Faculty Bibliography

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n = 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR) = 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR = 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR = 0.92, 95% CI: 0.73, 1.11).

Two articles recently published in this journal identified racial inequities in routine psychiatric practice. This Open Forum discusses the need for a paradigm shift in inequities research. The two articles reviewed here, one by Shea and colleagues on racial-ethnic inequities in inpatient psychiatric civil commitment and one by Garrett and colleagues on racial-ethnic disparities in psychiatric decisional capacity consultations, are examples of the new research gaze. Four topics are identified for enhancing understanding of racism and other forms of structural exclusion in psychiatric practice: medical authority and power imbalance between providers and patients, involuntary psychiatric commitment and requests for decisional capacity consultations as strategic research events, limited use of theory, and limitations of the literature on psychiatric inequities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:To inform clinical practice, we identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment. METHODS:Participants were 474 adults in a 24-week treatment trial for OUD. Depression symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D) at nine-time points. This was a secondary analysis of the Clinical Trials Network Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (XBOT) trial using a growth mixture model. RESULTS:Three distinct depression trajectories were identified: Class 1 High Recurring-10% with high HAM-D with initial partial reductions (of HAM-D across time), Class 2 Persistently High-5% with persistently high HAM-D, and Class 3 Low Declining-85% of the participants, with low HAM-D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse. DISCUSSION AND CONCLUSIONS/CONCLUSIONS:In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment.

IMPORTANCE:Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. OBJECTIVE:To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. DESIGN, SETTING, AND PARTICIPANTS:This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. INTERVENTIONS:Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. MAIN OUTCOMES AND MEASURES:Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. RESULTS:Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. CONCLUSIONS AND RELEVANCE:In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02941809.

BACKGROUND:Extended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications. METHODS:The CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected. DISCUSSION/CONCLUSIONS:If RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs. TRIAL REGISTRATION/BACKGROUND:NCT04762537 Registered February 21, 2021.

Insulin crosses the blood-brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor-nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states.

BACKGROUND/UNASSIGNED:Spirituality is a construct encompassing a diversity of strongly held beliefs and pursuits related to life's meaning and purpose. Empirical studies in key domains of spirituality related to substance use disorder (SUD) can be valuable in guiding research, and potentially clinical care. OBJECTIVES/UNASSIGNED:To conduct a scoping review of research on the psychological, biological, and cultural dimensions of spirituality and their role in relation to SUD. To identify limitations in empirical findings within these domains and identify promising areas for related research. DATA SOURCES, STUDY APPRAISAL, AND SYNTHESIS METHODS/UNASSIGNED:Illustrative studies available in the empirical literature are reviewed in order to characterize these three key domains. RESULTS/UNASSIGNED:Certain areas of importance stand out: On Psychology, attribution of SUD to a spiritual outlook; spiritual awakening; the relation of spirituality to drug craving; and spirituality in the context of psychedelic-assisted psychotherapy. On Biology, heritability of traits related to shared spiritual experience; neurophysiologic correlates of spiritually related experiences; and correlates in brain imaging; On Culture, spiritual aspects of SUD in different cultural settings; distinctions between spiritual and religious phenomena; roles that international organizations play; and context of acquiring recovery capital. The need for further research in each area is defined. CONCLUSIONS/UNASSIGNED:There is utility in examining the diversity of findings in the roles of psychology, biology, and culture in the SUD field. Further research, particularly applying randomization and clinical controls, would be useful in improving the effective application of the construct of spirituality in clinical care.

IMPORTANCE/UNASSIGNED:Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. OBSERVATIONS/UNASSIGNED:Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

BACKGROUND:De-escalation of behavioral emergencies in the inpatient medical setting may involve restrictive clinical interventions that directly challenge patient autonomy. OBJECTIVE:We describe a quality improvement framework used to examine associations between patient characteristics and behavioral emergency de-escalation strategies. This project may inform other Consultation-Liaison Psychiatry teams seeking to promote equity in care. METHODS:We examined behavioral emergency response team (BERT) management at an urban, tertiary-care medical center in the United States over a 3-year period. BERT data from an existing dataset were combined with demographic information from the hospital's electronic medical record. Race and ethnic identities were categorized as Black, Hispanic, Asian, White, and unknown. BERT events were coded based on the most restrictive intervention utilized per unique patient. Cross-tabulations and adjusted odds ratios from multivariate logistic regression were used to identify quality improvement targets in this exploratory project. RESULTS:The sample included N = 902 patients and 1532 BERT events. The most frequent intervention reached was verbal de-escalation (n = 419 patients, 46.45%) and the least frequent was 4-point restraints (n = 29 patients, 3.2%). Half of BERT activations for Asian and a third for Hispanic patients required interpreter services. Anxiety and cognitive disorders and 2 BERT interventions, verbal de-escalation, and intramuscular/intravenous/ medications, were significantly associated with race/ethnic category. The most restrictive intervention for BERTs involving Black and Asian patients were verbal de-escalation (60.1%) and intramuscular/intravenous(53.7%), respectively. These proportions were higher compared with other race/ethnic groups. There was a greater percentage of patients from the unknown (6.3%) and Black (5.9%) race/ethnic groups placed in 4-point restraints compared with other groups (3.2%) that did not reach statistical significance. A logistic regression model predicting 4-point restraints indicated that younger age, multiple BERTs, and violent behavior as a reason for BERT activation, but not race/ethnic group, resulted in significantly higher odds. CONCLUSIONS:This project illustrates that a quality improvement framework utilizing existing clinical data can be used to engage in organizational introspection and identify potential areas of bias in BERT management. Our findings suggest opportunities for further exploration, enhanced education, and programmatic improvements regarding BERT intervention; 4-point restraints; interpreter services; and the influence of race on perception of psychopathology.