A guide to the BRAIN Initiative Cell Census Network data ecosystem.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

Expression of the vesicular GABA transporter within neuromedin S+ neurons sustains behavioral circadian rhythms.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter Vgat from neuromedin-S (NMS)+ neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS-Vgat deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, Vgat deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of Vgat led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.

Sleep timing and the circadian clock in mammals: Past, present and the road ahead.

Nearly all mammals display robust daily rhythms of physiology and behavior. These approximately 24-h cycles, known as circadian rhythms, are driven by a master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and affect biological processes ranging from metabolism to immune function. Perhaps the most overt output of the circadian clock is the sleep-wake cycle, the integrity of which is critical for health and homeostasis of the organism. In this review, we summarize our current understanding of the circadian regulation of sleep. We discuss the neural circuitry and molecular mechanisms underlying daily sleep timing, and the trajectory of circadian regulation of sleep across development. We conclude by proposing future research priorities for the field that will significantly advance our mechanistic understanding of the circadian regulation of sleep.

Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.

BACKGROUND: Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia. METHODS: We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873. FINDINGS: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6. INTERPRETATION: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile. FUNDING: Cerevel Therapeutics.

Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-ß pathology but causes hyperexcitability and seizures.

Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-ß (Aß) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aß. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aß1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aß internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Substance use workforce training needs during intersecting epidemics: an analysis of events offered by a regional training center from 2017 to 2020.

BACKGROUND: Intersecting opioid overdose, COVID-19, and systemic racism epidemics have brought unprecedented challenges to the addiction treatment and recovery workforce. From 2017 to 2020, the New England Addiction Technology Transfer Center (ATTC) collected data in real-time on the training and technical assistance (TA) requested and attended by the front-line workforce. This article synthesizes practice-based evidence on the types of TA requests, topics of TA, attendance numbers, and socio-demographics of TA attendees over a 3-year period spanning an unprecedented public health syndemic. METHODS: We assessed TA events hosted by the New England ATTC using SAMHSA's Performance Accountability and Reporting System post-event survey data from 2017 to 2020. Events were coded by common themes to identify the most frequently requested training types/topics and most frequently attended training events. We also evaluated change in training topics and attendee demographics over the three-year timeline. RESULTS: A total of 258 ATTC events reaching 10,143 participants were analyzed. The number of TA events and attendance numbers surged in the 2019-2020 fiscal year as TA events shifted to fully virtual during the COVID-19 pandemic. The absolute number of opioid-related events increased, but the relative proportion remained stable over time. The relative proportions of events and attendance rates focused on evidence-based practice and health equity both increased over the 3-year period, with the largest increase after the onset of the pandemic and the murder of George Floyd. As events shifted to virtual, events were attended by providers with a broader range of educational backgrounds. CONCLUSIONS: Results of the current analysis indicate that the demand for TA increased during the pandemic, with a prioritization of TA focused on evidence-based practice and health equity. The practice-based evidence generated from the New England ATTC may help other training and TA centers to anticipate and nimbly respond to the needs of the workforce in the face of the intersecting epidemics.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Adjunctive Therapy in Adults With Major Depressive Disorder.

BACKGROUND: Long-term treatment is recommended in major depressive disorder (MDD) to prevent relapse and to restore functioning. The aim of this study (Orion; NCT01360866) was to assess the long-term safety, tolerability, and efficacy of open-label treatment with adjunctive brexpiprazole in adult patients with MDD. METHODS: Patients rolled over into this 52-week study (amended to 26 weeks) from 3 randomized, double-blind, placebo-controlled studies. Patients received brexpiprazole 0.5 to 3 mg/d (flexible dose) adjunct to their current antidepressant treatment. The primary outcome variable was the frequency and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed as a secondary objective using clinical rating scales. RESULTS: A total of 2944 patients were enrolled (1547 for 52 weeks, 1397 for 26 weeks), of whom 1895 (64.4%) completed the study. The TEAEs with incidence of 5% or greater were weight increase (17.7%), somnolence (8.0%), headache (7.2%), akathisia (6.7%), increased appetite (6.3%), insomnia (6.3%), fatigue (6.1%), viral upper respiratory tract infection (5.4%), and anxiety (5.2%). Most TEAEs were mild or moderate in severity. The mean increase in body weight was 2.7 kg to week 26 and 3.2 kg to week 52; 25.8% of patients had a weight increase of 7% or greater at any postbaseline visit. There were no clinically relevant findings related to extrapyramidal symptoms, prolactin, lipids, or glucose. Patients' symptoms and functioning showed continual improvement. CONCLUSIONS: Adjunctive treatment with open-label brexpiprazole 0.5 to 3 mg/d was generally well tolerated for up to 52 weeks in patients with MDD and was associated with continued improvement in efficacy measures and functional outcomes.

