Faculty Bibliography

Empirical evidence indicates a significant bidirectional association between mental disorders and physical diseases, but the prospective impact of men-tal disorders on clinical outcomes of physical diseases has not been comprehensively outlined. In this PRISMA- and COSMOS-E-compliant umbrella review, we searched PubMed, PsycINFO, Embase, and Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, up to March 15, 2022, to identify systematic reviews with meta-analysis that examined the prospective association between any mental disorder and clinical outcomes of physical diseases. Primary outcomes were disease-specific mortality and all-cause mortality. Secondary outcomes were disease-specific incidence, functioning and/or disability, symptom severity, quality of life, recurrence or progression, major cardiac events, and treatment-related outcomes. Additional inclusion criteria were further applied to primary studies. Random effect models were employed, along with I² statistic, 95% prediction intervals, small-study effects test, excess significance bias test, and risk of bias (ROBIS) assessment. Associations were classified into five credibility classes of evidence (I to IV and non-significant) according to established criteria, complemented by sensitivity and subgroup analyses to examine the robustness of the main analysis. Statistical analysis was performed using a new package for conducting umbrella reviews (https://metaumbrella.org). Population attributable fraction (PAF) and generalized impact fraction (GIF) were then calculated for class I-III associations. Forty-seven systematic reviews with meta-analysis, encompassing 251 non-overlapping primary studies and reporting 74 associations, were included (68% were at low risk of bias at the ROBIS assessment). Altogether, 43 primary outcomes (disease-specific mortality: n=17; all-cause mortality: n=26) and 31 secondary outcomes were investigated. Although 72% of associations were statistically significant (p<0.05), only two showed convincing (class I) evidence: that between depressive disorders and all-cause mortality in patients with heart failure (hazard ratio, HR=1.44, 95% CI: 1.26-1.65), and that between schizophrenia and cardiovascular mortality in patients with cardiovascular diseases (risk ratio, RR=1.54, 95% CI: 1.36-1.75). Six associations showed highly suggestive (class II) evidence: those between depressive disorders and all-cause mortality in patients with diabetes mellitus (HR=2.84, 95% CI: 2.00-4.03) and with kidney failure (HR=1.41, 95% CI: 1.31-1.51); that between depressive disorders and major cardiac events in patients with myocardial infarction (odds ratio, OR=1.52, 95% CI: 1.36-1.70); that between depressive disorders and dementia in patients with diabetes mellitus (HR=2.11, 95% CI: 1.77-2.52); that between alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C (RR=3.15, 95% CI: 2.87-3.46); and that between schizophrenia and cancer mortality in patients with cancer (standardized mean ratio, SMR=1.74, 95% CI: 1.41-2.15). Sensitivity/subgroup analyses confirmed these results. The largest PAFs were 30.56% (95% CI: 27.67-33.49) for alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C, 26.81% (95% CI: 16.61-37.67) for depressive disorders and all-cause mortality in patients with diabetes mellitus, 13.68% (95% CI: 9.87-17.58) for depressive disorders and major cardiac events in patients with myocardial infarction, 11.99% (95% CI: 8.29-15.84) for schizophrenia and cardiovascular mortality in patients with cardiovascular diseases, and 11.59% (95% CI: 9.09-14.14) for depressive disorders and all-cause mortality in patients with kidney failure. The GIFs confirmed the preventive capacity of these associations. This umbrella review demonstrates that mental disorders increase the risk of a poor clinical outcome in several physical diseases. Prevention targeting mental disorders - particularly alcohol use disorders, depressive disorders, and schizophrenia - can reduce the incidence of adverse clinical outcomes in people with physical diseases. These findings can inform clinical practice and trans-speciality preventive approaches cutting across psychiatric and somatic medicine.

