Buprenorphine prescribing and treatment accessibility in response to regulation changes due to the COVID-19 public health emergency.

BACKGROUND: In 2021, over 80,000 fatal overdoses occurred in the United States. Since 2020, the federal government has enacted multiple regulatory changes around buprenorphine prescribing for opioid use disorder (OUD) to increase access to buprenorphine. This study aims to explore trends in buprenorphine treatment initiation pre- and post-public health emergency to evaluate changes in the context of X-waiver relaxations and telehealth allowances. METHODS: In a cross-sectional study, all RI residents who filled a buprenorphine prescription at a pharmacy in Rhode Island (RI), Massachusetts, and Connecticut between January 2017 and December 2023 were obtained from the RI Prescription Drug Monitoring Program (PDMP). The study excluded buprenorphine products not approved for OUD treatment from the analysis. Identified individuals had initiated buprenorphine for OUD during the study period if they did not have a prior prescription or if they had >30 days without buprenorphine exposure between their prescriptions. Spearman's rank correlation tests were used to identify significant associations between outcomes and regulation changes. RESULTS: The average number of patients dispensed buprenorphine did not significantly change over the study period, however the average number of initiates significantly decreased (ρ = -0.38255, p = .0003). The average number of providers prescribing CII-CV substances in RI has increased 3.4 % over the study period. The average percentage of prescribers in the PDMP prescribing buprenorphine for OUD doubled (ρ = 0.96075, p < .0001). CONCLUSION: Though efforts have been made to increase buprenorphine initiation, buprenorphine initiates remain well below pre-PHE levels. Efforts must continue to eliminate existing barriers to treatment and improve access to individuals seeking treatment.

Trends in Initiate Pediatric Opioid Prescriptions in Rhode Island: 2017-2021.

OBJECTIVE: To analyze recent trends in initiate pediatric opioid prescriptions dispensed in Rhode Island. METHODS: All Rhode Island residents aged 0-17 years with an initiate opioid prescription dispensed between January 1, 2017 and December 31, 2021 were obtained from the Rhode Island Prescription Drug Monitoring Program. Analyses were conducted to investigate trends related to patient demographics, prescription characteristics, diagnosis codes, and prescriber type. RESULTS: From 2017-2021, there was a decrease in the number of unique pediatric patients dispensed an initiate prescription, the number of initiate pediatric opioid prescriptions, and the initiate prescription dosage. Initiate opioid prescriptions were primarily related to dental-related diagnoses, and dentists and oral and maxillofacial (OMF) surgeons comprised the largest category of prescriber type. CONCLUSION: Initiate pediatric opioid prescriptions have decreased in Rhode Island in recent years. However, there remain opportunities to educate prescribers on reducing opioid exposure to vulnerable populations, including the use of alternate analgesics.

Anger, agency, risk and action: a neurobehavioral model with proof-of-concept in healthy young adults.

Introduction: Anger can engender action by individuals and groups. It is thus important to understand anger's behavioral phenotypes and their underlying neural substrates. Here, we introduce a construct we term agentic anger, a negatively valenced internal state that motivates action to achieve risky goals. We evaluate our neurobehavioral model via testable hypotheses in two proof-of-concept studies. Study 1 Methods: Study 1 used the Incentive Balloon Analogue Risk Task in a within-subjects, repeated measures design in 39 healthy volunteers to evaluate: (a) impact of blockade of reward on agentic anger, assessed by self-reports of negative activation (NA), (b) impact of achievement of reward on exuberance, assessed by self-reports of positive activation (PA), (c) the interrelationship of these valenced states, and (d) their relationship with personality. Study 1 Results: Task-induced NA was positively correlated with task-induced PA, risk-taking on the task and trait Social Potency (SP), a measure of trait agency and reward sensitivity on the Multidimensional Personality Questionnaire Brief-Form. Study 2 Methods: Study 2 assessed functional MRI response to stakes for risk-taking in healthy volunteers receiving 20 mg d-amphetamine in a double-blinded, placebo-controlled crossover design (N = 10 males), providing preliminary information on ventral striatal response to risky rewards during catecholamine activation. Study 2 Results: Trait SP and task-induced PA were strongly positively related to catecholamine-facilitated BOLD response in the right nucleus accumbens, a brain region where DA prediction error signal shapes action value and selection. Participants' task-induced NA was strongly positively related with trait SP and task-induced PA, replicating the findings of Study 1. Discussion: Together these results inform the phenomenology and neurobiology of agentic anger, which recruits incentive motivational circuitry and motivates personal action in response to goals that entail risk (defined as exposure to uncertainty, obstacles, potential harm, loss and/or financial, emotional, bodily, or moral peril). Neural mechanisms of agency, anger, exuberance, and risk-taking are discussed, with implications for personal and group action, decision-making, social justice, and behavior change.