Efficacy and Safety of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia: a Randomized, Double-Blind, Placebo-Controlled Study.

Background: Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia. Methods: Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1-4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase. Those patients who met stability criteria for 12 weeks were randomized 1:1 to double-blind maintenance treatment with either brexpiprazole (at their stabilization dose) or placebo for up to 52 weeks. The primary efficacy endpoint was the time from randomization to impending relapse. Safety and tolerability were also assessed. Results: A total of 524 patients were enrolled, 202 of whom were stabilized on brexpiprazole and randomized to brexpiprazole (n=97) or placebo (n=105). Efficacy was demonstrated at a prespecified interim analysis (conducted after 45 events), and so the trial was terminated early. The final analysis showed that time to impending relapse was statistically significantly delayed with brexpiprazole treatment compared with placebo (P<.0001, log-rank test). The hazard ratio for the final analysis was 0.292 (95% confidence interval: 0.156, 0.548); mean dose at last visit, 3.6mg. The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (P<.0001). During the maintenance phase, the incidence of adverse events was comparable to placebo. Conclusions: or patients with schizophrenia already stabilized on brexpiprazole, maintenance treatment with brexpiprazole was efficacious, with a favorable safety profile.

Aripiprazole Once-Monthly in the Treatment of Acute Psychotic Episodes in Schizophrenia: Post Hoc Analysis of Positive and Negative Syndrome Scale Marder Factor Scores.

BACKGROUND: Long-acting injectable antipsychotics are treatment options for acute and long-term treatment of patients with schizophrenia. In a previously published 12-week randomized, double-blind, placebo-controlled clinical trial of patients with schizophrenia experiencing an acute psychotic episode, aripiprazole once-monthly 400 mg (AOM 400) produced significantly greater improvement than placebo on the primary endpoint, Positive and Negative Syndrome Scale (PANSS) total score at week 10. METHODS: To examine the efficacy of AOM 400 across a broader representation of schizophrenia symptoms, including agitation, a post hoc analysis of this trial was carried out to assess the change in PANSS Marder factor domains (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression) and the PANSS excited component (equivalent to Marder factor domain uncontrolled hostility/excitement plus the tension item) by comparing differences in change from baseline between AOM 400 and placebo using a mixed model for repeated measures. RESULTS: The differences between treatment and placebo for all factors were statistically significant, with improvements seen as early as week 1 or 2, and maintained through week 12. Thus, AOM 400, supplemented with oral aripiprazole in the first 2 weeks, showed significantly greater efficacy versus placebo in acutely ill patients with schizophrenia in all 5 Marder illness domains, as well as in agitation as conceptualized by the PANSS excited component score. CONCLUSIONS: These findings indicate that AOM 400 is efficacious across the spectrum of schizophrenia symptoms in acutely ill patients, with implications for both short-term and, by extension, long-term patient outcomes.

Effects of aripiprazole once-monthly on symptoms of schizophrenia in patients switched from oral antipsychotics.

OBJECTIVE: To assess the effects of aripiprazole once-monthly 400 mg (AOM 400) on clinical symptoms and global improvement in schizophrenia after switching from an oral antipsychotic. METHODS: In a multicenter, open-label, mirror-image, naturalistic study in patients with schizophrenia (>1 year, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), changes in efficacy measures were assessed during prospective treatment (6 months) with AOM 400 after switching from standard-of-care oral antipsychotics. During prospective treatment, patients were cross-titrated to oral aripiprazole monotherapy (1-4) weeks followed by open-label AOM 400 (24 weeks). Mean change from baseline of the open-label AOM 400 phase in Positive and Negative Syndrome Scale (PANSS) scores (total, positive and negative subscales) and Clinical Global Impression-Severity (CGI-S) scores; mean CGI-Improvement (CGI-I) score; and proportion of responders (≥30% decrease from baseline in PANSS total score or CGI-I score of 1 [very much improved] or 2 [much improved]) were assessed. RESULTS: PANSS and CGI-S scores improved from baseline (P<0.0001) and CGI-I demonstrated improvement at all time points. By the end of the study, 49.0% of patients were PANSS or CGI-I responders. CONCLUSIONS: In a community setting, patients with schizophrenia who were stabilized at baseline and switched to AOM 400 from oral antipsychotics showed clear improvements in clinical symptoms.

Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study.

BACKGROUND: Long-acting injectable formulations of antipsychotics are treatment alternatives to oral agents. AIMS: To assess the efficacy of aripiprazole once-monthly compared with oral aripiprazole for maintenance treatment of schizophrenia. METHOD: A 38-week, double-blind, active-controlled, non-inferiority study; randomisation (2:2:1) to aripiprazole once-monthly 400 mg, oral aripiprazole (10-30 mg/day) or aripiprazole once-monthly 50 mg (a dose below the therapeutic threshold for assay sensitivity). ( TRIAL REGISTRATION: clinicaltrials.gov, NCT00706654.) RESULTS: A total of 1118 patients were screened, and 662 responders to oral aripiprazole were randomised. Kaplan-Meier estimated impending relapse rates at week 26 were 7.12% for aripiprazole once-monthly 400 mg and 7.76% for oral aripiprazole. This difference (-0.64%, 95% CI -5.26 to 3.99) excluded the predefined non-inferiority margin of 11.5%. Treatments were superior to aripiprazole once-monthly 50 mg (21.80%, P < or = 0.001). CONCLUSIONS: Aripiprazole once-monthly 400 mg was non-inferior to oral aripiprazole, and the reduction in Kaplan-Meier estimated impending relapse rate at week 26 was statistically significant v. aripiprazole once-monthly 50 mg.

Diversity, equity, and inclusion in clinical trials: A practical guide from the perspective of a trial sponsor.

BACKGROUND: Considering diversity, equity, and inclusion (DEI) in clinical trials ensures that data collected for investigational treatments reflect the populations most likely to benefit from those therapies. Resources and recommendations regarding DEI were assembled by the trial sponsor to assist clinical trial development. METHODS: A cross-disciplinary team from the sponsoring organization was assembled to inform trial planning and collate resources that promote DEI throughout the clinical trial life cycle. RESULTS: Representatives from clinical operations, health economic outcomes research, medical affairs, patient advocacy, procurement, and research and development functional groups united together to implement DEI strategies in clinical trials. Planning strategies focus on eligibility, participant/patient engagement, feedback through patient advocacy organizations, and community interactions. Informed site, investigator, and vendor selection at trial startup supports efforts to recruit diverse target trial populations and engage underrepresented businesses; establishing relationships and demographic target-goal tracking should be maintained throughout trial management. Continued communication during trial closeout consolidates learnings and enhances partnerships with trial participants and patient advocacy organizations. The sponsoring organization continuously updates an internal library of resources to facilitate implementation of outlined strategies. CONCLUSIONS: This first iteration of guidance intends to improve the representation of target populations who will ultimately benefit from investigational therapies; to assist sponsor clinical trial teams in developing recruitment and retention plans; and to ensure compliance with federal granting agencies. The sponsoring organization anticipates data from future clinical trials will help characterize the impact of these initiatives to ensure evidence-based practices are used in future clinical trials to enhance DEI.

Brain Data Standards - A method for building data-driven cell-type ontologies.

Large-scale single-cell 'omics profiling is being used to define a complete catalogue of brain cell types, something that traditional methods struggle with due to the diversity and complexity of the brain. But this poses a problem: How do we organise such a catalogue - providing a standard way to refer to the cell types discovered, linking their classification and properties to supporting data? Cell ontologies provide a partial solution to these problems, but no existing ontology schemas support the definition of cell types by direct reference to supporting data, classification of cell types using classifications derived directly from data, or links from cell types to marker sets along with confidence scores. Here we describe a generally applicable schema that solves these problems and its application in a semi-automated pipeline to build a data-linked extension to the Cell Ontology representing cell types in the Primary Motor Cortex of humans, mice and marmosets. The methods and resulting ontology are designed to be scalable and applicable to similar whole-brain atlases currently in preparation.

Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392).

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode. METHODS: After a 9-24 week stabilization phase receiving single-blind ARI (10-30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery-Åsberg Depression Rating Scale total scores ≤ 12) with ARI+LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. RESULTS: A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30-1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5-121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and -1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). CONCLUSIONS: ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.

Actigraphy in mechanically ventilated pediatric ICU patients: comparison to PSG and evaluation of behavioral circadian rhythmicity.

