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Introduction: Antipsychotic-induced dystonia is a neurological side-effect and can be very disabling. Treatment is multidisciplinary, including physiotherapy., Objective: The aim was to show the contribution of physiotherapy in the management of people suffering from dystonia secondary to antipsychotics., Method: The Saint John of God Mental Health Centre in Lomé was used as the study setting. This involved a descriptive study about a case of cervical dystonia induced by antipsychotics, from 13 July to 30 August 2020., Results: Our observation concerned a male patient, aged 55 years, suffering from a persistent delirious disorder, on a poorly documented treatment, admitted for cervical dystonia and persistent delirium. A physiotherapy assessment revealed neck pain rated at 5/10, reduced neck muscle strength, and an inability to keep the neck stable at rest. He was started on olanzapine 20mg tablet a day, haloperidol decanoas injectable 50mg/month, and trihexyphenidyl 5mg tablet in the morning. Physiotherapy treatment consisted of 14 sessions using various techniques including passive-active stretching of the neck and head muscles. The evolution was marked by a significant regression of involuntary neck movements and an improvement in the patient's quality of life., Conclusion: Physiotherapy should be more involved in the management of dystonia in psychiatric practice., Competing Interests: Copyright © 2024 by West African Journal of Medicine., (The Authors declare that no competing interest exists.)

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: In the population of patients in the intensive care unit (ICU), most studies compared the use of atypical antipsychotics, such as quetiapine, with the use of traditional haloperidol in patients with delirium of various forms and etiologies. The role of such agents in patients with hyperactive delirium is not fully understood. This study compares the effectiveness of quetiapine with haloperidol in treating the hyperactive form of delirium in terms of their effects on the Delirium Rating Scale-Revised-98 (DRS-R-98), length of stay in the ICU, and mortality in critically ill patients., Methods: One hundred adult patients diagnosed with hyperactive delirium were randomly assigned to receive either oral quetiapine (25-50 mg/day) or haloperidol (1-2 mg/day). The response, defined as "a DRS-R-98 severity score reduction from baseline of 50% or more" and a DRS-R-98 severity score of 12 or less without relapse, was the primary outcome., Results: The mean age of all patients was 68 ± 6 years. The study population's overall response rate was 92%. Response rates for the two groups were remarkably equal (p = 0.609). Secondary outcomes were comparable in both groups, such as ICU mortality (p = 0.496), in-hospital mortality (p = 0.321), in-hospital stay (p = 0.310), and the need for mechanical ventilation (p > 0.99). But the quetiapine group showed a statistically reduced mean ICU stay (10.1 ± 2.0 vs. 11.7 ± 2.6 days, p = 0.018) and increased sleeping hours per night (p = 0.001)., Conclusions: Quetiapine may be equally as effective as haloperidol in treating the symptoms of hyperactive delirium in critically ill patients, with no mortality benefit., (© 2024. The Author(s).)

Background: The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown., Objective: To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy., Methods: A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron., Results: There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1)., Conclusions and Relevance: No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes., Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete., Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo., Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults., Funding: National Institutes of Health and the US Department of Veterans Affairs., Competing Interests: Declaration of interests The following declarations of interest are reported outside of the submitted work. MFM reports grants from the National Institutes of Health (NIH) and the US Department of Veterans Affairs. LMB reports grants from the NIH and the American Association of Critical Care Nurses. MNG reports grants from the NIH, the Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention; consulting fees for a role as scientific advisor for Endpoint Health; honoraria for grand rounds presentation at Yale University (New Haven, CT, USA); travel support from the American Thoracic Society executive committee; and participation on the data safety monitoring board for a trial on monoclonal antibodies for COVID-19, funded by Regeneron (NCT04452318). AM reports consulting fees from Zoll, Eli Lilly, LivaNova, and Jazz Pharmaceuticals; and a philanthropic contribution from ResMed to the University of California San Diego (La Jolla, CA, USA). BAK reports grants from the NIH, payment for expert testimony for a medicolegal case in the state of Indiana (USA), payment for participation on a data safety monitoring board for the PANDORA trial, and a leadership role as president of the American Delirium Society. SSC reports grants from the NIH and direct payments for participation on the data safety monitoring board of an NIH-funded study unrelated to delirium. CLH reports grants from the NIH. PR reports grants from the NIH and the US Department of Defense, payment and travel support for a