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Background: Patients with cancer often experience nausea. In some cases, a specific cause such as chemotherapeutic adverse effects, raised intracranial pressure or malignant bowel obstruction is identified. In other cases, no specific cause is apparent., Objective: This article summarises the evidence-based management of nausea in advanced cancer. It includes the nausea of select, specific contexts such as raised intracranial pressure and bowel obstruction., Discussion: It is not commonly appreciated that low-dose oral haloperidol is the standard of care arm for many trials looking to reduce nausea in advanced cancer. It is available cheaply through the Pharmaceutical Benefits Scheme. The relative merits of other medications are discussed, as are the merits of an empiric versus a mechanistic approach to treatment.

Background: Schizophrenia is often a severe and disabling psychiatric disorder. Antipsychotics remain the mainstay of psychotropic treatment for people with psychosis. In limited resource and humanitarian contexts, it is key to have several options for beneficial, low-cost antipsychotics, which require minimal monitoring. We wanted to compare oral haloperidol, as one of the most available antipsychotics in these settings, with a second-generation antipsychotic, olanzapine., Objectives: To assess the clinical benefits and harms of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia-spectrum disorders., Search Methods: We searched the Cochrane Schizophrenia study-based register of trials, which is based on monthly searches of CENTRAL, CINAHL, ClinicalTrials.gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. We screened the references of all included studies. We contacted relevant authors of trials for additional information where clarification was required or where data were incomplete. The register was last searched on 14 January 2023., Selection Criteria: Randomised clinical trials comparing haloperidol with olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. Our main outcomes of interest were clinically important change in global state, relapse, clinically important change in mental state, extrapyramidal side effects, weight increase, clinically important change in quality of life and leaving the study early due to adverse effects., Data Collection and Analysis: We independently evaluated and extracted data. For dichotomous outcomes, we calculated risk ratios (RR) and their 95% confidence intervals (CI) and the number needed to treat for an additional beneficial or harmful outcome (NNTB or NNTH) with 95% CI. For continuous data, we estimated mean differences (MD) or standardised mean differences (SMD) with 95% CIs. For all included studies, we assessed risk of bias (RoB 1) and we used the GRADE approach to create a summary of findings table., Main Results: We included 68 studies randomising 9132 participants. We are very uncertain whether there is a difference between haloperidol and olanzapine in clinically important change in global state (RR 0.84, 95% CI 0.69 to 1.02; 6 studies, 3078 participants; very low-certainty evidence). We are very uncertain whether there is a difference between haloperidol and olanzapine in relapse (RR 1.42, 95% CI 1.00 to 2.02; 7 studies, 1499 participants; very low-certainty evidence). Haloperidol may reduce the incidence of clinically important change in overall mental state compared to olanzapine (RR 0.70, 95% CI 0.60 to 0.81; 13 studies, 1210 participants; low-certainty evidence). For every eight people treated with haloperidol instead of olanzapine, one fewer person would experience this improvement. The evidence suggests that haloperidol may result in a large increase in extrapyramidal side effects compared to olanzapine (RR 3.38, 95% CI 2.28 to 5.02; 14 studies, 3290 participants; low-certainty evidence). For every three people treated with haloperidol instead of olanzapine, one additional person would experience extrapyramidal side effects. For weight gain, the evidence suggests that there may be a large reduction in the risk with haloperidol compared to olanzapine (RR 0.47, 95% CI 0.35 to 0.61; 18 studies, 4302 participants; low-certainty evidence). For every 10 people treated with haloperidol instead of olanzapine, one fewer person would experience weight increase. A single study suggests that haloperidol may reduce the incidence of clinically important change in quality of life compared to olanzapine (RR 0.72, 95% CI 0.57 to 0.91; 828 participants; low-certainty evidence). For every nine people treated with haloperidol instead of olanzapine, one fewer person would experience clinically important improvement in quality of life. Haloperidol may result in an increase in the incidence of leaving the study early due to adverse effects compared to olanzapine (RR 1.99, 95% CI 1.60 to 2.47; 21 studies, 5047 participants; low-certainty evidence). For every 22 people treated with haloperidol instead of olanzapine, one fewer person would experience this outcome. Thirty otherwise relevant studies and several endpoints from 14 included studies could not be evaluated due to inconsistencies and poor transparency of several parameters. Furthermore, even within studies that were included, it was often not possible to use data for the same reasons. Risk of bias differed substantially for different outcomes and the certainty of the evidence ranged from very low to low. The most common risks of bias leading to downgrading of the evidence were blinding (performance bias) and selective reporting (reporting bias)., Authors' Conclusions: Overall, the certainty of the evidence was low to very low for the main outcomes in this review, making it difficult to draw reliable conclusions. We are very uncertain whether there is a difference between haloperidol and olanzapine in terms of clinically important global state and relapse. Olanzapine may result in a slightly greater overall clinically important change in mental state and in a clinically important change in quality of life. Different side effect profiles were noted: haloperidol may result in a large increase in extrapyramidal side effects and olanzapine in a large increase in weight gain. The drug of choice needs to take into account side effect profiles and the preferences of the individual. These findings and the recent inclusion of olanzapine alongside haloperidol in the WHO Model List of Essential Medicines should increase the likelihood of it becoming more easily available in low- and middle- income countries, thereby improving choice and providing a greater ability to respond to side effects for people with lived experience of schizophrenia. There is a need for additional research using appropriate and equivalent dosages of these drugs. Some of this research needs to be done in low- and middle-income settings and should actively seek to account for factors relevant to these. Research on antipsychotics needs to be person-centred and prioritise factors that are of interest to people with lived experience of schizophrenia., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: To systematically review the evidence about the effect of haloperidol on postoperative delirium in elderly patients., Methods: PubMed, Embase, the Cochrane Library and China National Knowledge Infrastructure were used to find concerned studies for meta-analysis. The main outcome was the incidence of postoperative delirium, and the secondary outcomes were side effects of haloperidol and the length of hospital stay. The meta-analyses were conducted using the Review Manager Version 5.1. This study was conducted based on the PRISMA statement., Results: Eight RCTs (1569 patients) were included in the meta-analysis. There was a significant difference in the incidence of postoperative delirium between haloperidol and control groups (OR = 0.62, 95%CI 0.48-0.80, P = 0.0002, I 2  = 20%). In addition, side effects of haloperidol and the duration of hospitalization were comparable (OR = 0.58, 95%CI 0.25-1.35, P = 0.21, I 2  = 0%; MD =-0.01, 95%CI -0.16-0.15, P = 0.92, I 2  = 28%). Subgroup analysis implied the effect of haloperidol on postoperative delirium might vary with the dose (5 mg daily: OR = 0.40, 95%CI 0.22-0.71, P = 0.002, I 2  = 0%; <5 mg daily: OR = 0.72, 95%CI 0.42-1.23, P = 0.23, I 2  = 0%)., Conclusions: The meta-analysis revealed perioperative application of haloperidol could decrease the occurrence of postoperative delirium without obvious side effects in elderly people, and high-dose haloperidol (5 mg daily) possessed a greater positive effect., (© 2024. The Author(s).)