Sleep disruption is common in pediatric intensive care unit (PICU) patients, but measuring sleep in this population is challenging. We aimed to evaluate the utility of actigraphy for estimating circadian rhythmicity in mechanically ventilated PICU patients and its accuracy for measuring sleep by comparing it to polysomnogram (PSG). We conducted a single-center prospective observational study of children 6 months - 17 years of age receiving mechanical ventilation and standard, protocolized sedation for acute respiratory failure, excluding children with acute or historical neurologic injury. We enrolled 16 children and monitored them with up to 14 days of actigraphy and 24 hours of simultaneous limited (10 channel) PSG. Daily actigraphy-based activity profiles demonstrated that patients had a high level of nighttime activity (30-41% of total activity), suggesting disrupted circadian activity cycles. Among n = 12 patients with sufficient actigraphy and PSG data overlap, actigraphy-based sleep estimation showed poor agreement with PSG-identified sleep states, with good sensitivity (94%) but poor specificity (28%), low accuracy (70%,) and low agreement (Cohen's kappa = 0.2, 95% CI = 0.08-0.31). Using univariate linear regression, we identified that Cornell Assessment of Pediatric Delirium scores were associated with accuracy of actigraphy but that other clinical factors including sedative medication doses, activity levels, and restraint use were not. In this population, actigraphy did not reliably discern between sleep and wake states. However, in select patients, actigraphy was able to distinguish diurnal variation in activity patterns, and therefore may be useful for evaluating patients' response to circadian-oriented interventions.

Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study.

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI+Li / Val) compared with placebo (PLB) adjunctive to Li or Val (PLB+Li / Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. METHODS: Patients with a current manic/mixed episode received Li or Val for at least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score ≥ 16 and ≤ 35% decrease from baseline at 2 weeks] received adjunctive single-blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤ 12] for 12 consecutive weeks were randomized to double-blind ARI (10-30 mg/day) or PLB+Li / Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated. RESULTS: A total of 337 patients were randomized to ARI+ Li / Val (n=168) or PLB+Li / Val (n=169). The Kaplan-Meier relapse rate at 52 weeks was 17% with ARI+Li / Val and 29% with PLB+Li / Val. ARI+Li / Val significantly delayed time to any relapse compared with PLB+Li / Val; hazard ratio=0.54 (95% confidence interval: 0.33-0.89; log-rank p=0.014). The most common AEs ≥ 5%(ARI+Li / Val versus PLB+Li / Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). CONCLUSIONS: Continuation of ARI+Li / Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one-year study. These findings suggest that there is a long-term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved.

Substance Use Workforce Training Needs during Intersecting Epidemics: An Analysis of Events Offered by a Regional Training Center from 2017-2020.

Background: Intersecting opioid overdose, COVID-19, and systemic racism epidemics havebrought unprecedented challenges to the addiction treatment and recovery workforce. From 2017-2020, the New England Addiction Technology Transfer Center (ATTC) collected data in real-time on the training and technical assistance (TA) requested and attended by the front-line workforce. This article synthesizes practice-based evidence on the types of TA requests, topics of TA, attendance numbers, and socio-demographics of TA attendees over a 3-year period spanning an unprecedented public health syndemic. Methods: We assessed TA events hosted by the New England ATTC using SAMHSA’s Performance Accountability and Reporting System post-event survey data from 2017-2020. Events were coded by common themes to identify the most frequently requested training types/topics and most frequently attended training events. We also evaluated change in training topics and attendee demographics over the three-year timeline. Results: A total of 258 ATTC events reaching 10,143 participants were analyzed. The number of TA events and attendance numbers surged in the 2019-2020 fiscal year as TA events shifted to fully virtual during the COVID-19 pandemic. The absolute number of opioid-related events increased, but the relative proportion remained stable over time. The relative proportions of events and attendance rates focused on evidence-based practice and health equity both increased over the 3-year period, with the largest increase after the onset of the pandemic and the murder of George Floyd. As events shifted to virtual, events were attended by providers with a broader range of educational backgrounds. Conclusions: Results of the current analysis indicate that the demand for TA increased during the pandemic, with a prioritization of TA focused on evidence-based practice and health equity. The practice-based evidence generated from the New England ATTC may help other training and TA centers to anticipate and nimbly respond to the needs of the workforce in the face of the intersecting epidemics.

Vasopressin Neurons: Master Integrators of Time and Homeostasis.

A recent article by Gizowski and Bourque shows that vasopressinergic (VP) neurons within the suprachiasmatic nucleus (SCN) master circadian clock have the ability of encoding afferent input from osmosensors and generating appropriate homeostatic responses, suggesting that SCN neurons can integrate internal circadian time and acute changes in homeostatic markers.

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study.

BACKGROUND: Well-tolerated and effective therapies for bipolar mania are required. AIMS: To evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Patients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks. RESULTS: Mean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7). Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%). CONCLUSIONS: Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.