Faculty Bibliography

The differential influence of sex on premature mortality in schizophrenia is unclear. This study assessed the differences in all-cause and specific cause mortality risks in people with schizophrenia compared to several control groups stratified by sex. We conducted a PRISMA 2020-compliant systematic review and random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) for people with schizophrenia, comparing by sex. We measured publication bias and conducted a quality assessment through the Newcastle-Ottawa scale. We meta-analyzed 43 studies reporting on 2,700,825 people with schizophrenia. Both males and females with schizophrenia had increased all-cause mortality vs. comparison groups (males, RR=2.62, 95%CI 2.35-2.92; females, RR=2.56, 95%CI 2.27-2.87), suicide (males, RR=9.02, 95%CI 5.96-13.67; females, RR=12.09, 95%CI 9.00-16.25), and natural cause mortality (males, RR=2.11, 95%CI 1.88-2.38; females, RR=2.14, 95%CI 1.93-2.38). No statistically significant differences in sex-dependent mortality risk emerged. There was an age-group-dependent increased mortality risk in females < 40 years vs. >/=40 years old (RR=4.23/2.17), and significantly higher risk of death due to neurological disorders (dementia) in males vs. females (RR=5.19/2.40). Increased mortality risks were often associated with specific modifiable risk factors. The increased mortality risk did not improve over time, calling for more studies to identify modifiable factors, and for better physical healthcare for males and females with schizophrenia.

Individuals with attention-deficit/hyperactivity disorder (ADHD) exhibit varied responses to pharmacological treatments (e.g. stimulants and non-stimulants). Accurately and promptly detecting treatment-related improvements, response failure, or deterioration poses significant challenges, as current monitoring primarily relies on subjective ratings. In this commentary, we critically evaluate the evidence supporting the use of QbTest for objectively monitoring ADHD treatment response in clinical practice. We also offer recommendations for future research, advocating for rigorous clinical trials and longitudinal studies to further explore the potential utilisation of QbTest and other tools for monitoring treatment responses in individuals with ADHD.

PURPOSE OF REVIEW/OBJECTIVE:There is a mental health crisis affecting youth, and the utility of existing treatments is often limited by lack of effectiveness and tolerability. The aim of this review is to report on outcomes of clinical trials for psilocybin-assisted psychotherapy for adults with depression and MDMA-assisted psychotherapy for adults with post-traumatic stress disorder (PTSD) and discuss recommendations for exploring these treatments in adolescent populations. RECENT FINDINGS/RESULTS:There have been encouraging data supporting the use of psilocybin-assisted psychotherapy for depression, including previously treatment-resistant symptoms. MDMA-assisted psychotherapy is showing similar promise in treating PTSD, with excellent response and remission rates that appear durable. However, no studies have looked at the use of these treatments in younger patients. The safety and efficacy of psychedelic- and MDMA-assisted psychotherapies should be investigated in adolescents, especially considering the burden of untreated and undertreated psychiatric illness in youth, and the benefits of a potentially earlier, more effective, and more tolerable recovery process. Research and implementation should be tailored to the needs of this population, and equity and access should be considered at every stage. In this novel and rapidly evolving landscape, the psychiatric community is encouraged to advocate for safe, appropriate, and inclusive inquiry into, and application and scaling of these treatment models in adolescent patients.

We aimed to examine the role of shared decision-making (SDM) in family participation in the treatment of adolescents and young adults with first-episode psychosis (FEP). Based on responses of 144 family members of OnTrackNY (OTNY) participants, we divided the sample into low participators and high participators. We calculated the total SDM score for each participant by summing the ratings across items inquiring about SDM and assessed the extent to which loved ones encouraged family participation in their care. Our results indicated that the level of loved ones' encouragement was significantly related to family participation. When controlling for loved ones' encouragement, we found that the total SDM score was significantly higher in the high participator group. These findings suggest that SDM may be influenced by loved ones' attitudes towards family involvement in treatment and SDM may play a role in promoting family participation in care for individuals with FEP.

BACKGROUND:Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals. METHODS:We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020. Hypothetical RCT ineligibility was established using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Quasi-Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalisations, injuries or accidents, and substance use disorder within 1 year of initiating ADHD medications. People with lived experience of ADHD were not involved in the research and writing process. FINDINGS/RESULTS:Of 189 699 individuals included in the study cohort (112 153 men and boys [59%] and 77 546 women and girls [41%]; mean age 21·52 years [SD 12·83; range 4-68]) initiating ADHD medication, 53% (76 477 [74%] of 103 023 adults [aged >17 years], 12 658 [35%] of 35 681 adolescents [aged 13-17 years], and 10 643 [21%] of 50 995 children [aged <13 years]) would have been ineligible for RCT participation. Ethnicity data were not available. Ineligible individuals had a higher likelihood of treatment switching (hazard ratio 1·14, 95% CI 1·12-1·16) and a decreased likelihood of medication discontinuation (0·96, 0·94-0·98) compared with eligible individuals. Individuals ineligible for RCTs had significantly higher rates of psychiatric hospitalisations (ncidence rate ratio 9·68, 95% CI 9·57-9·78) and specialist care visits related to substance use disorder (14·78, 14·64-14·91), depression (6·00, 5·94-6·06), and anxiety (11·63, 11·56-11·69). INTERPRETATION/CONCLUSIONS:Individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real-world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines. FUNDING/BACKGROUND:National Institute of Healthcare and Research, European Union's Horizon 2020, and Swedish Research Council.