continuing medical education event at the Johns Hopkins School of Medicine, and previous leadership of the Association of Academic Anesthesiology Chairs and Society of Academic Associations of Anesthesiology and Perioperative Medicine. BTP reports leadership as co-chair of the Society of Critical Care Medicine ICU Liberation Committee. PPP reports grants from the NIH. NEB reports grants from the NIH and travel support for the Society of Intensive Care Medicine Singapore annual meeting. CGH reports consulting fees for Sedana Medical. MBP reports grants from CSL Behring, the NIH, and the US Department of Defense; royalties for serving as an associate editor with Elsevier on a surgical textbook; travel support for continuing medical education events with the Eastern Association for the Surgery of Trauma, Society of University Surgeons, and American College of Surgeons; a patent for image-derived prognostic models unrelated to this work; participation on a data safety monitoring board for Liberate Medical; and leadership as treasurer for the Eastern Association for the Surgery of Trauma. JLS reports honoria for presentations for the Society of Critical Care Medicine, American College of Chest Physicians, the Chilean Society of Critical Care Medicine, and the Spanish Society of Hospital Pharmacy; travel support for meetings with the Society of Critical Care Medicine, the Saudi Society of Clinical Pharmacy, and the Chilean Society of Critical Care Medicine; and leadership on committees with the Society of Critical Care Medicine. EWE reports grant support from the NIH and the US Department of Veterans Affairs, honoraria for continuing medical education lectures sponsored by Pfizer, and study support (investigational drug provision, no direct payments) from Eli Lilly. TDG reports grants from the NIH, research funding from Ceribell, and personal fees from Haisco Pharmaceutical and Lungpacer Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. 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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.)

Background: Delirium is a neuropsychiatric condition that commonly occurs in medical settings, especially among older individuals. Despite the lack of strong evidence in the literature, haloperidol is considered the first-line pharmacological intervention. Unfortunately, its adverse effects can be severe, and psychiatrists are considering the use of alternative drugs targeting dopamine and serotonin domains (atypical antipsychotics). Among them, aripiprazole is considered to have one of the safest pharmacological profiles., Aims: The purpose of this study is to examine the studies on aripiprazole as a pharmacological treatment of delirium present in today's literature., Methods: We carried out systematic research of MedLine, PubMed, Cochrane, Embase, and ScienceDirect examining articles written between January 2002 and September 2023, including experimental studies published in peer-reviewed journals., Results: The 6 final included studies examined a total of 130 patients, showing a delirium resolution in a 7-day span of 73.8% of patients treated with aripiprazole., Conclusions: Considering the limited data currently available, we can assert that aripiprazole is at least as efficient as haloperidol, the true point is that it has a far better tolerability and safety profile. Nonetheless, further studies are necessary to provide more compelling data, together with a more precise indication regarding minimum efficient dose, as the main limitations of our review are the very small sample size, the small percentage of subjects with preexisting dementia, and the fact that most studies used scales with low specificity for the examined condition., 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.

Joint models linking longitudinal biomarkers or recurrent event processes with a terminal event, for example, mortality, have been studied extensively. Motivated by studies of recurrent delirium events in patients receiving care in an intensive care unit (ICU), we devise a joint model for a recurrent event process and multiple terminal events. Being discharged alive from the ICU or experiencing mortality may be associated with a patient's hazard of delirium, violating the assumption of independent censoring. Moreover, the direction of the association between the hazards of delirium and mortality may be opposite of the direction of association between the hazards of delirium and ICU discharge. Hence treating either terminal event as independent censoring may bias inferences. We propose a competing joint model that uses a latent frailty to link a patient's recurrent and competing terminal event processes. We fit our model to data from a completed placebo-controlled clinical trial, which studied whether Haloperidol could prevent death and delirium among ICU patients. The clinical trial served as a foundation for a simulation study, in which we evaluate the properties, for example, bias and confidence interval coverage, of the competing joint model. As part of the simulation study, we demonstrate the shortcomings of using a joint model with a recurrent delirium process and a single terminal event to study delirium in the ICU. Lastly, we discuss limitations and possible extensions for the competing joint model. The competing joint model has been added to frailtypack, an R package for fitting an assortment of joint models., (© 2024 John Wiley & Sons Ltd.)