Dispensed Opioid, Buprenorphine, Benzodiazepine, and Stimulant Prescriptions among Rhode Island Residents, 2017-2021.

The Rhode Island Prescription Drug Monitoring Program (PDMP) requires dispensers with an active Controlled Substance Registration to report Schedule II-V substances and opioid antagonists within 24 hours of dispensing. This database was designed to surveille diversion and identify high-risk prescribing to prevent drug related harms. Using PDMP data from January 1, 2017, to December 31, 2021, opioid, buprenorphine, stimulant, and benzodiazepine dispensing trends were explored. During this time, opioid prescriptions dispensed annually decreased by 27.3% (from 576,421 to 419,220), and benzodiazepine prescriptions dispensed annually decreased by 12.3% (552,430 to 484,496). High-risk prescribing also decreased with opioids prescriptions > 90 daily MME decreasing by 52.1% and instances of overlapping benzodiazepine and opioid prescriptions decreasing by 34.1%. Buprenorphine and stimulant dispensing have increased by 11.1% and 20.7%, respectively. Prevention interventions will continue to educate providers on appropriate prescribing practices and work to further reduce unnecessary prescribing within the state.

Trends and Risk Factors for Overlapping Stimulant and Opioid Prescriptions - Rhode Island, April 1, 2016-March 31, 2020.

OBJECTIVE: To investigate possible trends and risk factors for overlapping stimulant and opioid prescriptions in Rhode Island (RI). METHODS: All RI residents with a stimulant prescription dispensed between April 1, 2016 and March 31, 2020 were obtained from the RI Prescription Drug Monitoring Program (PDMP). Individuals were stratified by overlapping stimulant/opioid exposure and compared by demographic and prescription characteristics. RESULTS: While stimulant prescribing remained relatively constant, the percent of individuals with an overlapping opioid prescription declined. Individuals prescribed overlapping stimulant/opioid prescriptions differed significantly as a function of age, sex, payment method, type of stimulant prescribed, and prescriber type. CONCLUSIONS: Among residents who were dispensed at least one stimulant prescription, individuals who were older, female, and on Medicare insurance were more likely to have an overlapping stimulant/opioid prescription. The RI PDMP can be used to identify trends and risk factors regarding prescribing patterns, which can inform future health policy and practice.

The neurobiology of wellness: 1H-MRS correlates of agency, flexibility and neuroaffective reserves in healthy young adults.

Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive imaging technique that measures the concentration of metabolites in defined areas of the human brain in vivo. The underlying structure of natural metabolism-emotion relationships is unknown. Further, there is a wide range of between-person differences in metabolite concentration in healthy individuals, but the significance of this variation for understanding emotion in healthy humans is unclear. Here we investigated the relationship of two emotional constructs, agency and flexibility, with the metabolites glutamate and glutamine (Glx), N-acetylaspartate (tNAA), choline (Cho), creatine (tCr), and myo-inositol (Ins) in the right dorsal anterior cingulate cortex (dACC) in medically and psychiatrically healthy volunteers (N = 20, 9 female; mean age = 22.8 years, SD = 3.40). The dACC was selected because this region is an integrative hub involved in multiple brain networks of emotion, cognition and behavior. Emotional traits were assessed using the Multidimensional Personality Questionnaire Brief Form (MPQ-BF), an empirically derived self-report instrument with an orthogonal factor structure. Phenotypes evaluated were positive and negative agency (MPQ-BF Social Potency, Aggression), emotional and behavioral flexibility (MPQ-BF Absorption, Control-reversed), and positive and negative affect (MPQ-BF Social Closeness; Stress Reaction, Alienation). The resting concentration of tNAA in the dACC was robustly positively correlated with Absorption (r = +0.56, unadjusted p = .005), moderately positively correlated with Social Potency (r = +0.42, unadjusted p = .03), and robustly negatively correlated with Aggression (r = -0.59, unadjusted p = .003). Absorption and Aggression accounted for substantial variance in tNAA (R2 = 0.31, 0.35; combined R2 = 0.50), and survived correction for multiple comparisons (Holm-Bonferroni adjusted p = .032, 0.021, respectively). dACC Glx and Cho had modest relationships with behavioral flexibility and social affiliation that did not survive this multiple correction, providing effect sizes for future work. Principal Component Analysis (PCA) revealed a three-factor orthogonal solution indicating specific relationships between: 1) Glx and behavioral engagement; 2) Cho and affiliative bonding; and 3) tNAA and a novel dimension that we term neuroaffective reserves. Our results inform the neurobiology of agency and flexibility and lay the groundwork for understanding mechanisms of natural emotion using 1H-MRS.

Neurocognitive, Autonomic, and Mood Effects of Adderall: A Pilot Study of Healthy College Students.

Prescription stimulant medications are considered a safe and long-term effective treatment for Attention Deficit Hyperactivity Disorder (ADHD). Studies support that stimulants enhance attention, memory, self-regulation and executive function in individuals with ADHD. Recent research, however, has found that many college students without ADHD report misusing prescription stimulants, primarily to enhance their cognitive abilities. This practice raises the question whether stimulants actually enhance cognitive functioning in college students without ADHD. We investigated the effects of mixed-salts amphetamine (i.e., Adderall, 30 mg) on cognitive, autonomic and emotional functioning in a pilot sample of healthy college students without ADHD (n = 13), using a double-blind, placebo-controlled, within-subjects design. The present study was the first to explore cognitive effects in conjunction with mood, autonomic effects, and self-perceptions of cognitive enhancement. Results revealed that Adderall had minimal, but mixed, effects on cognitive processes relevant to neurocognitive enhancement (small effects), and substantial effects on autonomic responses, subjective drug experiences, and positive states of activated emotion (large effects). Overall, the present findings indicate dissociation between the effects of Adderall on activation and neurocognition, and more importantly, contrary to common belief, Adderall had little impact on neurocognitive performance in healthy college students. Given the pilot design of the study and small sample size these findings should be interpreted cautiously. The results have implications for future studies and the education of healthy college students and adults who commonly use Adderall to enhance neurocognition.

Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.

Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.

Dopamine D1 signaling organizes network dynamics underlying working memory.

Local prefrontal dopamine signaling supports working memory by tuning pyramidal neurons to task-relevant stimuli. Enabled by simultaneous positron emission tomography-magnetic resonance imaging (PET-MRI), we determined whether neuromodulatory effects of dopamine scale to the level of cortical networks and coordinate their interplay during working memory. Among network territories, mean cortical D1 receptor densities differed substantially but were strongly interrelated, suggesting cross-network regulation. Indeed, mean cortical D1 density predicted working memory-emergent decoupling of the frontoparietal and default networks, which respectively manage task-related and internal stimuli. In contrast, striatal D1 predicted opposing effects within these two networks but no between-network effects. These findings specifically link cortical dopamine signaling to network crosstalk that redirects cognitive resources to working memory, echoing neuromodulatory effects of D1 signaling on the level of cortical microcircuits.

Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance.

Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls>patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia.

Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.

A hypomethylating variant of MTHFR, 677C>T, blunts the neural response to errors in patients with schizophrenia and healthy individuals.

BACKGROUND: Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%. METHODOLOGY/PRINCIPAL FINDINGS: Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele. CONCLUSIONS/SIGNIFICANCE: These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.