To date, haloperidol has been widely used to treat patients with acute alcoholic hallucinosis. There is strong evidence that haloperidol therapy is commonly associated with adverse drug reactions (ADRs). The 392A > G polymorphism of the CYP3A4 * 1B gene (rs2740574) is known to affect the metabolism rates of haloperidol; hence it correlates with both therapy efficacy and safety parameters., Objective: The study objective was to investigate the effect of 392A > G polymorphism of the CYP3A4 * 1B gene (rs2740574) on the efficacy and safety profiles of haloperidol in patients with acute alcoholic hallucinosis., Methods: This study enrolled 100 male patients suffering from acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile of haloperidol was assessed using the PANSS (Positive and Negative Syndrome Scale) validated psychometric scale. The safety profile of therapy was assessed with the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR)., Results: There were no statistically significant results for the efficacy rates (dynamics of the PANSS score: AA genotype -14.00 [-16.00; -12.00], AG genotype -13.00 [-14.00; -10.50], p = 0.306). Similarly, there was no statistically significant difference in the safety profiles (dynamics of the UKU score: AA genotype - 9.00 [7.00; 13.00], AG genotype - 8.50 [7.25; 10.50], p = 0.620; dynamics of the SAS score: AA genotype -12.00 [10.00; 16.75], AG genotype - 10.00 [10.00; 12.25], p = 0.321)., Conclusion: The study demonstrated that the 392A > G polymorphism of the CYP3A4 * 1B gene (rs2740574) in patients with acute alcoholic hallucinosis does not affect the efficacy and safety rates of haloperidol therapy., (Copyright © 1964–2023 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Haloperidol is currently used in addictology for the treatment of acute psychotic disorders, including acute alcoholic hallucinosis. The use of haloperidol is often accompanied by the occurrence of adverse drug reactions (ADRs). There is evidence that CYP2D6 isoenzyme is involved in the biotransformation of haloperidol., Aim: The study aimed to evaluate the relationship of 1846G > A polymorphism of the CYP2D6 gene to the equilibrium concentration levels of haloperidol in patients with acute alcoholic hallucinosis., Material and Methods: The study was conducted on 100 male patients with acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile was evaluated using the PANSS (Positive and Negative Syndrome Scale) scale. The safety of therapy was assessed using the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Equilibrium plasma concentration levels of haloperidol were investigated using the high-performance liquid chromatography with mass spectrometry (HPLC with MS/MS)., Results: No statistically significant results were obtained during the therapy efficacy assessment (dynamics of the PANSS score: GG genotype (-13.00 [-16.00; -16.00; -11.00]), GA genotype (-15.00 [-16.75; -13.00], p = 0.728). There was a statistically significant difference in safety assessment scores (dynamics of the UKU score: GG genotype (8.00 [7.00; 10.00]), GA genotype (15.00 [9.25; 18.00], p < 0.001); dynamics of the SAS score: GG genotype (11.00 [9.00; 14.00]), GA genotype (14.50 [12.00; 18.00], p < 0.001). The pharmacokinetic study results showed a statistically significant difference: GG (3.13 [2.32; 3.95]), GA (3.89 [2.92; 5.26], p = 0.010). Thus, a study conducted on a group of 100 patients with acute alcoholic hallucinosis demonstrated an association between the 1846G > A polymorphism of the CYP2D6 gene ( rs3892097 ) and the safety profile of haloperidol therapy. We also revealed the presence of statistically significant difference in the equilibrium concentration levels of haloperidol in patients with the GG and AG genotypes., Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients carrying the GG genotype. It is shown that 1846G > A polymorphism of the CYP2D6 gene ( rs3892097 ) has a statistically significant effect on the equilibrium concentration levels of haloperidol., (Copyright © 1964–2023 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Antipsychotics are commonly prescribed to treat several neuropsychiatric disorders, including schizophrenia, mania in bipolar disorder, autism spectrum disorder, delirium, and organic or secondary psychosis, for example, in dementias such as Alzheimer's disease. There is evidence that typical antipsychotics such as haloperidol are more effective in reducing positive symptoms than negative symptoms and/or cognitive deficits. In contrast, atypical antipsychotic agents have gained popularity over typical antipsychotics, due to fewer extrapyramidal side effects and their theoretical efficacy in controlling both positive and negative symptoms. Although these therapies focus on neuron-based therapeutic schemes, glial cells have been recognized as important regulators of the pathophysiology of neuropsychiatric disorders, as well as targets to improve the efficacy of these drugs. Glial cells (astrocytes, oligodendrocytes, and microglia) are critical for the central nervous system in both physiological and pathological conditions. Astrocytes are the most abundant glial cells and play important roles in brain homeostasis, regulating neurotransmitter systems and gliotransmission, since they express a wide variety of functional receptors for different neurotransmitters. In addition, converging lines of evidence indicate that psychiatric disorders are commonly associated with the triad neuroinflammation, oxidative stress, and excitotoxicity, and that glial cells may contribute to the gliotoxicity process. Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning. In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism. This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glioprotective molecules to improve the action of antipsychotics., Competing Interests: Declaration Of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium., Methods: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life., Results: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I 2  = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I 2  = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo., Conclusions: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients., Trial Registration: CRD42017081133, date of registration 28 November 2017., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance., Experimental Design: Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells., Results: In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis., Conclusions: Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application., (©2023 American Association for Cancer Research.)

Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic treatment in SCZ improves positive symptoms but has major side effects and little impact on negative symptoms and cognitive impairment. The pathoetiology of SCZ remains unclear, but is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)-treated male mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced VD impairment. Fasudil also significantly suppressed the increase in the number of c-Fos-positive cells in the infralimbic medial prefrontal cortex (infralimbic mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, another Rho kinase inhibitor, into the infralimbic mPFC or DMS significantly ameliorated METH-induced VD impairment. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Oral administration of haloperidol and fasudil ameliorated METH-induced VD impairment, while clozapine had little effect. Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit., Competing Interests: Declaration of Competing Interest This study was funded in part by Sumitomo Pharma Co., Ltd., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Motor disturbances are observed in schizophrenia patients, but the neuroanatomical background is unknown. Our aim was to investigate the pyramidal cells of the primary motor cortex (BA 4) in both hemispheres of postmortem control and schizophrenia subjects-8 subjects in each group-with 2.5-5.5 h postmortem interval. The density and size of the Sternberger monoclonal incorporated antibody 32 (SMI32)-immunostained pyramidal cells in layer 3 and 5 showed no change; however, the proportion of larger pyramidal cells is decreased in layer 5. Giant pyramidal neurons (Betz cells) were investigated distinctively with SMI32- and parvalbumin (PV) immunostainings. In the right hemisphere of schizophrenia subjects, the density of Betz cells was decreased and their PV-immunopositive perisomatic input showed impairment. Part of the Betz cells contained PV in both groups, but the proportion of PV-positive cells has declined with age. The rat model of antipsychotic treatment with haloperidol and olanzapine showed no differences in size and density of SMI32-immunopositive pyramidal cells. Our results suggest that motor impairment of schizophrenia patients may have a morphological basis involving the Betz cells in the right hemisphere. These alterations can have neurodevelopmental and neurodegenerative explanations, but antipsychotic treatment does not explain them., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Brexpiprazole is an atypical antipsychotic drug widely used in Japan for the treatment of schizophrenia. Previous studies have investigated the therapeutic effects of some antipsychotics on sleep variables; however, to our knowledge, the effects of brexpiprazole on sleep architecture have not been examined in patients with schizophrenia. Therefore, we aimed to exploratorily investigate the effect of brexpiprazole on sleep variables measured by polysomnography in patients with schizophrenia., Methods: This study included 10 patients with schizophrenia who were originally treated with haloperidol alone. Sleep variables of the participants were measured using polysomnography. After excluding those who did not meet the study criteria, seven patients (five men and two women; mean age [SD], 59.0 [10.0] years) were eligible for further analysis. Polysomnography was repeated at 4 weeks after the participants were prescribed brexpiprazole in addition to haloperidol. We compared the sleep architecture of the participants, measured using polysomnography, before and after taking brexpiprazole., Results: Add-on brexpiprazole significantly prolonged rapid eye movement latency, increased the duration and percentage of stage N2 and stage N3 sleep (min, %), and decreased the duration and percentage of stage rapid eye movement sleep (min, %) at a significance level of nominal p < 0.05., Conclusion: Although not significant after correcting for multiple comparisons, the present results showed that add-on brexpiprazole could alter the sleep architecture of patients with schizophrenia. Future studies are warranted to replicate these findings and to further investigate the beneficial influence of brexpiprazole on sleep., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Importance: There are limited data on discontinuation rates of antipsychotic medications (APMs) used to treat delirium due to acute hospitalization in the routine care of older adults., Objective: To investigate discontinuation rates and patient characteristics of APMs used to treat delirium following infection-related hospitalization among older US adults., Design, Setting, and Participants: This retrospective cohort study was conducted using US claims data (Optum's deidentified Clinformatics Data Mart database) for January 1, 2004, to May 31, 2022. Patients were aged 65 years or older without prior psychiatric disorders and had newly initiated an APM prescription within 30 days of an infection-related hospitalization. Statistical analysis was performed on December 15, 2022., Exposures: New use (no prior use any time before cohort entry) of oral haloperidol and atypical APMs (aripiprazole, olanzapine, quetiapine, risperidone, etc)., Main Outcomes and Measures: The primary outcome was APM discontinuation, defined as a gap of more than 15 days following the end of an APM dispensing. Survival analyses and Kaplan-Meier analyses were used., Results: Our study population included 5835 patients. Of these individuals, 790 (13.5%) were new haloperidol users (mean [SD] age, 81.5 [6.7] years; 422 women [53.4%]) and 5045 (86.5%) were new atypical APM users (mean [SD] age, 79.8 [7.0] years; 2636 women [52.2%]). The cumulative incidence of discontinuation by 30 days after initiation was 11.4% (95% CI, 10.4%-12.3%) among atypical APM users and 52.1% (95% CI, 48.2%-55.7%) among haloperidol users (P < .001 for difference between haloperidol vs atypical APMs). We observed an increasing trend in discontinuation rates from 2004 to 2022 (5% increase [95% CI, 3%-7%] per year) for haloperidol users (adjusted hazard ratio, 1.05 [1.03-1.07]; P < .001) but not for atypical APM users (1.00 [0.99-1.01]; P = .67). Prolonged hospitalization and dementia were inversely associated with the discontinuation of haloperidol and atypical APMs., Conclusions and Relevance: The findings of this cohort study suggest that the discontinuation rate of newly initiated APMs for delirium following infection-related hospitalization was lower in atypical APM users than in haloperidol users, with prolonged hospitalization and dementia as major associated variables. The discontinuation rate was substantially higher in recent years for haloperidol but not for atypical APMs.

Question: Are antipsychotic dose equivalents between acute mania and schizophrenia the same?, Study Selection and Analysis: Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia., Findings: We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%)., Conclusions: Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

Schizophrenia (SCZ) is a severe mental illness mainly characterized by a number of psychiatric symptoms. Obsessive-compulsive disorder (OCD) is a long-lasting and devastating mental disorder. SCZ has high co-occurrence with OCD resulting in the emergence of a concept entitled "schizo-obsessive disorder" as a new specific clinical entity with more severe psychiatric symptoms. Many studies have been done on SCZ and OCD, but the common pathogenesis between them is not clear yet. Therefore, this study aimed to identify shared genetic basis, potential biomarkers and therapeutic targets between these two disorders. Gene sets were extracted from the Geneweaver and Harmonizome databases for each disorder. Interestingly, the combination of both sets revealed 89 common genes between SCZ and OCD, the most important of which were BDNF, SLC6A4, GAD1, HTR2A, GRIN2B, DRD2, SLC6A3, COMT, TH and DLG4. Then, we conducted a comprehensive bioinformatics analysis of the common genes. Receptor activity as the molecular functions, neuron projection and synapse as the cellular components as well as serotonergic synapse, dopaminergic synapse and alcoholism as the pathways were the most significant commonalities in enrichment analyses. In addition, transcription factor (TFs) analysis predicted significant TFs such as HMGA1, MAPK14, HINFP and TEAD2. Hsa-miR-3121-3p and hsa-miR-495-3p were the most important microRNAs (miRNAs) associated with both disorders. Finally, our study predicted 19 existing drugs (importantly, Haloperidol, Fluoxetine and Melatonin) that may have a potential influence on this co-occurrence. To summarize, this study may help us to better understand and handle the co-occurrence of SCZ and OCD by identifying potential biomarkers and therapeutic targets., (© 2023. The Author(s).)