Context: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited., Objectives: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days., Methods: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3., Results: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics., Conclusion: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications., Competing Interests: Disclosures The authors declare no financial relationships with commercial interests., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Nausea and vomiting after surgery are the most common complications. Therefore, we performed this study to compare the effect of ondansetron and haloperidol on nausea and vomiting after laparoscopic cholecystectomy., Patients and Methods: In this randomized clinical trial, 60 patients candidates for elective laparoscopic cholecystectomy were allocated to haloperidol (0.05 mg/kg, n = 30) and ondansetron (0.15 mg/kg, n = 30) groups. An Ocular Analog Scale was used to assess postoperative nausea and vomiting. Every 15 minutes in the recovery room, heart rate and blood pressure were measured up to 6 hours after surgery. In addition, patient satisfaction was assessed postoperatively., Results: Haloperidol and ondansetron have the same effect on postoperative nausea and vomiting in the recovery room and ward. It was found that the trend of Visual Analog Scale variable changes in the recovery room was similar in the haloperidol and ondansetron group ( P = 0.58); it was also true for the ward ( P = 0.79). Comparing the length of stay in a recovery room in the 2 groups was not statistically significant ( P = 0.19). In addition, the 2 groups did not differ in satisfaction postoperatively ( P = 0.82)., Conclusion: Haloperidol and ondansetron had an equal effect on reducing nausea and vomiting in the recovery room and ward after laparoscopic cholecystectomy. Patient satisfaction and length of stay in the recovery room did not differ between groups., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Haloperidol, the first butyrophenone neuroleptic, was created in Europe by Janssen Pharmaceuticals in 1958 and was introduced swiftly throughout the continent with great enthusiasm. On September 15, 1959, at Janssen's headquarters in Belgium, teams from around Europe praised the effectiveness of haloperidol. In the United States, on the contrary, its introduction was a tremendous failure, plagued by accusations of inefficacy and patent disputes. A clinical trial in Manhattan has been blamed for this commercial failure. The results of the Manhattan trial were seen as radically different from the results obtained in continental Europe. This divide would have considerable impact not only with regard to haloperidol's path on both sides of the Atlantic, but also possibly on the practical experience and theoretical construction of psychiatry. This article tries to reconstruct the story of that trial based mainly on published papers and interviews. Exploring how societal changes and issues of gender and race shaped this process, this investigation attempts to understand and contextualize different possible reasons for this Atlantic rift.

Purpose of Review: Acute encephalopathy (AE) - which frequently develops in critically ill patients with and without primary brain injury - is defined as an acute process that evolves rapidly and leads to changes in baseline cognitive status, ranging from delirium to coma. The diagnosis, monitoring, and management of AE is challenging. Here, we discuss advances in definitions, diagnostic approaches, therapeutic options, and implications to outcomes of the clinical spectrum of AE in ICU patients without primary brain injury., Recent Findings: Understanding and definitions of delirium and coma have evolved. Delirium is a neurocognitive disorder involving impairment of attention and cognition, usually fluctuating, and developing over hours to days. Coma is a state of unresponsiveness, with absence of command following, intelligible speech, or visual pursuit, with no imaging or neurophysiological evidence of cognitive motor dissociation. The CAM-ICU(-7) and the ICDSC are validated, guideline-recommended tools for clinical delirium assessment, with identification of clinical subtypes and stratification of severity. In comatose patients, the roles of continuous EEG monitoring and neuroimaging have grown for the early detection of secondary brain injury and treatment of reversible causes., Summary: Evidence-based pharmacologic treatments for delirium are limited. Dexmedetomidine is effective for mechanically ventilated patients with delirium, while haloperidol has minimal effect of delirium but may have other benefits. Specific treatments for coma in nonprimary brain injury are still lacking., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC 50 values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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).)

