Faculty Bibliography

Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

Individuals with Down syndrome (DS) are at risk for early-onset Alzheimer's disease (AD), marked by neurodegeneration in hippocampal and basal forebrain circuits. Early-life interventions offer therapeutic potential, including maternal choline supplementation (MCS). MCS improves cognitive outcomes and neuroplasticity in rodent models of neurodevelopmental and neurodegenerative disorders, yet cell-type specific molecular effects remain unknown. We investigated the effect of MCS upon the onset of septohippocampal degeneration at 6 months of age in the Ts65Dn mouse model of DS/AD. Using laser capture microdissection and single population RNA-sequencing, transcriptomic changes were profiled within hippocampal CA1 and CA3 pyramidal neurons and dentate gyrus granule cells comparing trisomic and disomic offspring. Bioinformatic analysis revealed MCS-mediated downregulation of apoptotic pathways and upregulation of cognition-related functions across all populations, alongside cell-specific responses. These findings highlight MCS as a promising strategy for modulating disease-relevant pathways in a hippocampal cell-type-specific manner during early neurodegeneration in DS/AD.

Youth are presenting to Emergency Departments (EDs) following a suicide-related crisis at higher rates and younger ages. Clinicians lack tools to effectively discern suicide risk in younger patients. The present investigation examines how ED-based, suicidal pre-adolescents and adolescents conceptualize death. One hundred and sixty-seven suicidal pre-adolescents and adolescents (10-17 years; M = 12, SD = 1.4) presenting to a psychiatric ED with a suicide-related chief complaint completed assessments of suicidal ideation (SI; passive and active thoughts), suicide attempt (SA), depressive symptoms, and death conceptualizations (Death Avoidance, Escape Acceptance, Neutral Acceptance). Post-discharge SI and SA were assessed via survey emailed to participants 6 months later and via electronic medical record. At baseline, lower levels of Death Avoidance and higher levels of Escape Acceptance were most robustly associated with active SI. Pre-adolescents reported higher levels of Death Avoidance and lower levels of Escape Acceptance than adolescents at baseline. Death conceptualizations did not predict follow-up SI and SA. Youth who have recently experienced a suicide-related crisis are more likely to accept death as an escape from painand spend less time avoiding thoughts about death. This profile appears to be more representative of adolescents, relativeto pre-adolescents who display the opposite pattern.

OBJECTIVE:Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This pre-registered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. METHOD/METHODS:Temperament assessments (behavioral observations, parental/teacher reports or self-reports on cIT before age 13) and MRI-data (age at scan: 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness and surface area (main analyses) and detailed subcortical characteristics (e.g. subnuclei, subfields, partial volume effects; exploratory analyses) were considered. RESULTS:= 0.029) in youth with parental/teacher reports on cIT-levels. Exploratory analyses revealed findings in hippocampus, putamen and caudate, but most did not survive statistical correction for multiple testing. CONCLUSION/CONCLUSIONS:This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs.

Exposure to trauma is common and frequently overlooked in behaviorally dysregulated youth. Common trauma-related symptoms, such as exaggerated startle responses, dissociative episodes, and irritability, may resemble behavioral dysregulation. These responses may not be recognized as being related to trauma. As a result, traumatized young people are often misdiagnosed and treated with antipsychotics. Trauma-informed care in health care settings, which includes systematic screening, staff training, trauma skills groups, and ongoing monitoring, is one way of addressing the effects of trauma and ensuring that young people receive access to the evidence-based care they deserve.

Trauma exposure in children and adolescents is a significant public health concern due to its profound impact on mental health and development. This study explores the complexities of trauma in youth, including the differentiation between trauma exposure and posttraumatic stress disorder, and the long-term effects of adverse childhood experiences. The study discusses the risks and benefits of polypharmacy in treating complex trauma and comorbid conditions in youth. Given the current gaps in research, the study emphasizes the need for comprehensive, individualized treatment plans that integrate psychotherapy, pharmacologic interventions, and psychosocial support to foster resilience and improve outcomes for trauma-exposed youth.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Individuals with attention-deficit/hyperactivity disorder, their families and clinicians may report worsening symptoms despite compliant use of medication, suggesting potential tolerance, but evidence remains conflicting. Some studies have also suggested tachyphylaxis, or acute tolerance, though research is limited. We conducted the first systematic review of empirical studies focussing on tolerance/tachyphylaxis to attention-deficit/hyperactivity disorder medication to clarify their potential clinical relevance. METHODS:As registered on PROSPERO (CRD42024594759), we searched PubMed, OVID (including PsychInfo and MEDLINE) and Web of Knowledge up to 1 September, 2024, and assessed the risk of bias using National Institutes of Health quality assessment tools. RESULTS:The identified 17 studies were either interventional or observational, and varied greatly in design and duration. Four investigated tachyphylaxis, nine tolerance to the subjective and behavioural effects, and four tolerance to cardiovascular effects. We found preliminary evidence of tachyphylaxis to the affective or behavioural effects of stimulants, as well as tolerance to the subjective effects of d-amphetamine, such as drug liking and excitation, in neurotypical volunteers in the short term. Conversely, there was little or no evidence for tolerance to the therapeutic or cardiovascular effects of attention-deficit/hyperactivity disorder medication in clinical settings in the longer term. Quality was rated as low in most studies because of small sample sizes and methodological limitations. CONCLUSIONS:Overall, these results do not support the hypothesis that tolerance commonly develops to the therapeutic effects of attention-deficit/hyperactivity disorder medication, although robustly designed longitudinal studies are needed to provide more conclusive evidence. Clinicians may consider other potential explanations for reduced therapeutic effects over time, including natural fluctuations of symptoms, limited compliance, life events and co-occurrent mental health conditions.