Coprophagia or the ingestion of faeces has been associated with medical conditions (seizure disorders, cerebral atrophy and tumours) and psychiatric disorders (mental retardation, alcoholism, depression, obsessive compulsive disorder, schizophrenia, fetishes, delirium and dementia). The case of a woman in her 30s presenting with coprophagia and psychotic symptoms following hypoxic brain injury is reported. The case is discussed and literature is reviewed. We investigate cariprazine, a relatively new atypical antipsychotic for treating coprophagia, associated with psychotic symptoms. Psychiatric evaluation revealed cognitive dysfunction and psychotic symptoms. Physical examination and laboratory evaluation were unremarkable. She was treated with haloperidol resulting in resolution of coprophagia. Attempts at switching to alternative antipsychotics, due to side effects, resulted in recurrence of coprophagia. Subsequent relapses required higher doses of haloperidol for remission of coprophagia and psychotic symptoms. She finally responded to cariprazine. While firm conclusions are not possible from the experience of a single case, we suggest cariprazine may also be a treatment option for coprophagia, particularly in patients with psychotic symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antipsychotic medications are frequently prescribed in acute care for clinical indications other than primary psychiatric disorders such as delirium. Unfortunately, they are commonly continued at hospital discharge and at follow-ups thereafter. The objective of this scoping review was to characterize antipsychotic medication prescribing practices, to describe healthcare professional perceptions on antipsychotic prescribing and deprescribing practices, and to report on antipsychotic deprescribing strategies within acute care., Methods: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Web of Science databases from inception date to July 3, 2021 for published primary research studies reporting on antipsychotic medication prescribing and deprescribing practices, and perceptions on those practices within acute care. We included all study designs excluding protocols, editorials, opinion pieces, and systematic or scoping reviews. Two reviewers screened and abstracted data independently and in duplicate. The protocol was registered on Open Science Framework prior to data abstraction (10.17605/OSF.IO/W635Z)., Results: Of 4528 studies screened, we included 80 studies. Healthcare professionals across all acute care settings (intensive care, inpatient, emergency department) perceived prescribing haloperidol (n = 36/36, 100%) most frequently, while measured prescribing practices reported common quetiapine prescribing (n = 26/36, 76%). Indications for antipsychotic prescribing were delirium (n = 48/69, 70%) and agitation (n = 20/69, 29%). Quetiapine (n = 18/18, 100%) was most frequently prescribed at hospital discharge. Three studies reported in-hospital antipsychotic deprescribing strategies focused on pharmacist-driven deprescribing authority, handoff tools, and educational sessions., Conclusions: Perceived antipsychotic prescribing practices differed from measured prescribing practices in acute care settings. Few in-hospital deprescribing strategies were described. Ongoing evaluation of antipsychotic deprescribing strategies are needed to evaluate their efficacy and risk., (© 2022. The Author(s).)

Objectives: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data., Design: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation., Setting: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge., Participants: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium., Primary and Secondary Outcome Measures: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium., Results: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days., Conclusions: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients., Competing Interests: Competing interests: NU, MI, KO, HS, KT, ST and SO are employees of MSD KK, Tokyo, Japan, a subsidiary of Merck & Co Inc, Rahway, New Jersey, USA, and may own stock and/or hold stock options in Merck & Co Inc, Rahway, New Jersey, USA. ZPQ is an employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, New Jersey, USA, and may own stock and/or hold stock options in Merck & Co Inc, Kenilworth, New Jersey, USA. AO and YO have received funding from MSD KK, Tokyo, Japan for research consulting., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of this survey was to identify areas where doctors have divergent practices in pharmacological treatment for hyperactive delirium in terminally ill patients with cancer., Methods: We conducted a survey of Japanese palliative care physicians and liaison psychiatrists. Inquiries were made regarding: (i) choice of drug class in the first-line treatment, (ii) administration methods of the first-line antipsychotic treatment, (iii) starting dose of antipsychotics in the first line treatment and maximum dose of antipsychotics in refractory delirium, and (iv) choice of treatment when the first-line haloperidol treatment failed. Respondents used a five-point Likert scale., Results: Regarding choice of drug class in the first-line treatment, more doctors reported that they 'frequently' or 'very frequently' use antipsychotics only than antipsychotics and benzodiazepine (oral: 73.4 vs. 12.2%; injection: 61.3 vs. 11.6%, respectively). Regarding administration methods of the first-line antipsychotic treatment, the percentage of doctors who reported that they used antipsychotics as needed and around the clock were 55.4 and 68.8% (oral), 49.2 and 45.4% (injection), respectively. There were different opinions on the maximum dose of antipsychotics in refractory delirium. Regarding the choice of treatment when the first-line haloperidol treatment failed, the percentage of doctors who reported that they increased the dose of haloperidol, used haloperidol and benzodiazepines, and switched to chlorpromazine were 47.0, 32.1 and 16.4%, respectively., Conclusions: Doctors have divergent practices in administration methods of the first-line antipsychotic treatment, maximum dose of antipsychotics, and choice of treatment when the first-line haloperidol treatment failed. Further studies are needed to determine the optimal treatment., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study was conducted to compare the response rate of Quetiapine and Haloperidol in patients with acute manic episodes. A total of 120 patients with acute episode of mania with baseline Young Mania Rating Scale (YMRS) of more than 20 were included and randomly allocated to either Quetiapine (Group A) or Haloperidol (Group B). Each patient was assessed at baseline. YMRS was administered at the start and at follow-up visit after six weeks. Comparison of response rate (>50% reduction in YMRS) was not statistically significant between the two groups (70% vs. 71.7%; p=0.410) after six weeks in acute manic episode. Quetiapine and Haloperidol emerged as equally effective pharmacological strategies for the treatment of bipolar mania. Quetiapine may be used as an alternative to conventional antipsychotics; Haloperidol can be used as replacement of Quetiapine as well, as it is of low cost.

Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX , Sox2 , BDNF , and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells' proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL's/OLA's inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes' expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes' expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.

Although correct diagnosis and management of patients with schizophrenia and a comorbid substance use disorder (SUD) would determine a decrease in morbidity and mortality in these patients, development of efficient therapeutic strategies is still pending. We present recommendations on the pharmacological and psychological management of these patients following the 'PICO' structure (Patient-Intervention-Comparison-Outcomes). Evaluation of the quality of studies and summary of the evidence for each question was performed following the recommendations of the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) working group. Our results suggest: 1) In patients with schizophrenia and cannabis use disorder, it is not possible to recommend one antipsychotic drug over another (between olanzapine, risperidone or haloperidol) for improving psychotic symptoms, reducing cannabis use, or improving pragmatic variables (weak recommendation). Clozapine cannot be recommended to reduce cannabis use (weak recommendation). 2) In patients with schizophrenia and cocaine use disorder we recommend haloperidol over olanzapine to reduce craving (moderate recommendation), and olanzapine over haloperidol to improve motor side effects in these patients (moderate recommendation). 3) In patients with schizophrenia and alcohol use disorder while naltrexone is recommended to reduce alcohol use (in terms of reducing alcohol craving) (weak recommendation), there is insufficient evidence to make any recommendation on the use of adjuvant acamprosate (weak recommendation). 4) In patients with schizophrenia and nicotine use disorder, adjuvant bupropion and varenicline are recommended for reducing nicotine use and nicotine abstinence (strong/moderate recommendation). 5) In patients with schizophrenia and polydrug use disorder, second-generation over first-generation antipsychotic drugs and olanzapine over other second-generation antipsychotics are recommended to improve psychotic symptoms (moderate/weak recommendation).