Purpose: We investigated the association of age, sex, race, and insurance status on antipsychotic medication use among intensive care unit (ICU) patients., Materials and Methods: Retrospective study of adults admitted to ICUs at a tertiary academic center. Patient characteristics, hospital course, and medication (olanzapine, quetiapine, and haloperidol) data were collected. Logistic regression models evaluated the independent association of age, sex, race, and insurance status on the use of each antipsychotic, adjusting for prespecified covariates., Results: Of 27,137 encounters identified, 6191 (22.8%) received antipsychotics. Age was significantly associated with the odds of receiving olanzapine ( P  < .001), quetiapine ( P  = .001), and haloperidol ( P  = .0046). Male sex and public insurance status were associated with increased odds of receiving antipsychotics olanzapine, quetiapine, and haloperidol (Male vs Female: OR 1.13, 95% CI [1.04, 1.24], P  = .0005; OR 1.22, 95% CI [1.10, 1.34], P  = .0001; OR 1.28, 95% CI [1.17, 1.40], P  < .0001, respectively; public insurance vs private insurance: OR 1.32, 95% CI [1.20, 1.46], P  < .0001; OR 1.21, 95% CI [1.09, 1.34], P  = .0004; OR 1.15, 95% CI [1.04, 1.27], P  = .0058, respectively). Black race was also associated with a decreased odds of receiving all antipsychotics (olanzapine ( P  = .0177), quetiapine ( P  = .004), haloperidol ( P  = .0041))., Conclusions: Age, sex, race, and insurance status were associated with the use of all antipsychotic medications investigated, highlighting the importance of investigating the potential impact of these prescribing decisions on patient outcomes across diverse populations. Recognizing how nonmodifiable patient factors have the potential to influence prescribing practices may be considered an important factor toward optimizing medication regimens., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CSB and CGH are consultants for Sedana Medical. The remaining authors declared no potential conflicts of interest.

Background: There is debate about the generalisability of results from randomised clinical trials (RCTs) to real-world settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy and effectiveness of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects using all available RCT and real-world evidence., Methods: We conducted network meta-analyses using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was adults (age >18 and <65 years) with schizophrenia and schizoaffective disorder with stabilised symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% CIs for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions studied were antipsychotics, no antipsychotic use, and placebo. We compared HRs versus a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs. We synthesised evidence using network meta-analysis and compared results from our network meta-analysis of real-world data with our network meta-analysis of RCT data, including oral versus long-acting injectable (LAI) formulations. Finally, we conducted a joint real-world and RCT network meta-analysis., Findings: We included 90 469 individuals from the Swedish and Finnish registries (mean age 45·9 [SD 14·6] years; 43 025 [47·5%] women and 47 467 [52·5%] men, ethnicity data unavailable) and 10 091 individuals from 30 RCTs (mean age 39·6 years [SD 11·7]; 3724 [36·9%] women and 6367 [63·1%] men, 6022 White [59·7%]). We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (HR ratio 0·97, 95% CI 0·88-1·08). Drug effectiveness versus no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (HR ratio 1·40 [1·24-1·59]). Efficacy versus placebo in RCTs was larger than effectiveness versus no antipsychotic in real-world (HR ratio 2·58 [2·02-3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (HR ratio vs oral haloperidol 1·17 [0·83-1·65], where HR ratio >1 means superior effectiveness in real-world to RCTs), except for LAI versus oral comparisons (HR ratio 0·73 [0·53-0·99], indicating superior effectiveness in real-world data relative to RCTs). The real-world network meta-analysis showed clozapine was most effective, followed by olanzapine LAI. The RCT network meta-analysis exhibited heterogeneity and inconsistency. The joint real-world and RCT network meta-analysis identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and the real world registries., Interpretation: LAI antipsychotics perform slightly better in the real world than according to RCTs. Otherwise, RCT evidence was in line with real-world evidence for most between-drug comparisons, but RCTs might overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and can inform preferential prescribing guidelines., Funding: None., Competing Interests: Declaration of interests OE has received honoraria and consulting fees from Biogen to his institution, all unrelated to the current work. JPE has received Continuing Medical Education (CME) speaker fees and other non-financial honoraria from Otsuka, Lundbeck, Casen Recordati, Rovi, Angelini Pharma, Neuraxpharm, and Janssen, outside the submitted work; and has participated in research projects coordinated by IQVIA. EV has received grants and served as consultant, advisor, or CME speaker for AB-Biotics, Abbvie, Aimentia, Angelini, Boehringer Ingelheim, Celon, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo Smith-Kline, Idorsia, Janssen, Lundbeck, Organon, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. JT, EMR, HT, and ATa have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. HT reports personal fees from Gedeon Richter, Janssen-Cilag, Lundbeck, and Otsuka. JT has participated in research projects funded by grants from Janssen to his employing institution. JT has served as a consultant for HLS Therapeutics, Janssen, Orion, and WebMed Global and has received honoraria from Janssen and Otsuka. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, and Proxymm Science, outside the current study. AC has received research, educational, and consultancy fees from the Italian Network for Paediatric Trials, CARIPLO Foundation, Lundbeck, and Angelini Pharma, outside the submitted work. He is the Clinical Lead and Principal Investigator of a trial of seltorexant in adolescent depression, sponsored by Janssen. SL has received honoraria as an advisor or for lectures or educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharpp and Dome, Mitshubishi, Neurotorium, NovoNordisk, Otsuka, Recordati, Roche, Rovi, Sanofi Aventis, and TEVA. NC has received grants and acted as a CME consultant, advisor, or speaker for Angelini, Esteve, Exeltis, Janssen, Lundbeck, Novartis, Pfizer, and Servier, outside the submitted work. All other authors declare no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring-guided antipsychotic drug therapy. The optimal therapeutic windows for D 2 antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search., Methods: This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D 2 -like and 5-HT 2A receptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion., Results: The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect., Conclusions: Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring., Competing Interests: X. M. Hart was supported by the Overseas Research Fellow Award by the Japan Society for the Promotion of Science. Dr. H. Uchida has received grants from Daiichi Sankyo, Eisai, Mochida, Otsuka, and Sumitomo Pharma; speaker's fees from Eisai, Janssen, Lundbeck, Meiji Seika Pharma, Otsuka, and Sumitomo Pharma; and advisory board fees from Lundbeck, Sumitomo Pharma, Takeda Pharmaceutical Company, and Boehringer Ingelheim Japan. Dr. G. Gründer has served as a consultant for Allergan, Boehringer Ingelheim, the Institute for Quality and Efficiency in Health Care (IQWiG), Janssen-Cilag, Lundbeck, Otsuka, Recordati, ROVI, Sage, and Takeda. He has served on the speakers' bureau of Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, and Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck, and Saladax. He is cofounder and/or shareholder of Mind and Brain Institute GmbH, Brainfoods GmbH, OVID Health Systems GmbH, and MIND Foundation gGmbH. The other authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Describe the incidence and factors associated with recurrent delirium in the intensive care unit (ICU)., Materials and Methods: Retrospective study of ICU patients diagnosed with delirium. Delirium clearance defined as 48 h of negative delirium assessments following initial episode and recurrent delirium as any positive delirium assessment following clearance. Multivariable logistic regression model assessed independent association of patient and hospital factors on development of recurrent delirium, adjusting for pre-defined covariates., Results: Among 8591 ICU admissions identified with delirium, 1067 (12.4%) had recurrent symptoms. Factors associated with increased odds of recurrent delirium were age (nonlinear; p = 0.02), shock (OR 1.45, 95% CI [1.20, 1.75]), admission to medical (OR 3.25, 95% CI [2.42, 4.37]), surgical (OR 3.00, 95% CI [2.21, 4.06]), or trauma (OR 2.17, 95% CI [1.58, 3.00]) ICU vs. cardiovascular ICU, increased duration of mechanical ventilation (OR 2.43, 95% CI [2.22, 2.65]), propofol use (OR 1.35, 95% CI [1.02, 1.80]), and antipsychotic medications (haloperidol OR 1.53, 95% CI [1.26, 1.86]; quetiapine OR 2.45, 95% CI [1.98, 3.02]; and olanzapine OR 1.54, 95% CI [1.25, 1.88])., Conclusions: Over 10% of delirious ICU patients had recurrent symptoms. Factors associated with recurrence included age, duration of mechanical ventilation and medication exposure., Clinical Trial Number: Not applicable., Competing Interests: Declaration of Competing Interest CSB and CGH are consultants for Sedana Medical. CGH has received research grant funding from Kohler Chemie