INTRODUCTION/BACKGROUND:Emotional dysregulation and irritability are common in individuals with autism spectrum disorder (ASD). We conducted the first meta-analysis assessing the efficacy of a broad range of pharmacological interventions for emotional dysregulation and irritability in ASD and predictors of response. METHOD/METHODS:Following a pre-registered protocol (PROSPERO: CRD42021235779), we systematically searched multiple databases until 01/01/2021. We included placebo-controlled randomized controlled trials (RCTs) and evaluated the efficacy of pharmacological interventions and predictors of response for emotional dysregulation and irritability. We assessed heterogeneity using Q statistics and publication bias. We conducted sub-analyses and meta-regressions to identify predictors of response. The primary effect size was the Standardized Mean Difference. Quality of studies was assessed using the "Cochrane Risk of Bias Tool" (RoB2). RESULTS:2,856 individuals with ASD in 45 studies were included, of which 26.7% of RCTs were at high risk of bias. Compared to placebo, antipsychotics (1.028, 0.824 to 1.232) and medications used to treat ADHD (0.471, 0.061 to 0.881) were significantly better than placebo in improving emotional dysregulation and irritability, while evidence of efficacy was not found for other drug classes (p>0.05). Within individual medications, evidence of efficacy was found for aripiprazole (1.179, 0.838 to 1.520) and risperidone (1.074, 0.818 to 1.331). Increased rates of comorbid epilepsy (β=-0.049, p=0.026) were associated with a lower efficacy. CONCLUSION/CONCLUSIONS:Some pharmacological interventions (particularly risperidone and aripiprazole) have proved efficacy for short-term treatment of emotional dysregulation and irritability in ASD and should be considered within a multimodal treatment plan, taking into account also tolerability profile and families' preferences.

In this Clinical Perspective, we argue that, at least for some patients, formulation, rather than diagnosis, should be the cornerstone in clinical practice in child and adolescent psychiatry. As opposed to a rigid, tick-the-box approach to formulation, we advocate for a conceptualization of formulation that moves the practice of (child and adolescent) psychiatry into the realm of storytelling and construction of narratives. We suggest that the use of role playing and narrative art forms, such as novels or films, during the training may contribute to develop the skills in telling a story (ie, the formulation) about/to a patient.

OBJECTIVE:Symptoms of attention-deficit/hyperactivity disorder (ADHD) and sleep disturbances frequently co-occur, and can result in significant functional impairments that worsen quality of life. Despite a growing number of studies focusing on the association between sleep disturbances and ADHD symptoms over the last 20 years, the directionality of this association from childhood to early adulthood remains unclear. METHOD:A sample of French parents (n = 1,055) were followed-up over a 9-year period. At children mean ages of 9, 13, and 18 years, parents were interviewed about their children's ADHD symptoms and sleep disturbances. Random-intercept cross-lagged panel models assessed the directionality of the association from childhood to early adulthood. RESULTS:Parent-reported sleep disturbances at a mean age of 13 years predicted increased ADHD symptoms 5 years later. Additional analyses suggested that this effect might be limited to inattentive symptoms, and that ADHD symptoms at a mean age of 9 predicted increased sleep disturbances 4 years later. CONCLUSION:The present study provides evidence of a directional longitudinal association between parent-reported sleep disturbances and ADHD symptoms from adolescence to early adulthood. Our results highlight the importance of identifying sleep disturbances and ADHD symptoms for the design of preventive interventions. Future studies investigating this association in children with a clinical diagnosis of ADHD have the potential to provide important information for clinical practice.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.

INTRODUCTION/UNASSIGNED:A large number of randomized controlled trials (RCTs) and observational studies on the pharmacotherapy of ADHD are available. AREAS COVERED/UNASSIGNED:Based on a search in PubMed and PsycInfo (up to 15 September 2022), this review addresses to which extent this body of research is currently able to inform routine prescribing practice, in terms of the choice of medication, titration strategy, augmentation treatments, and use of alternative, non-approved treatments. EXPERT OPINION/UNASSIGNED:A growing body of evidence is informing prescribers on some, but certainly not all, aspects related to the pharmacological treatment of ADHD in the daily clinical practice, with important weaknesses/gaps that need to be addressed. First, evidence synthesis of RCTs is not able to inform decision-making at the individual patient level. Second, the maximum safe and effective doses, possibly beyond those currently recommended, are not well understood. Third, evidence from RCTs on augmenting strategies is still limited. Fourth, no novel agents with the same or higher effect size of stimulants, in terms of efficacy, but with better tolerability and lower abuse potential, have been found. Implementation of precision psychiatry approaches and stratification of patients in future RCTs will be key to, respectively, individualize the treatment strategies and test etiopathophysiology-based agents.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read.

