive predictors were used in 35%, 31%, and 27% of the studies, respectively. The performance of ADHD prediction models was increased in those models including, compared to those models not including, clinical predictors (β = 6.54, p = 0.007). Type of validation, age range, type of model, number of predictors, study quality, and other type of predictors did not alter the AUC. Several prediction models have been developed to support the diagnosis of ADHD. However, efforts to predict outcomes or treatment response have been limited, and none of the available models is ready for implementation into clinical practice. The use of clinical predictors, which may be combined with other type of predictors, seems to improve the performance of the models. A new generation of research should address these gaps by conducting high quality, replicable, and externally validated models, followed by implementation research.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Professor Alessandro Zuddas, from the University of Cagliari (Italy), passed away prematurely in July 2022. As a prominent figure in child and adolescent neuropsychiatry, he substantially influenced the fields of neurodevelopmental disorders and neuropsychopharmacology both nationally and internationally. Professor Zuddas was a renowned expert in basic and clinical research in child and adolescent psychopharmacology, an enlightened and stimulating educator, and a mentor to many students, residents, and senior colleagues. With his enthusiasm and unique ability to network, he contributed enormously to trace a path in the field that we continue to follow. His name will remain in the textbooks and articles he authored. Here, as colleagues and friends who had the honor to work with him, we provide our personal views of Alessandro's impact and legacy, which go far beyond his publications.