GMBH. The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: While total intravenous anesthesia (TIVA) protocols include Dexamethasone and Ondansetron prophylaxis, bariatric patients continue to be considered at particularly high risk for postoperative nausea/vomiting (PONV). A multimodal approach for prophylaxis is recommended by the Bariatric Enhanced Recovery After Surgery (ERAS) Society however, there remains a lack of consensus on the optimal strategy to manage PONV in these patients. Haloperidol has been shown at low doses to have a therapeutic effect in treatment of refractory nausea and in PONV prophylaxis in other high risk surgical populations. We sought to investigate its efficacy as a prophylactic medication for PONV in the bariatric population and to identify which perioperative strategies were most effective at reducing episodes of PONV., Methods: An institutional bariatric database was created by retrospectively reviewing patients undergoing elective minimally invasive bariatric procedures from 2018 to 2022. Demographic data reviewed included age, gender, preoperative body mass index (BMI), ethnicity, and primary language. Primary endpoints included patient reported episodes of PONV, total doses of Ondansetron administered, need for a second antiemetic (rescue medication), complication rate (most commonly readmission within 30 days), and length of stay. Fisher's exact test, Mann-Whitney test, and ANOVA were used to evaluate the effect of perioperative management on various endpoints., Results: A total of 475 patients were analyzed with Haloperidol being utilized in 15.8% of all patients. Patients receiving Haloperidol were less likely to require Ondansetron outside of the immediate perioperative period (34.7% vs. 49.8%, p = 0.02), experienced less PONV (41.3% vs. 64.3%, p = 0.01) and also had a decreased median length of stay (27.3 vs. 35.8 h, p < 0.0001)., Conclusions: Addition of low dose Haloperidol to Bariatric ERAS protocols decreases incidence of PONV and the need for additional antiemetic coverage resulting in a significantly shorter length of stay, increasing the likelihood of safe discharge on postoperative day 1., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo., Methods: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values., Results: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS., Conclusions: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL., (© 2023. 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.)

Background: Our systematic review examines the effectiveness and safety of non-pharmacologic and pharmacologic interventions in preventing or treating traumatic brain injury (TBI)-related delirium in acute care., Methods: We searched four electronic databases (MEDLINE, EMBASE, CENTRAL/CDSR, and PsycINFO) to identify randomized controlled trials (RCTs), quasi-experimental, and observational studies. Eligible studies included adults with TBI, at least one comparator group, delirium as an outcome and took place in acute care. Two reviewers independently completed all study screening, data abstraction, and risk of bias assessment using the Cochrane risk of bias 2 tool for RCTs or risk of bias in non-randomized studies-of interventions tool for observational studies. We implemented the PROGRESS-Plus framework to describe social determinants of health (SDoH) reporting., Results: We identified 20,022 citations, reviewed 301 in full text, and included eight studies in the descriptive synthesis. The mean age of study participants ranged from 32 to 62 years. 12.5% of included studies reported SDoH. Included studies had moderate-to-high risk of bias. Studies compared reorientation programs and an intervention bundle to usual care, but these interventions were not better than usual care in treating TBI-related delirium. Individual studies found that rosuvastatin and aripiprazole were more efficacious than placebo, and dexmedetomidine was more efficacious than propofol and haloperidol for preventing TBI-related delirium. No studies reported safety as the primary outcome., Conclusions: We identified efficacious pharmacologic interventions for preventing TBI-related delirium, but these studies were at moderate-to-high risk of bias, which limits our confidence in these findings. Future studies should incorporate safety outcomes, and a diverse study population, including older adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects., Methods: Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008-2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication., Results: 38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2-2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1-2.2 percentage points, representing 32.4-64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses., Conclusions: Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.

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.

