Faculty Bibliography

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.

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.

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.

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.

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.

Parental depression is a risk factor for children's cognitive and psychological development. Literature has found reciprocal relations between parental depression and child psychopathology and effects of parental depression on children's cognition. The present study is the first to examine reciprocity among parental depression and child cognition, and pathways to child psychopathology. Structural equation models were conducted using data from the Early Head Start Research and Evaluation Project, a nationally representative sample of 3,001 economically marginalized families. Measures were collected in four waves from 14 months to 10-11 years. Reciprocal associations emerged between maternal and paternal depression at from 14 months to 5 years. Reciprocal parental depression was associated with greater psychopathology at age 10-11. Maternal depression predicted poorer child cognition, which indirectly predicted increased depression in mothers of children aged 3-5 through paternal depression, and in fathers at age 3, through earlier paternal depression. This study was unable to parse within- and between-person effects. Additionally, data for paternal depression was limited to ages 2 and 3. Findings emphasize the transactional nature of child cognition and child and parent psychopathology, supporting family focused intervention and prevention efforts that target parent psychopathology and child cognition.

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.

OBJECTIVE/UNASSIGNED:This study assessed the utility and effectiveness of the new general health integration (GHI) framework among community behavioral health organizations designated as certified community behavioral health clinics (CCBHCs) or in the process of applying to become a CCBHC. METHODS/UNASSIGNED:Nineteen licensed community behavioral health clinics, 18 of which had CCBHC status, participated in a 12-month learning collaborative. They used the GHI framework to assess their integration stage for 15 subdomains within eight domains of evidence-based practice. The clinics worked to improve their GHI practices with the support of monthly learning collaborative webinars, individual consultation calls, and technical assistance sessions. Clinics reported on performance quality metrics aligned with national CCBHC standards. Outcome measures included GHI framework scores at baseline and 1-year follow-up, capacity to report quality metrics at baseline and at the end of the collaborative, and average performance on the quality metrics at baseline versus at the end of the collaborative. RESULTS/UNASSIGNED:Clinics showed overall improvement in integration stage over the study period. Of note, higher baseline GHI framework scores demonstrated a significant association with greater-quality performance at baseline (r=0.577, p=0.024) and follow-up (r=0.782, p=0.001). Capacity to track and report quality metrics increased significantly during the learning collaborative, as did average performance on quality metrics. CONCLUSIONS/UNASSIGNED:Community behavioral health clinics using the GHI framework were able to advance their GHI practices with a 12-month learning collaborative project. The framework has the potential to serve as a useful tool for clinics aiming to enhance GHI practices.

OBJECTIVE/UNASSIGNED:receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder. METHODS/UNASSIGNED:Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS/UNASSIGNED:There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS/UNASSIGNED:There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.

BACKGROUND:The prevalence of trauma among individuals with HIV has prompted efforts to integrate trauma-informed care (TIC) into HIV care and treatment to improve health outcomes. A TIC Implementation Model, developed by a US capacity-building organization focuses on organizational changes, aligning cultural and physical environments, emphasizing values like safety and trustworthiness, engaging leadership, and training staff in skills-based TIC services. Despite growing research, gaps remain in understanding the relationship between organizational capacity, provider knowledge, and the dosage of technical assistance (TA) required to sustain TIC integration. Researchers investigated how the project team adapted the type and amount of TA based on initial Cultural Assessment scores (measuring core TIC values) and its impact on Implementation Status scores. METHODS:This study focuses on eight of 20 HIV care agencies in New Jersey that had largely met their TIC implementation goals by Spring 2022. As part of the TIC Implementation Model to measure agency capacity and implementation progress over time, agency staff and clients completed a Cultural Assessment (n = 72) and Physical Assessment (n = 43); staff completed a Pre/Post Training Survey (n = 296); and implementation teams at 8 agencies completed an Implementation Status Assessment Tool. Additionally, TA Logs capturing the details of TA meetings with the eight agencies were recorded by project staff. Data from these tools were analyzed in aggregate by agency using descriptive and correlational analyses. RESULTS:Results demonstrated responsive TA correlated with agencies' baseline capacity. Agencies with lower capacity received significantly more frequent and extended TA encounters, which were associated with higher implementation scores and improvements in cultural environments for staff and clients (e.g., new protocols for staff response plans). CONCLUSIONS:These findings underscore the importance of tailored TA in fostering diverse organizational cultures conducive to TIC implementation. For HIV care agencies, successful TIC implementation can impact health behaviors and outcomes for clients impacted by trauma. The TIC Implementation Model significantly advanced organizations' ability to transform their culture and systems, increasing their capacity to implement and sustain TIC integration. These results align with existing research that emphasizes when time is invested to shift organizational culture and develop leadership, new practices can effectively be implemented and scaled-up.