Background: Chronic psychotic disorders (CPD) impose a particularly significant burden in resource-limited settings. Combining long-acting antipsychotic medication (LAI) with a customized adherence enhancement intervention (CAE-L) has potential to advance care., Methods: Nineteen adults ≥ age 18 with CPD who self-reported missing ≥20% of antipsychotic medication within the last month were stabilized on oral haloperidol prior to transitioning to monthly haloperidol decanote for 25 weeks. Outcome evaluations were conducted at baseline and Week 25. Primary outcomes were oral medication adherence assessed via the Tablet Routines Questionnaire (TRQ) and LAI injection frequency. Secondary outcomes included CPD symptoms measured by the Brief Psychiatric Rating Scale and Clinical Global Impressions, functioning evaluated using the Social and Occupational Functioning Scale, and medication attitudes assessed with the Drug Attitudes Inventory., Results: Mean sample age was 38.79 (SD = 9.31) with 18 individuals completing the study. There was one serious adverse event, a relapse into substance use, not deemed study-related. Mean endpoint LAI dosage was 65.79 mg (SD = 22.38). TRQ mean scores were 21.84 (SD =13.83) and 12.94 (SD = 11.93) at screen and baseline respectively. For only two individuals who were on concomitant oral medication at 25 weeks, TRQ change was not calculated. LAI injection frequency was 100%. Medication attitudes scores significantly improved from 7.89 (SD = 2.72) to 9.83 (SD = 0.52) (p = .001.) Changes in CPD symptoms and functioning were non-significant., Conclusions: CAE-L appears to be preliminarily feasible and acceptable in Tanzanians with CPD., Trial Registration: The study was registered on ClinicalTrials.gov (NCT04327843) on March 31, 2020., (© 2022. The Author(s).)

Background: The use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as an add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review, we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors, antipsychotics, and psychostimulants., Methods: MEDLINE and Web of Science were searched., Results: Twenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of 5 studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine's antidepressant effect. For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, 2 other studies did not. Four papers investigated risperidone, including 3 neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia but not in healthy participants. One paper reported no effect of olanzapine on ketamine's acute psychotomimetic effects., Conclusion: Current literature shows that benzodiazepines and probably lamotrigine reduce ketamine's treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol, and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

To study the efficacy and safety of intranasal administration of 5 mg haloperidol on mild-moderate agitated patients with schizophrenia or schizoaffective disorder in an acute psychiatry unit setting.

Introduction: Haloperidol (HL) has successfully been used for nausea and abdominal pain in emergency departments (EDs). This study examines outcomes and predictive factors for clinical improvement of patients presenting to an ED with gastrointestinal (GI) symptoms (nausea, vomiting, and abdominal pain) who received HL., Methods: Review of patients' records who presented to our ED between August 2016 and March 2019 with GI symptoms and received HL. International Classification of Diseases, Tenth Revision codes were used to identify patients., Results: In all, 281 patients (410 encounters) presented to the ED with GI symptoms and received HL for their symptoms: 66% were women, 32% had diabetes, 68% used marijuana, and 27% used chronic opioids. Patients received HL 1.1 ± 0.3 times with dose 2.5 ± 3.0 mg, mostly intravenously (84.6%). Total ED length of stay was 7.5 ± 3.9 hours (3.2 ± 2.1 hours before HL and 4.4 ± 3.4 hours after). Approximately 4.4% of patients developed side effects to HL, including 2 patients with dystonia which improved with medication before discharge. Most patients (56.6%) were discharged home while 43.2% were admitted to hospital mostly because of refractory nausea or vomiting (70.1%). Receiving HL as the only medication in the ED led to lower hospital admission (odds ratio = 0.25, P < 0.05). Diabetes, cannabinoid use, anxiety, male sex, and longer ED stay were associated with increased hospital admissions., Discussion: Most patients treated in our ED with HL for GI symptoms, particularly nausea, vomiting, and/or abdominal pain, were successfully treated and discharged home. HL use seemed relatively safe and, when used as the only medication, led to less frequent hospital admissions., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Delirium is a common disorder among hospitalized older patients and results in increased morbidity and mortality. The prevention of delirium is still challenging in older patient care. The role of antipsychotics in delirium prevention has been limited. Therefore, we conducted a trial to investigate the efficacy of quetiapine use to prevent delirium in hospitalized older medical patients., Methods: This study was a randomized double-blind controlled trial conducted at Ramathibodi Hospital, Bangkok, Thailand. Patients aged ≥65 years hospitalized in the internal medicine service were randomized to quetiapine 12.5 mg or placebo once daily at bedtime for a maximum 7-day duration. The primary end point was delirium incidence. Secondary end points were delirium duration, length of hospital stay, ICU admission, rehospitalization and mortality within 30 and 90 days., Results: A total of 122 patients were enrolled in the study. Eight (6.6%) left the trial before receiving the first dose of the intervention, whereas 114 (93.4%) were included in an intention-to-treat analysis allocated to the quetiapine or placebo group (n = 57 each). The delirium incidence rates in the quetiapine and placebo groups were 14.0 and 8.8% (OR = 1.698, 95% CI 0.520-5.545, P = 0.381), respectively. Other endpoints in the quetiapine and placebo groups were the median length of hospital stay, 6 (4-8) days versus 5 (4-8) days (P = 0.133), respectively; delirium duration, 4 (2.3-6.5) versus 3 (1.5-4.0) days (P = 0.557), respectively; ICU admission, 3 (5.3%) patients from both groups (P = 1.000); and mortality in the quetiapine and placebo groups, 1 (1.8%) versus 2 (3.5%) at 30 days (P = 0.566) and 7 (12.3%) versus 9 (15.8%) days at 90 days (P = 0.591). There were no significant differences in other outcomes. None of the participants reported adverse events., Conclusions: Quetiapine prophylaxis did not reduce delirium incidence in hospitalized older medical patients. The use of quetiapine to prevent delirium in this population group should not be recommended., Trial Registration: This trial was retrospectively registered with the Thai clinical trials registry (TCTR) at clinicaltrials.in.th (TCTR20190927001) on September 26, 2019.

Background: In this quality improvement project, we set out to study the effectiveness and feasibility of using music as an adjunct or replacement for pharmacologic agitation management on an inpatient psychiatric unit. We hypothesized music intervention would not only assist in de-escalation/calming of agitated patients, but also reduce overall administration of PRN medications on the unit., Method: The project included 172 volunteer participants over 6 months: Three months without music available and 3 months with a music de-escalation option. During the latter period, patients were given the option of selecting a preferred music genre and provided with wireless headphones for up to 30 min. The number of as needed (PRN) medications administered for agitation and anxiety (including oral, sublingual, and intramuscular routes) was compiled from raw data using pharmacy records. Patients and nurses were provided with self-report surveys regarding the music intervention., Results: The average weekly PRN medication administrations decreased significantly during the 3 months with music for both haloperidol (8.46 [+/- 1.79, p < 0.05] to 5.00 [+/- 1.44, p < 0.05] administrations/week) and olanzapine (9.69 [+/- 2.32, p < 0.05] to 4.62 [+/- 1.51, p < 0.05] administrations/week), compared to the 3 months prior to music implementation. There was a non-significant increase in administration of lorazepam (3.23 [+/- 1.09, p < 0.05] to 6.38 [+/- 2.46, p < 0.05] average administrations/week). The patient survey responses were 96% positive (non-neutral; either agree or strongly agree with calming effect). Nurses agreed that the project was easy to implement; 56% agreed that music helped to calm patients down. Other exploratory outcomes included observed reductions in average length of hospital stay and number of seclusion events., Conclusion: Music may play a significant role in reducing the utilization of PRN agitation medications on acute inpatient psychiatric units. More studies are needed to expand on these findings and explore the effect of PRN music on other therapeutic outcomes., Trial Registration: Protocol registration NCT04514432 , retrospectively registered on 08/13/2020.

Objective: To study plasma adipokines (adiponectin, leptin, adipsin) in patients with the first episode of schizophrenia treated with haloperidol and risperidone., Material and Methods: Two hundred and twelve patients with the first episode of paranoid schizophrenia (F20.09) were examined. Patients were divided into the haloperidol group ( n =107) and the risperidone group ( n =105). The control group included 132 healthy people. Body mass index was recorded at baseline and in 2, 4, 6, 8 week of treatment. Adiponectin, adipsin and leptin were determined by the multiplex analysis. Blood test was conducted prior to therapy and after 8 weeks of treatment., Results: An increase in body mass index is recorded in both clinical groups, with no statistically significant differences between groups. Before treatment with antipsychotics, the levels of adiponectin and adipsin increase in both clinical groups. In the course of therapy, the levels of adiponectin and adipsin significantly increase in the haloperidol group and the levels of adiponectin and leptin in the risperidone group., Conclusion: The increase in body weight is not the only mechanism of changes in adipokines in blood during treatment with antipsychotics. Further studies on the relationship between the levels of adipokines and pharmacogenic metabolic disorders are required.

Individual response to medication depends on several factors (age, gender, body weight, general clinical condition, genetics, diet, hydration status, comorbidities, co-administered drugs and their mode of administration, smoking, alcohol overuse, environmental factors, e.g. sunlight) that may contribute to adverse drug reactions even at therapeutic doses. Patients in palliative care are at increased risk of these reactions. Unwanted drug effects diminish the quality of life and may lead to a suboptimal dying process. Haloperidol is one of the three most commonly used drugs in palliative care and the most commonly employed typical antipsychotic. It has also been recommended for inclusion into the palliative care emergency kit of home care teams. As such, it is important to be fully conversant with the indications, benefits, and risks of haloperidol, especially in the context of palliative care., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking-based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19. KEY MESSAGES: •Inhibitors of sigma receptors are considered as potent drugs against COVID-19. •Antipsychotic drug, haloperidol, binds strongly to NSP6 and induces the minimal changes in structure and dynamics of NSP6. •Dextromethorphan, agonist of sigma receptors, binding leads to overall destabilization of NSP6. •These two drugs bind with NSP6 differently and also induce differences in the structural and conformational changes that explain their different mechanisms of action. •Haloperidol can be explored as a candidate drug against COVID-19.

Recently, the herbal medicine Ukgansan (Yigansan in China, Yokukansan in Japan) was reported to be effective in the management of movement disorders. We report the case of a 62-year-old woman with herpes simplex encephalitis exhibiting atypical abnormal movements in the chronic stage. While controlling the abnormal movements with haloperidol, an antipsychotic agent, we prescribed Ukgansan-gami, an extract of a variant of Ukgansan, at a dose of 12 g/day to prevent the recurrence of abnormal movements and allow for the discontinuation of haloperidol. The patient was successfully treated with Ukgansan-gami, with no further recurrence of symptoms, making the use of haloperidol no longer necessary. The potential mechanism of action of Ukgansan involves the inhibition of nervous system hyperexcitability through the suppression of glutamate sodium channels, as well as attenuation of hypermotility through serotonin regulation. The present case suggests that herbal medicine therapy was likely to be an alternative to antipsychotics., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Delirium is one of the most frequently reported neuropsychiatric complications in the perioperative period, especially in the population of elderly patients who often suffer from numerous comorbidities undergoing extensive or urgent surgery. It can affect up to 80% of patients who require hospitalization in an intensive care setting postoperatively. Delirium increases mortality, morbidity, length of hospital stay, and cost of treatment. An episode of delirium in the acute phase may lower the general quality of life and increases the risk of cognitive decline long-term. Since pharmacological treatment of delirium is not highly effective, focus of research has shifted towards developing preventive strategies. We aimed to perform a review of the topic based on the most recent literature. We conclude that, based on the available data, it seems impossible to make strong recommendations for using antipsychotic drugs in prophylaxis. Further research should answer the question what, if any, benefit patients receive from the pharmacological prevention of delirium, and which agents should be used.

Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness. Dosing recommendations however are often based on strategies used in patients with normal body habitus. Recommendations specific to critically ill patients with extreme obesity are lacking. Nonetheless, clinicians must craft dosing regimens for this population. This paper is intended to help clinicians design initial dosing regimens for medications commonly used in the management of pain, agitation, and delirium in critically ill patients with extreme obesity. A detailed literature search was conducted with an emphasis on obesity, pharmacokinetics, and dosing. Relevant manuscripts were reviewed and strategies for dosing are provided.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In the current analysis, we searched for SARS-CoV-2 sequences within the human genome. To compare the SARS-CoV-2 genome to the human genome, we used the blast-like alignment tool (BLAT) of the University of California, Santa Cruz Genome Browser. BLAT can align a user sequence of 25 bases or more to the genome. BLAT search results revealed a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 orf1b (open reading frames) gene. The SARS-CoV-2 human sequence lies within non-structural proteins 14 and 15 (NSP14 and NSP15), and is quite close to the viral spike sequence, separated only by NSP16, a 904-base pair sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 and internalization of the complex by the host cell. It is probably no accident that a sequence from the SARS-CoV-2 orf1b gene is found in the human NTNG1 gene, implicated in schizophrenia, and that haloperidol, used to treat schizophrenia, may also be a treatment for COVID-19. We suggest, therefore, that it is important to investigate other haloperidol analogs. Among them are benperidol, bromperidol, bromperidol decanoate, droperidol, seperidol hydrochloride, and trifluperidol. These analogs might be valuable in the treatment of COVID-19 and other coronavirus infections., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Nausea is a mental sensation of unease and discomfort before vomiting. Vomiting refers to the return of the contents of the upper gastrointestinal tract to the mouth caused by contractions of chest and abdomen muscles. Postoperative nausea and vomiting is an unpleasant experience with high treatment costs. Therefore, this study aimed to compare the effects of haloperidol, metoclopramide, dexmedetomidine, and ginger on postoperative nausea and vomiting after laparoscopy. This double-blind clinical trial was performed on all laparoscopy candidates at Valiasr hospital, Arak, Iran. The patients were randomly divided into four groups (haloperidol, metoclopramide, dexmedetomidine and ginger), and all patients underwent general anesthesia using fentanyl, midazolam, atracurium, and propofol. After intubation, tube fixation, and stable hemodynamic conditions, the patients received four ginger capsules with a hint of lemon. A group of patients received 25 μg of dexmedetomidine. In the Plasil group, 10 mg of metoclopramide was given 30 minutes before the completion of surgery. In addition, 0.5 cc of haloperidol (5 mg) was administered to a group of patients. Heart rate, blood pressure, and oxygen saturation were recorded from the beginning of surgery, every 15 minutes until the end of the surgery. Furthermore, the occurrence of nausea and vomiting was recorded during recovery, 2 and 4 hours after surgery. Data were then analyzed using the SPSS software v.23. Eighty-eight patients were enrolled in the study. The youngest and the oldest were 30 years and 70 years old, respectively, and the mean age was 48.02 ± 9.31 years. Moreover, the number of women in the four groups was higher than that of men. Blood pressure in the dexmedetomidine group was lower than the other four groups (P <0.05). The lowest heart rate was observed in the haloperidol group, while the highest heart rate was seen in the plasil group (P <0.05). The occurrence of vomiting and nausea was not significantly different between the four groups (P <0.05). Our results showed no significant difference in postoperative nausea and vomiting between the four drugs. Due to the hemodynamic changes induced by each drug, it is best to use these drugs based on the patient's condition. Ginger is also a herbal remedy that has fewer side effects, and this drug can be a good option for patients when there is no contraindication., (©Carol Davila University Press.)

