Faculty Bibliography

This chapter describes recent clinical trials for opioid use disorder (OUD), an area that has rapidly accelerated in response to the opioid overdose crisis in the USA and newly appropriated funding. Trials involve a wide range of compounds including cannabinoids and psychedelics, new and existing compounds targeting domains emerging from addiction neuroscience, agents repurposed from other indications, and novel strategies including vaccines, enzymes, and other biologicals. In parallel, new formulations of existing compounds offer immediate promise, as do a variety of web-based interventions and smartphone-delivered apps. Trials focused on implementing existing effective interventions in mainstream healthcare settings, and others focused on special populations, e.g., adolescents, criminal justice, pregnant women, native Americans, etc., have the potential to vastly expand treatment in the near term. Given the range of ongoing and recent trials, this chapter is not intended to be an exhaustive review but rather to present an overview of approaches within the framework of the opioid treatment cascade and the context of current OUD pharmacotherapies.

BACKGROUND AND PURPOSE/OBJECTIVE:Asymmetric atrophy of the hippocampus is an important clinical finding in normal aging and Alzheimer disease. In this study, we investigate the associations between the magnitude and asymmetry of hippocampal volumetric integrity and age, sex, and dementia severity. MATERIALS AND METHODS/METHODS:= 30). We used linear mixed-effects models to analyze the hippocampal parenchymal fraction and its asymmetry with respect to age, sex, dementia severity, and intracranial volume. RESULTS:After controlling for age, sex, and intracranial volume, we found that the magnitude of the hippocampal parenchymal fraction decreased and its asymmetry increased significantly with dementia severity. Also, hippocampal parenchymal fraction asymmetry was significantly higher in men after controlling for all other variables, but there was no sex effect on hippocampal parenchymal fraction magnitude. The magnitude of the hippocampal parenchymal fraction decreased and its asymmetry increased significantly with age in subjects who were cognitively healthy, but associations with age were different in nature in the mild cognitive impairment and Alzheimer disease groups. CONCLUSIONS:Hippocampal atrophy progresses asymmetrically with age in cognitively healthy subjects. Hippocampal parenchymal fraction asymmetry is significantly higher in men than women and in mild cognitive impairment/Alzheimer disease relative to cognitively healthy individuals.

Pre-deployment identification of risk and resilience factors is crucial in developing targets to reduce or prevent posttraumatic stress symptoms in military personnel. The Fort Campbell Cohort study was designed to assess pre-deployment biological and behavioral markers and build predictive models to identify risk and resistance for posttraumatic stress disorder (PTSD) following deployment. The aim of the current study was to use high-resolution metabolomics profiling to identify metabolic pathways and networks associated with PTSD checklist score differences and changes across multiple pre and post-deployment time points. In addition, we have investigated how deployment affects metabolomics profile changes within individuals independent of PTSD score changes. Untargeted metabolomics profiling of plasma has been completed using both liquid and gas chromatography with mass spectrometry. Our preliminary data indicates that deployment has complex metabolic effects that must be considered in evaluation of deployment-associated exposures in military personnel. Our in depth-data analysis may further elucidate pathways, novel compounds, and biomarkers associated with PTSD in its relation to military deployment. These findings may have clinical implications for understanding the pathogenesis of PTSD and provide insights to avert chronic PTSD

RATIONALE: We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia. OBJECTIVES: We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats. METHODS: Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured. RESULTS: Clozapine (30 mug-2 mg/kg), chlorpromazine (0.1-5 mg/kg), and risperidone (6.25 mug-1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia. CONCLUSIONS: Chlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D2 receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties.