Selective border permeability: Governing complex environmental issues through and beyond COVID-19.

COVID-19 has changed the permeability of borders in transboundary environmental governance regimes. While borders have always been selectively permeable, the pandemic has reconfigured the nature of cross-border flows of people, natural resources, finances and technologies. This has altered the availability of spaces for enacting sustainability initiatives within and between countries. In Southeast Asia, national governments and businesses seeking to expedite economic recovery from the pandemic-induced recession have selectively re-opened borders by accelerating production and revitalizing agro-export growth. Widening regional inequities have also contributed to increased cross-border flows of illicit commodities, such as trafficked wildlife. At the same time, border restrictions under the exigencies of controlling the pandemic have led to a rolling back and scaling down of transboundary environmental agreements, regulations and programs, with important implications for environmental democracy, socio-ecological justice and sustainability. Drawing on evidence from Southeast Asia, the article assesses the policy challenges and opportunities posed by the shifting permeability of borders for organising and operationalising environmental activities at different scales of transboundary governance.

An evaluation of the variation and underuse of clozapine in the United Kingdom.

BACKGROUND: Clozapine is the only licensed treatment for treatment refractory schizophrenia. Despite this, it remains grossly underused relative to the prevalence of refractory schizophrenia. The extent of underuse and the degree of regional variation in prescribing in the United Kingdom is unknown. It is also unclear, how the UK compares with other European countries in rates of clozapine prescribing. METHODS: We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We examined regional variation in clozapine use across England, corrected for the known prevalence of severe mental illness (SMI). We also compared the UK rate of clozapine use per 100,000 population to that described in other European countries. FINDINGS: There is substantial variation in clozapine prescribing across different regions of England and only about a third of potentially eligible patients were prescribed the drug in the UK. Clozapine prescribing rate in the UK was lower than in several European countries. INTERPRETATION: There is clear regional inequity in access to the most effective treatment in refractory schizophrenia in England. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia.

A prospective, randomized, double-blind trial of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department.

OBJECTIVE: To compare the efficacy of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department (ED). BACKGROUND: Migraine is a common, incapacitating neurological condition. Although chlorpromazine and prochlorperazine are known to be safe, efficacious treatments for migraine, they have never been directly compared. DESIGN: We performed a prospective, randomized, double-blind clinical trial at a tertiary hospital in Melbourne, Australia. Adults aged 18-65 years, who presented with migraine, were eligible for recruitment. Sixty-six patients were randomized to either chlorpromazine 12.5 mg or prochlorperazine 12.5 mg, both infused in 500 ml of sodium chloride 0.9% over 30 min. Headache severity score, nausea severity score, and the presence of photophobia and phonophobia were assessed at 0, 30, 60, and 120 min. Adverse effects and the need for rescue therapy were recorded. The primary outcome was a reduction in headache severity score from baseline at 60 min post-commencement of the study medicine infusion. RESULTS: Sixty-five patients were included in the analysis. There was a median reduction in headache severity score at 60 min of 3.0 (interquartile range 1.0-4.0) in the chlorpromazine arm versus 2.0 (1.0-4.0) in the prochlorperazine arm (median difference -0.5 (95% confidence interval, -1.9 to 0.9)). We saw no evidence of a difference in secondary outcomes at 30, 60, or 120 min. Side effects were reported in 16/32 (50%) patients in the chlorpromazine group versus 7/33 (21%) in the prochlorperazine group (p = 0.020). Rescue therapy was required in 7/32 (22%) patients in the chlorpromazine group versus 12/33 (36%) in the prochlorperazine group (p = 0.277). CONCLUSIONS: Both chlorpromazine and prochlorperazine are efficacious treatments for acute migraine in adult patients presenting to the ED. This trial found no evidence of superiority of either agent over the other. Caution should be used when prescribing these medicines in the borderline hypotensive patient; in that circumstance, prochlorperazine should be preferentially used.

The Effect of the Consent Process on Patient Satisfaction With Pain Management: A Randomized Controlled Trial.

STUDY OBJECTIVE: We aim to determine whether the timing and context of informed consent affects the subjective outcome of patient satisfaction with pain management. METHODS: We conducted a randomized controlled trial in a single emergency department (ED). Patients aged 18 years or older with a triage pain score of greater than or equal to 4 provided consent to participate in a pain management study. They were randomized to consent in the ED or at follow-up. All patients were followed up at 48 hours post-ED discharge. Patients who consented at follow-up were unaware of the study until cold called. The primary outcome was patient satisfaction with pain management. Secondary analyses examined effects on follow-up and participation rates. Variables associated with patients' being very satisfied were determined with multivariate logistic regression. RESULTS: Outcome data were obtained on 655 of 825 patients enrolled (79.4%). Patients who provided consent at follow-up were less likely to be very satisfied compared with those who consented in the ED (difference in proportions 11.5%; 95% confidence interval 3.5 to 19.4). Follow-up and participation rates did not differ between the groups. Patients who received pain advice and adequate analgesia (both as defined in this study) were more likely to be very satisfied (odds ratio 5.18, 95% confidence interval 2.82 to 9.52; and odds ratio 1.54, 95% confidence interval 1.07 to 2.22, respectively). CONCLUSION: The timing and context of informed consent significantly affect the subjective outcome of patient satisfaction, and this should be considered during study design. Clinicians should strive to provide pain advice and adequate analgesia to maximize their patients' satisfaction.

The CANBACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain.

OBJECTIVE: To assess the analgesic efficacy and safety of single-dose oral cannabidiol (CBD) as an adjunct to standard care for patients presenting to an emergency department with acute low back pain. DESIGN: Randomised, double blinded, placebo-controlled clinical trial. SETTING: The tertiary emergency department of Austin Hospital, Melbourne. PARTICIPANTS: Patients who presented with acute, non-traumatic low back pain between 21 May 2018 and 13 June 2019. INTERVENTION: One hundred eligible patients were randomised to receiving 400 mg CBD or placebo in addition to standard emergency department analgesic medication. MAIN OUTCOME MEASURES: Pain score two hours after administration of study agent, on a verbal numerical pain scale (range, 0-10). Secondary outcomes were length of stay, need for rescue analgesia, and adverse events. RESULTS: The median age of the 100 participants was 47 years (IQR, 34-60 years); 44 were women. Mean pain scores at two hours were similar for the CBD (6.2 points; 95% CI, 5.5-6.9 points) and placebo groups (5.8 points; 95% CI, 5.1-6.6 points; absolute difference, -0.3 points; 95% CI, -1.3 to 0.6 points). The median length of stay was 9.0 hours (IQR, 7.4-12 hours) for the CBD group and 8.5 hours (IQR, 6.5-21 hours) for the placebo group. Oxycodone use during the four hours preceding and the four hours after receiving CBD or placebo was similar for the two groups, as were reported side effects. CONCLUSION: CBD was not superior to placebo as an adjunct medication for relieving acute non-traumatic low back pain in the emergency department. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618000487213 (prospective).

Ethnopharmacology†.

BACKGROUND: Ethnopharmacology relates to the study of substances used medicinally by different ethnic or cultural groups or handling of, drugs-based ethnicity or pharmacogenetics. AIMS: To review the key aspects of ethnopharmacology. METHOD: This lecture gives an overview of the relationship between geography, culture, pharmacogenomics and prescribing. RESULTS: Although the majority of antipsychotics, antidepressants and mood-stabilisers are widely and cheaply available in generic forms, prescription rates can vary. Clozapine is one such example with prescribing-rates ranging from less than 10 patients per 100,000 people to nearly 180 patients/100,000 people. Pharmacogenetic studies of antipsychotics and antidepressants concern gene polymorphisms that may affect both, pharmacodynamic or pharmacokinetic properties. Considerable genetic and ethnic variability has been seen for the P450 microsomal enzymes CYP 2D6 and 1A2. CONCLUSIONS: With accelerated global mobility and increased understanding of medicinal substances at molecular level, understanding of ethnopharmacology will become increasingly important in routine clinical practice.

Reducing the stigma of long acting injectable antipsychotics - current concepts and future developments.

BACKGROUND: Long acting injectable antipsychotics (LAI-APs) are considered a major advance in psychiatric treatment concerning treatment adherence and outcomes. Yet, both, doctors and patients remain sceptical. AIM: To explain the rationale for using LAI-APs, review their effectiveness and explore barriers to use. METHOD: Clinical overview of LAI-APs from the patient and doctor's perspective. RESULTS: LAI-APs were developed to increase adherence to treatment, thereby improving treatment outcomes. LAI-APs may reduce the risk of relapse and hospitalisation. Yet, the evidence from the few meta-analyses available remains weak. Both patients and doctors may associate LAI-APs with stigma and coercion. Current means of improving adherence include more focus on the therapeutic relationship, better information, adverse effects minimisation and half-life extension of LAI-APs. Future means of improving adherence include novel administration techniques that abolish the need for injection. CONCLUSIONS: For both, clinicians and drug developers, drug adherence remains a major target for improving treatment outcomes.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. METHODS/PROCEDURES: We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. FINDINGS/RESULTS: We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred. IMPLICATIONS/CONCLUSIONS: Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Impact of disease on the survival of three commercially fished species.

Recent increases in emergent infectious diseases have raised concerns about the sustainability of some marine species. The complexity and expense of studying diseases in marine systems often dictate that conservation and management decisions are made without quantitative data on population-level impacts of disease. Mark-recapture is a powerful, underutilized, tool for calculating impacts of disease on population size and structure, even in the absence of etiological information. We applied logistic regression models to mark-recapture data to obtain estimates of disease-associated mortality rates in three commercially important marine species: snow crab (Chionoecetes opilio) in Newfoundland, Canada, that experience sporadic epizootics of bitter crab disease; striped bass (Morone saxatilis) in the Chesapeake Bay, USA, that experience chronic dermal and visceral mycobacteriosis; and American lobster (Homarus americanus) in the Southern New England stock, that experience chronic epizootic shell disease. All three diseases decreased survival of diseased hosts. Survival of diseased adult male crabs was 1% (0.003-0.022, 95% CI) that of uninfected crabs indicating nearly complete mortality of infected crabs in this life stage. Survival of moderately and severely diseased striped bass (which comprised 15% and 11% of the population, respectively) was 84% (70-100%, 95% CI), and 54% (42-68%, 95% CI) that of healthy striped bass. The disease-adjusted yearly natural mortality rate for striped bass was 0.29, nearly double the previously accepted value, which did not include disease. Survival of moderately and severely diseased lobsters was 30% (15-60%, 95% CI) that of healthy lobsters and survival of mildly diseased lobsters was 45% (27-75%, 95% CI) that of healthy lobsters. High disease mortality in ovigerous females may explain the poor recruitment and rapid declines observed in this population. Stock assessments should account for disease-related mortality when resource management options are evaluated.

Anticholinergic effect on cognition (AEC) of drugs commonly used in older people.

OBJECTIVE: Use of anticholinergic drugs in older people is associated with increased risk of cognitive decline and of dementia and death. METHOD: We identified drugs widely used in older people and attempted to classify their anticholinergic effect on cognition (AEC) according to our three-point scale which scored AEC according to in vitro anticholinergic potency, capacity to cross the blood-brain barrier and statements made in standard texts. RESULTS: In total, 165 drugs were examined. We identified 21 drugs with an AEC score of 3, 18 with a score of 2, 21 with a score of 1 and 62 with a score of 0. Owing to insufficient information, we were unable to classify 43 drugs. CONCLUSIONS: A large number of drugs commonly used in older people are likely to be associated with cognitive impairment. Copyright © 2016 John Wiley & Sons, Ltd.

Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases.

BACKGROUND: Serotonin syndrome is a toxic state, caused by serotonin (5HT) excess in the central nervous system. Serotonin syndrome's main feature is neuro-muscular hyperexcitability, which in many cases is mild but in some cases can become life-threatening. The diagnosis of serotonin syndrome remains challenging since it can only be made on clinical grounds. Three diagnostic criteria systems, Sternbach, Radomski and Hunter classifications, are available. Here we test the validity of four assumptions that have become widely accepted: (1) The Hunter classification performs clinically better than the Sternbach and Radomski criteria; (2) in contrast to neuroleptic malignant syndrome, the onset of serotonin syndrome is usually rapid; (3) hyperthermia is a hallmark of severe serotonin syndrome; and (4) serotonin syndrome can readily be distinguished from neuroleptic malignant syndrome on clinical grounds and on the basis of medication history. METHODS: Systematic review and meta-analysis of all cases of serotonin syndrome and toxicity published between 2004 and 2014, using PubMed and Web of Science. RESULTS: Two of the four assumptions (1 and 2) are based on only one published study each and have not been independently validated. There is little agreement between current criteria systems for the diagnosis of serotonin syndrome. Although frequently thought to be the gold standard for the diagnosis of the serotonin syndrome, the Hunter criteria did not perform better than the Sternbach and Radomski criteria. Not all cases seem to be of rapid onset and only relatively few cases may present with hyperthermia. The 0 differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome is not always clear-cut. CONCLUSIONS: Our findings challenge four commonly made assumptions about serotonin syndrome. We propose our meta-analysis of cases (MAC) method as a new way to systematically pool and interpret anecdotal but important clinical information concerning uncommon or emergent phenomena that cannot be captured in any other way but through case reports.

MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.

We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and that this therapeutic effect is associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show that enhancing MKP-1 expression is sufficient to achieve neuroprotection in lentiviral models of HD. Wild-type MKP-1 overexpression inhibited apoptosis in primary striatal neurons exposed to an N-terminal fragment of polyglutamine-expanded huntingtin (Htt171-82Q), blocking caspase-3 activation and significantly reducing neuronal cell death. This neuroprotective effect of MKP-1 was demonstrated to be dependent on its enzymatic activity, being ablated by mutation of its phosphatase domain and being attributed to inhibition of specific MAP kinases (MAPKs). Overexpression of MKP-1 prevented the polyglutamine-expanded huntingtin-induced activation of c-Jun N-terminal kinases (JNKs) and p38 MAPKs, whereas extracellular signal-regulated kinase (ERK) 1/2 activation was not altered by either polyglutamine-expanded Htt or MKP-1. Moreover, mutants of MKP-1 that selectively prevented p38 or JNK binding confirmed the important dual contributions of p38 and JNK regulation to MKP-1-mediated neuroprotection. These results demonstrate additive effects of p38 and JNK MAPK inhibition by MKP-1 without consequence to ERK activation in this striatal neuron-based paradigm. MKP-1 also provided neuroprotection in vivo in a lentiviral model of HD neuropathology in rat striatum. Together, these data extend previous evidence that JNK- and p38-mediated pathways contribute to HD pathogenesis and, importantly, show that therapies simultaneously inhibiting both JNK and p38 signaling pathways may lead to improved neuroprotective outcomes.

Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs.

Background: Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). Objectives: We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. Design: We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Methods: Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Results: Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Conclusion: Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

Computer-based research on the best way to reduce the dose and eventually stop three depot antipsychotics What is the problem? Psychosis affects how someone experiences reality. Antipsychotics are used to treat psychosis. They work by blocking a chemical called dopamine. Stopping these too rapidly can cause psychosis to occur again. This might be because the dopamine block is removed suddenly. Sometimes antipsychotics are given by injection. Injections stay in the body for a longer time than tablets. The best way to reduce these injections is currently unknown. What did we do? We explored the best way to reduce and stop antipsychotic injections. We looked at three different types of psychosis injection. We used existing data to assess how these drugs affect the brain. We examined what would happen if an antipsychotic injection was suddenly stopped. We then evaluated the effect of reducing the dose gradually. What did we find? Stopping antipsychotic injections suddenly would lead to rapid changes at brain receptors. This might lead to symptoms of withdrawal and a high risk of psychosis recurring. Reducing the dose of injections leads to less change than stopping suddenly. Switching to a tablet allows for more control when reducing dose. Having injections more often also reduce the changes occurring between injections. We outline three different rates of dose reduction. What does this mean? Antipsychotic injections stay in the body longer than tablets. However, stopping injections suddenly may still not be safe. We recommend that people reduce the dose of their injection instead. We also recommend people switch to tablets or liquid before stopping. It should be noted that our research is computer-based. We would like to see our recommendations tested in the real world.

Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases.

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

STUDY OBJECTIVE: Parenteral benzodiazepines or antipsychotics are often used to manage acute agitation in emergency department (ED) settings in which alternative strategies have failed or are not feasible. There are scant data comparing parenteral medication regimens. We aim to determine the efficacy and safety of intravenous droperidol or olanzapine as an adjunct to intravenous midazolam for rapid patient sedation. METHODS: We undertook a randomized, double-blind, placebo-controlled, double-dummy, clinical trial in 3 EDs (August 2009 to March 2011). Adult patients (n=336) requiring intravenous drug sedation for acute agitation were randomized to receive a saline solution (control), droperidol (5 mg), or olanzapine (5 mg) bolus. This was immediately followed by incremental intravenous midazolam boluses (2.5 to 5 mg) until sedation was achieved. The primary outcome was time to sedation. Secondary outcomes were need for "rescue" drugs and adverse events. RESULTS: Three hundred thirty-six patients were randomized to the 3 groups. Baseline characteristics were similar across groups. The differences in medians for times to sedation between the control and droperidol and control and olanzapine groups were 4 minutes (95% confidence interval [CI] 1 to 6 minutes) and 5 minutes (95% CI 1 to 6 minutes), respectively. At any point, patients in the droperidol and olanzapine groups were approximately 1.6 times more likely to be sedated compared with controls: droperidol and olanzapine group hazard ratios were 1.61 (95% CI 1.23 to 2.11) and 1.66 (95% CI 1.27 to 2.17), respectively. Patients in the droperidol and olanzapine groups required less rescue or alternative drug use after initial sedation. The 3 groups' adverse event profiles and lengths of stay did not differ. CONCLUSION: Intravenous droperidol or olanzapine as an adjunct to midazolam is effective and decreases the time to adequate sedation compared with midazolam alone.

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.

Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.

Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study.

Gradual, hyperbolic tapering has been proposed as a method to reduce the risk of withdrawal effects and potential relapse of an underlying condition by minimising disruption of existing equilibria. We applied hyperbolic tapering principles in silico to long-acting aripiprazole to generate regimens for withdrawal in clinical practice. We derived thresholds for taper rates using existing studies and consensus. Using pharmacokinetic data for aripiprazole long-acting injectable antipsychotic (ALAI), we conducted in silico modelling to examine the impact of abrupt cessation of long-acting injectable antipsychotic (LAI) medication and the effect of prolonging inter-dose interval on plasma aripiprazole levels and consequent D2 occupancy. We also modelled transitions from LAI medication to oral medication. Regimens were designed to afford a rate of reduction between 5 and 12.5 percentage points of D2 occupancy per month. Abrupt discontinuation of ALAI was shown to lead to a maximal D2 occupancy reduction of 16.8 percentage points per month; prolongation of the inter-dose interval of ALAI produced a slower reduction. Specifically, hyperbolic tapering was afforded by prolongation of a 400 mg ALAI inter-dose interval from 4 to 7 weeks, before reducing the dose to 300 mg ALAI. This could then be administered at up to 4-week (for 6% maximal D2 occupancy change), 6-week (9% change) or 7-week (11% change) intervals. Switching to oral medication - 5, 2.5 and 1.25 mg for the three regimens, respectively - is required for ALAI to complete full cessation to prevent too rapid a reduction in D2 occupancy. Oral medication should probably be maintained at a consistent dose for 3-6 months before further reductions to account for residual LAI being concurrently eliminated. Hyperbolic dose tapering is possible with ALAI through prolongation of the inter-dose interval and may reduce the risk of relapse compared to abrupt discontinuation of LAI medication.

Data-Driven Taxonomy for Antipsychotic Medication: A New Classification System.

BACKGROUND: Globally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous classification does not reflect the diversity of their pharmacological and clinical profiles. There is a need for a data-driven antipsychotic classification scheme suitable for clinicians and researchers that maps onto both pharmacological and clinical effects. Receptor affinity provides one starting point for such a scheme. METHODS: We analyzed affinities of 27 antipsychotics for 42 receptors from 3325 in vitro receptor binding studies. We used a clustering algorithm to group antipsychotics based on receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced clinical effects quantified according to an umbrella review of clinical trial and treatment guideline data. RESULTS: Clustering resulted in 4 groups of antipsychotics. The predominant receptor affinity and clinical effect "fingerprints" of these 4 groups were defined as follows: group 1, muscarinic (M2-M5) receptor antagonism (cholinergic and metabolic side effects); group 2, dopamine (D2) partial agonism and adrenergic antagonism (overall low side-effect burden); group 3, serotonergic and dopaminergic antagonism (overall moderate side-effect burden); and group 4, dopaminergic antagonism (extrapyramidal side effects and hyperprolactinemia). Groups 1 and 4 were more efficacious than groups 2 and 3. The classification was shown to predict out-of-sample clinical effects of individual drugs. CONCLUSIONS: A receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences. This approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development.

BACKGROUND: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. METHODS: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). FINDINGS: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. INTERPRETATION: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. FUNDING: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.