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to examine molecular associations of HTR1A, HTR1B, HTR2A, HTR2C and HTR6 gene polymorphisms with acute EPS in 229 male schizophrenia patients, following two weeks of haloperidol monotherapy. The Simpson-Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS) were used to evaluate EPS severity. Genotyping was performed using real-time PCR, following extraction of blood DNA. Significant acute EPS appeared in 48.03% of schizophrenia patients. For the rs13212041 HTR1B gene polymorphism, affecting microRNA regulation of HTR1B gene expression, a higher frequency of TT carriers was found among haloperidol-treated patients with akathisia when compared to the group without akathisia symptoms. In comparison to C-allele carriers, patients carrying the TT genotype had higher akathisia severity, as determined by the SAS, BARS and ESRS scales. These molecular findings suggest potential involvement of 5-HT 1B receptors in akathisia development following haloperidol treatment, as well as possible epigenetic mechanisms of serotonergic modulation associated with antipsychotic-induced EPS.

Background: Delirium is a very common condition associated with significant morbidity, mortality, and costs. Current critical care guidelines recommend first and foremost the use of nonpharmacological strategies in both the prevention and treatment of delirium. Pharmacological interventions may augment these approaches and they are currently used widely in clinical practice to manage the symptoms of delirium. Benzodiazepines are currently used in clinical practice to treat behavioural disturbances associated with delirium but current guidelines do not recommend their use for this indication. The use of these medicines is controversial because there is uncertainty about whether they are effective for patients or have the potential to harm them., Objectives: To assess the effectiveness and safety of benzodiazepines in the treatment of delirium (excluding delirium related to withdrawal from alcohol or benzodiazepines) in any healthcare settings other than intensive care units (ICU)., Search Methods: We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register up to 10 April 2019. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (including MEDLINE, Embase, PsycINFO, CINAHL, LILACS), numerous trial registries (including national, international and pharmaceutical registries), and grey literature sources., Selection Criteria: We included randomised controlled trials (RCTs) conducted in healthcare settings that ranged from nursing homes and long-term care facilities to any hospital setting except for ICUs, involving adult patients with delirium excluding those with delirium related to alcohol or benzodiazepine withdrawal. Included RCTs had to assess the effect of benzodiazepines, at any dose and given by any route, compared with placebo or another drug intended to treat delirium., Data Collection and Analysis: Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of included studies. We decided whether or not to pool data on the basis of clinical heterogeneity between studies. We used GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods to assess the quality of evidence., Main Results: We identified only two trials that satisfied the selection criteria. We did not pool the data because of the substantial clinical differences between the trials. In one trial, participants (n = 58) were patients in an acute palliative care unit with advanced cancer who had a mean age of 64 years. All of the participants had delirium, were treated with haloperidol, and were randomised to receive either lorazepam or placebo in combination with it. Due to very serious imprecision, all evidence was of low certainty. We were unable to determine whether there were clinically important differences in the severity of delirium (mean difference (MD) 2.10, 95% CI -0.96 to 5.16; n = 50), length of hospital admission (MD 0.00, 95% CI -3.45 to 3.45; n = 58), mortality from all causes (risk ratio (RR) 0.33, 95% CI 0.04 to 3.02; participants = 58) or any of a number of adverse events. Important effects could not be confirmed or excluded. The study authors did not report the length of the delirium episode. In the other trial, participants (n = 30) were patients in general medical wards with acquired immune deficiency syndrome (AIDS) who had a mean age of 39.2 years. Investigators compared three drug treatments: all participants had delirium, and were randomised to receive lorazepam, chlorpromazine, or haloperidol. Very low-certainty evidence was identified, and we could not determine whether lorazepam differed from either of the other treatments in the effect on severity of delirium, any adverse event, or mortality from all causes. The study authors did not report the length of the delirium episode or the length of hospital admission., Authors' Conclusions: There is no enough evidence to determine whether benzodiazepines are effective when used to treat patients with delirium who are cared for in non-ICU settings. The available evidence does not support their routine use for this indication. Because of the scarcity of data from randomised controlled trials, further research is required to determine whether or not there is a role for benzodiazepines in the treatment of delirium in non-ICU settings., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Delirium is a syndrome characterised by an acute disturbance of attention and awareness which develops over a short time period and fluctuates in severity over the course of the day. It is commonly experienced during inpatient admission in the terminal phase of illness. It can cause symptoms such as agitation and hallucinations and is distressing for terminally ill people, their families and staff. Delirium may arise from any number of causes and treatment should aim to address these causes. When this is not possible, or treatment is unsuccessful, drug therapy to manage the symptoms may become necessary. This is the second update of the review first published in 2004., Objectives: To evaluate the effectiveness and safety of drug therapies to manage delirium symptoms in terminally ill adults., Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO from inception to July 2019, reference lists of retrieved papers, and online trial registries., Selection Criteria: We included randomised controlled trials of drug therapies in any dose by any route, compared to another drug therapy, a non-pharmacological approach, placebo, standard care or wait-list control, for the management of delirium symptoms in terminally ill adults (18 years or older)., Data Collection and Analysis: We independently screened citations, extracted data and assessed risk of bias. Primary outcomes were delirium symptoms; agitation score; adverse events. Secondary outcomes were: use of rescue medication; cognitive status; survival. We applied the GRADE approach to assess the overall quality of the evidence for each outcome and we include eight 'Summary of findings' tables., Main Results: We included four studies (three new to this update), with 399 participants. Most participants had advanced cancer or advanced AIDS, and mild- to moderate-severity delirium. Meta-analysis was not possible because no two studies examined the same comparison. Each study was at high risk of bias for at least one criterion. Most evidence was low to very low quality, downgraded due to very serious study limitations, imprecision or because there were so few data. Most studies reported delirium symptoms; two reported agitation scores; three reported adverse events with data on extrapyramidal effects; and none reported serious adverse events. 1. Haloperidol versus placebo There may be little to no difference between placebo and haloperidol in delirium symptoms within 24 hours (mean difference (MD) 0.34, 95% confidence interval (CI) -0.07 to 0.75; 133 participants). Haloperidol may slightly worsen delirium symptoms compared with placebo at 48 hours (MD 0.49, 95% CI 0.10 to 0.88; 123 participants with mild- to moderate-severity delirium). Haloperidol may reduce agitation slightly compared with placebo between 24 and 48 hours (MD -0.14, 95% -0.28 to -0.00; 123 participants with mild- to moderate-severity delirium). Haloperidol probably increases extrapyramidal adverse effects compared with placebo (MD 0.79, 95% CI 0.17 to 1.41; 123 participants with mild- to moderate-severity delirium). 