In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research., Aims: This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus., Methods: We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis., Results: Survey participants ( N  = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis., Conclusions: As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This article reviews the results of a randomized controlled trial, "Rapid Agitation Control with Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial" by D. Barbic et al. (2021), comparing time to sedation, level of sedation, and adverse outcomes between intramuscular ketamine versus intramuscular midazolam and haloperidol among acutely agitated patients presenting to the emergency department (ED). The findings are discussed in the context of practice change for patient stabilization within the ED. Emergency department nurse practitioners must employ continuing education and remain current with clinical practices and treatment options to ensure that patients receive optimal safe care. Although the use of midazolam and haloperidol has historically been the first-line treatment for the acutely agitated patient, use of ketamine shows promise in providing a safe alternative for expedited patient stabilization for acutely agitated patients presenting to the ED., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In the present study, nanoemulsion (NE) loaded with lisuride were formulated for delivering drug to brain via intranasal route. Dopamine levels, pharmacokinetic, and antioxidant activity were estimated. Antioxidant effect of lisuride NE was assessed in-vivo using oxidative stress models revealing symptoms like those of Parkinson's disease. Intranasally administered lisuride NE-treated group revealed a greater number of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione (GSH) as compared to the intravenously administered lisuride suspension in haloperidol rat model. Additionally, it was observed that lisuride NE can decrease dopamine loss. When lisuride NE was administered intranasally resulted in considerably higher dopamine concentrations (17.48 ± 0.05 ng/mL) in comparison to rats receiving haloperidol (7.28 ± 0.02 ng/mL). From study, it is suggested that NE is a possible strategy to deliver lisuride intranasally to lower free radical damage and prevent the biochemical alterations associated with Parkinson's disease., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Haloperidol is frequently used as first-line treatment for delirium. The Swiss Smarter medicine campaign recommends to favor non-pharmacological interventions and treatment of the underlying causes, in order to limit the use of haloperidol. When antipsychotics are necessary, they should be prescribed cautiously, taking into account contraindications and potential side effects. This article emphasizes the importance of history taking in patient with delirium before prescribing haloperidol., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The pathophysiological mechanism behind the link between antipsychotic drugs and sexual dysfunction is still unknown. The goal of this research is to compare the potential effects of antipsychotics on the male reproductive system. Fifty rats were randomly assigned into the five groups indicated: Control, Haloperidol, Risperidone, Quetiapine and Aripiprazole. Sperm parameters were significantly impaired in all antipsychotics-treated groups. Haloperidol and Risperidone significantly decreased the level of testosterone. All antipsychotics had significantly reduced inhibin B level. A significant reduction was observed in SOD activity in all antipsychotics-treated groups. While GSH levels diminished, MDA levels were rising in the Haloperidol and Risperidone groups. Also, the GSH level was significantly elevated in the Quetiapine and Aripiprazole groups. By causing oxidative stress and altering hormone levels, Haloperidol and Risperidone are damaging to male reproductivity. This study represents useful starting point for exploring further aspects of the underlying mechanisms reproductive toxicity of antipsychotics., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: The current research was designed to assess the efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder., Patients and Methods: A total of 154 children with tic disorder co-morbid with attention deficit hyperactivity disorder admitted to our hospital from July 2019 to July 2022 were recruited and assigned to receive either methylphenidate hydrochloride plus haloperidol (observation group) or clonidine (experimental group), with 77 cases in each group. Outcome measures included clinical efficacy, Yale Global Tic Severity Scale (YGTSS) scores, Conners Parent Symptom Questionnaire (PSQ) scores, and adverse events., Results: Clonidine was associated with markedly higher clinical efficacy vs. methylphenidate hydrochloride plus haloperidol (p<0.05). Clonidine offered more significant mitigation of the tic disorder vs. methylphenidate hydrochloride plus haloperidol, as evinced by the lower kinetic tic scores, vocal tic scores, and total scores (p<0.05). Children exhibited markedly milder tic symptoms after clonidine monotherapy vs. those with dual therapy of methylphenidate hydrochloride and haloperidol, suggested by the lower scores of character problems, learning problems, psychosomatic disorders, hyperactivity/impulsivity, anxiety index, and hyperactivity index (p<0.05). Clonidine features a higher safety profile than methylphenidate hydrochloride plus haloperidol by reducing the incidence of adverse events (p<0.05)., Conclusions: Clonidine effectively alleviates tic symptoms, reduces attention deficit and hyperactivity/impulsivity in children with tic disorder co-morbid attention deficit hyperactivity disorder, and features a high safety profile.