INTRODUCTION/BACKGROUND: High-functioning depression (HFD) is described as experiencing depressive symptoms such as fatigue, anhedonia, poor concentration, guilt, restlessness, sleep disturbances, and appetite changes without experiencing a lack of functioning or significant distress. The purpose of this study is to characterize the clinical correlates of HFD. METHODS:This study entailed a descriptive, cross-sectional design based on interviews administered to120 English-speaking participants with HFD (aged 18-75). The interview involved administering a semi-structured HFD Analysis Questionnaire, the Joseph HFD Inventory, the HFD Trauma Inventory, and the Joseph HFD Anhedonia Scale in a single, 30-minute session for each participant. Big traumas, defined as extremely traumatic events, were analyzed by the trauma inventory. RESULTS:Out of the 120 participants, 72 (60%) demonstrated HFD, and 17 (14%) demonstrated very HFD. A correlation was observed between symptoms of HFD, such as anhedonia and marital status, as post hoc tests showed that the average Anhedonia Scale score was higher for married or partnered participants than those who were single (p=0.038). As anticipated, the participants with higher Anhedonia Scale scores had higher HFD scores (p=0.003). These participants also experienced higher trauma inventory scores and big traumas. Furthermore, as participant education level increased, the number of big traumas reported decreased (p<0.001). Participants who were parents/caregivers of children also had the highest Anhedonia Scale and HFD scores (p=0.0126 and p=0.0210, respectively). CONCLUSION/CONCLUSIONS:The results supported the hypothesis that individuals with HFD have increased levels of anhedonia and trauma. However, trauma scores were inversely associated with education level in HFD.

OBJECTIVE:To better understand the value of DNR orders for critically ill infants in the NICU. METHODS:A prospective mixed-methods approach was utilized including chart review of infants who died in a regional NICU over a twenty-six-month period and surveys of their neonatologists, neonatal fellows, and nurses. RESULTS:40 infants died during the study period and 120 staff surveys were completed. Infants with DNR orders were of a higher gestational age at birth and a higher chronological age at death. Nurses were more likely to perceive benefit from DNR orders than physicians. Medical staff recollection of the existence of DNR orders was not always accurate. Time and fear of adding unnecessary emotional burden to parents were identified as barriers to DNR order implementation. An advanced care planning model built on open communication instead of DNR order documentation was deemed the best approach. CONCLUSION/CONCLUSIONS:Though DNR orders are beneficial for a subset of infants, DNR orders are likely not applicable for all infants who die in the NICU. More important is supportive, individualized communication between families and the medical team to ensure quality end-of-life care. IMPACT/CONCLUSIONS:In the adult and pediatric ICU literature, DNR orders are associated with improved qualitative "good death" assessments and decreased familial decision regret. In the NICU, rates of DNR usage aren't well reported and their overall utility is unclear. Though DNR orders can help guide clinical decision making in the NICU and may be associated with higher quality ethical discussion, our data suggest that they are not applicable in all patient cases. We hope that this work will help guide approaches to end-of-life care in the NICU and underscore the importance of frequent, open communication between families and their medical team.

Although parenting interventions are recommended by major clinical guidelines for managing children's behavioral challenges, including ADHD, their uptake in clinical practice remains limited. Building on the contributions of Hodson et al. and Nijboer et al. in the current issue of this journal, we here explore solutions to enhance this uptake. We first summarize the usual suspects: solutions that could be implemented in our current mental healthcare systems. Digital and brief interventions could remove obstacles that are often experienced with traditional parenting interventions, and nudges inspired by behavioral economic theories can help remove dynamic, time-varying barriers experienced by parents that may arise during the course of the intervention. We then zoom out and present a paradigmatic challenge. The current narrative surrounding behavioral problems like ADHD is predominantly biomedical, which tends to elevate expectations for treatments such as medication while simultaneously diminishing confidence in parenting interventions. From this perspective, it is unsurprising that engagement issues arise when a context-focused intervention such as parent training is proposed as a solution to a decontextualized problem like ADHD. Adopting a truly balanced biopsychosocial-societal perspective on behavioral problems like ADHD would better reflect their complex and heterogeneous etiology, and would broaden the scope for interventions, such as parenting programs, that focus on optimizing children's contextual environments.

Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.