AIM/OBJECTIVE:To conduct the first systematic review and meta-analysis assessing whether attention-deficit/hyperactivity disorder (ADHD) is associated with disorders of the eye, and/or altered measures of visual function. METHOD/METHODS:Based on a pre-registered protocol (PROSPERO: CRD42021256352), we searched PubMed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycINFO up to 16th November 2021, with no language/type of document restrictions. We included observational studies reporting at least one measure of vision in people of any age meeting DSM/ICD criteria for ADHD and in people without ADHD; or the prevalence of ADHD in people with and without vision disorders. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS). Random effects meta-analyses were used for data synthesis. RESULTS:We included 42 studies in the narrative synthesis and 35 studies in the meta-analyses (3,250,905 participants). We found meta-analytic evidence of increased risk of astigmatism (OR = 1.79 [CI: 1.50, 2.14]), hyperopia and hypermetropia (OR = 1.79 [CI: 1.66, 1.94]), strabismus (OR = 1.93 [CI: 1.75, 2.12]), unspecified vision problems (OR = 1.94 [CI: 1.38, 2.73]) and reduced near point of convergence (OR = 5.02 [CI: 1.78, 14.11]); increased lag (Hedge's g = 0.63 [CI: 0.30, 0.96]) and variability (Hedge's g = 0.40 [CI: 0.17, 0.64]) of the accommodative response; and increased self-reported vision problems (Hedge's g = 0.63 [CI: 0.44, 0.82]) in people with ADHD compared to those without ADHD (with no significant heterogeneity). We also found meta-analytic evidence of no differences between people with and without ADHD on retinal nerve fiber layer thickness (Hedge's g = -0.19 [CI: -0.41, 0.02]) and refractive error (Hedge's g = 0.08 [CI: -0.26, 0.42]) (with no significant heterogeneity). DISCUSSION/CONCLUSIONS:ADHD is associated with some self-reported and objectively ascertained functional vision problems, but not with structural alterations of the eye. Further studies should clarify the causal relationship, if any, between ADHD and problems of vision. TRIAL REGISTRATION/BACKGROUND:PROSPERO registration: CRD42021256352.

INTRODUCTION:Neurological/neuropsychiatric symptoms are commonly reported by children/young people with long COVID, especially headache, fatigue, cognitive deficits, anosmia and ageusia, dizziness, mood symptoms, and sleep problems. However, reported prevalence estimates are highly variable due to study heterogeneity and often small sample size; most studies only considered short-term follow-ups; and, apart from mood and sleep problems, neuropsychiatric conditions have received less attention. Considering the potential debilitating effects of neurological/neuropsychiatric conditions, a comprehensive review of the topic is timely, and needed to support clinical recognition as well as to set the direction for future research. AREAS COVERED:The authors discuss neurological/neuropsychiatric manifestations of long COVID in pediatric populations, with a focus on prevalence, associated demographic characteristics, and potential pathogenetic mechanisms. EXPERT OPINION:Children/young people may develop persistent neurological/neuropsychiatric symptoms following acute SARS-CoV-2 infection, which may affect daily functioning and well-being. Studies in larger samples with longer follow-ups are needed to clarify prevalence and symptom duration; as well as less investigated risk factors, including genetic predisposition, ethnicity, and comorbidities. Controlled studies may help separate infection-related direct effects from pandemic-related psychosocial stressors. Clarifying pathogenetic mechanisms is paramount to develop more targeted and effective treatments; whilst screening programs and psychoeducation may enhance early recognition.