2. Haloperidol versus risperidone There may be little to no difference in delirium symptoms with haloperidol compared with risperidone within 24 hours (MD -0.42, 95% CI -0.90 to 0.06; 126 participants) or 48 hours (MD -0.36, 95% CI -0.92 to 0.20; 106 participants with mild- to moderate-severity delirium). Agitation scores and adverse events were not reported for this comparison. 3. Haloperidol versus olanzapine We are uncertain whether haloperidol reduces delirium symptoms compared with olanzapine within 24 hours (MD 2.36, 95% CI -0.75 to 5.47; 28 participants) or 48 hours (MD 1.90, 95% CI -1.50 to 5.30, 24 participants). Agitation scores and adverse events were not reported for this comparison. 4. Risperidone versus placebo Risperidone may slightly worsen delirium symptoms compared with placebo within 24 hours (MD 0.76, 95% CI 0.30 to 1.22; 129 participants); and at 48 hours (MD 0.85, 95% CI 0.32 to 1.38; 111 participants with mild- to moderate-severity delirium). There may be little to no difference in agitation with risperidone compared with placebo between 24 and 48 hours (MD -0.05, 95% CI -0.19 to 0.09; 111 participants with mild- to moderate-severity delirium). Risperidone may increase extrapyramidal adverse effects compared with placebo (MD 0.73 95% CI 0.09 to 1.37; 111 participants with mild- to moderate-severity delirium). 5. Lorazepam plus haloperidol versus placebo plus haloperidol We are uncertain whether lorazepam plus haloperidol compared with placebo plus haloperidol improves delirium symptoms within 24 hours (MD 2.10, 95% CI -1.00 to 5.20; 50 participants with moderate to severe delirium), reduces agitation within 24 hours (MD 1.90, 95% CI 0.90 to 2.80; 52 participants), or increases adverse events (RR 0.70, 95% CI -0.19 to 2.63; 31 participants with moderate to severe delirium). 6. Haloperidol versus chlorpromazine We are uncertain whether haloperidol reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 0.37, 95% CI -4.58 to 5.32; 24 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with chlorpromazine (MD 0.46, 95% CI -4.22 to 5.14; 24 participants). 7. Haloperidol versus lorazepam We are uncertain whether haloperidol reduces delirium symptoms compared with lorazepam at 48 hours (MD -4.88, 95% CI -9.70 to 0.06; 17 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with lorazepam (MD -6.66, 95% CI -14.85 to 1.53; 17 participants). 8. Lorazepam versus chlorpromazine We are uncertain whether lorazepam reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 5.25, 95% CI 0.38 to 10.12; 19 participants), or increases adverse events (MD 7.12, 95% CI 1.08 to 15.32; 18 participants). Agitation scores were not reported., Secondary Outcomes: use of rescue medication, cognitive impairment, survival There were insufficient data to draw conclusions or assess GRADE., Authors' Conclusions: We found no high-quality evidence to support or refute the use of drug therapy for delirium symptoms in terminally ill adults. We found low-quality evidence that risperidone or haloperidol may slightly worsen delirium symptoms of mild to moderate severity for terminally ill people compared with placebo. We found moderate- to low-quality evidence that haloperidol and risperidone may slightly increase extrapyramidal adverse events for people with mild- to moderate-severity delirium. Given the small number of studies and participants on which current evidence is based, further research is essential., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Involuntary movements can be a troublesome condition and represent a real challenge for emergency doctors, particularly for patients of paediatric age. We report a case of a 17-year-old boy with painful involuntary movements mostly affecting his mouth and lower limbs, but also the trunk. After reviewing the patient's history, it was revealed that the adolescent had had acute alcohol intoxication with severe acute agitation and therefore was given a single dose of 10 mg intravenous haloperidol. The concealment of the recent event posed serious difficulties in reaching the diagnosis. When the diagnosis of haloperidol-induced acute dystonia was made, 3 mg of intravenous biperiden was promptly administered with complete clinical resolution in 15 min., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This Japanese, multicenter, randomized, double-blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia., Methods: A total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions-Improvement (CGI-I) and the Positive and Negative Syndrome Scale (PANSS)., Results: Blonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI-I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (-10.3 vs -7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed., Conclusions: Blonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Agitated and aggressive behaviours are common in the psychiatric setting and rapid tranquilisation is sometimes unavoidable. A survey of Lebanese practice has shown that an intramuscular haloperidol, promethazine and chlorpromazine combination is a preferred form of treatment but there are no randomised trials of this triple therapy. Methods: This is a pragmatic randomised trial. Setting - the psychiatric wards of the Psychiatric Hospital of the Cross, Jal Eddib, Lebanon. Participants - any adult patient in the hospital who displays an aggressive episode for whom rapid tranquilisation is unavoidable, who has not been randomised before, for whom there are no known contraindications. Randomisation - stratified (by ward) randomisation and concealed in closed opaque envelope by independent parties. Procedure - if the clinical situation arises requiring rapid tranquilisation, medical residents overseeing the patient will open a TREC-Lebanon envelope in which will be notification of which group of treatments should be preferred [Haloperidol + Promethazine + Chlorpromazine (HPC) or Haloperidol + Promethazine (HP)], along with forms for primary, secondary and serious adverse effects. Treatment is not given blindly. Outcome - primary outcome is calm or tranquil at 20 minutes post intervention. Secondary outcomes are calm/tranquil at 40, 60 and 120 minutes post intervention, asleep, adverse effects, use of straitjacket and leaving the ward. Follow-up will be up to two weeks post randomisation. Discussion: Findings from this study will compare the HPC versus HP combination used in Lebanon's psychiatry emergency routine practice. Trial registration: ClinicalTrials.gov NCT03639558. Registration date, August 21, 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Dib JE et al.)

Background: Respiratory adverse events are not uncommon in the post-anesthesia care unit (PACU) following general anesthesia. In this regard, hyperventilation leading to apnea and desaturation is a rare entity. Here we have reported a case of a 15-year-old girl who, following an uneventful general anesthesia, developed severe hyperventilation leading to apnea and desaturation in the PACU., Case Presentation: The 15-year-old girl underwent cortical mastoidectomy under general anesthesia. After a smooth anesthesia and an uneventful early recovery, she developed hyperventilation after about 15 min in the PACU. The symptom was severe enough to lead to apnea, desaturation and severe respiratory alkalosis. She required bag and mask ventilation and the symptoms resolved only transiently with propofol sedation. Finally, she responded to intravenous haloperidol and did not have any further episode after receiving haloperidol., Conclusion: Hyperventilation after a smooth recovery from anesthesia is not a common presentation. In this article we have tried to discuss the possible cause of such symptom in our patient and how we successfully managed this case. We have also proposed an algorithmic approach to diagnose and manage such cases in the PACU.