Purpose: The AID-ICU trial was a randomised, blinded, placebo-controlled trial investigating effects of haloperidol versus placebo in acutely admitted, adult patients admitted in intensive care unit (ICU) with delirium. This pre-planned Bayesian analysis facilitates probabilistic interpretation of the AID-ICU trial results., Methods: We used adjusted Bayesian linear and logistic regression models with weakly informative priors to analyse all primary and secondary outcomes reported up to day 90, and with sensitivity analyses using other priors. The probabilities for any benefit/harm, clinically important benefit/harm, and no clinically important differences with haloperidol treatment according to pre-defined thresholds are presented for all outcomes., Results: The mean difference for days alive and out of hospital to day 90 (primary outcome) was 2.9 days (95% credible interval (CrI) - 1.1 to 6.9) with probabilities of 92% for any benefit and 82% for clinically important benefit. The risk difference for mortality was - 6.8 percentage points (95% CrI - 12.8 to - 0.8) with probabilities of 99% for any benefit and 94% for clinically important benefit. The adjusted risk difference for serious adverse reactions was 0.3 percentage points (95% CrI - 1.3 to 1.9) with 98% probability of no clinically important difference. Results were consistent across sensitivity analyses using different priors, with more than 83% probability of benefit and less than 17% probability of harm with haloperidol treatment., Conclusions: We found high probabilities of benefits and low probabilities of harm with haloperidol treatment compared with placebo in acutely admitted, adult ICU patients with delirium for the primary and most secondary outcomes., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

We recently reported that the "Dopamine Neuron Challenge Test" (DNC Test), a diagnostic method that measures the levels of dopamine metabolites in cerebrospinal fluid (CSF) and plasma samples after pharmacologically inducing a transient dopamine release, can detect early-stage Parkinson's disease (PD) with high sensitivity and selectivity in mouse models. The use of haloperidol in the original DNC test to challenge dopamine neurons was less than ideal, as it may cause extrapyramidal motor symptoms. Here we report an improved DNC Test, in which the original challenging agents, haloperidol and methylphenidate, are replaced by a single challenging agent, a dopamine autoreceptor preferring antagonist AJ76 or UH232. We show that the improved DNC Test can achieve the same level of sensitivity and selectivity in detecting early PD in a mouse model without causing motor side effects. These findings significantly improve the practicality of using the DNC Test as a screening or diagnostic test for detecting early-stage PD in the high-risk population in humans., Competing Interests: Declaration of competing interest The authors have declared that NO conflict of interest exists., (Published by Elsevier Ltd.)

Background: Delirium is a common distressing symptom observed in patients with terminal respiratory diseases and is treated with antipsychotic medications such as haloperidol. Its management is difficult, especially in palliative home care, because its administration is limited to oral or injection methods. Recently, the blonanserin transdermal patch was developed as the first antipsychotic percutaneous agent. After it became available, we recognized its potential for the management of delirium and the alleviation of uncontrolled dyspnea in clinical practice. Thus, this study aimed to assess its efficacy in patients with terminal respiratory diseases., Methods: This retrospective study included 113 patients with respiratory diseases who were cared for at home. The efficacy was evaluated through the prevalence of terminal delirium before and after its treatment initiation for uncontrolled dyspnea., Results: Blonanserin transdermal patch treatment for uncontrolled dyspnea improved the prevalence and severity of terminal delirium (from 70.4% to 16.3%, p < 0.001) and reduced the number of doctors' visits to patients' homes within a week before their death (from 4.0 to 3.0, p = 0.086). A sub-group analysis of 23 patients with interstitial pneumonia revealed that the treatment prevented dyspnea progression by inhibiting terminal delirium., Conclusions: Blonanserin transdermal patch performed similarly to haloperidol, as previously reported, for managing terminal delirium. Our study suggests that a blonanserin transdermal patch potentially prevents terminal delirium and alleviates uncontrolled dyspnea in patients with respiratory diseases. Our findings encourage clinical trials to evaluate the safety and efficacy of blonanserin transdermal patches for patients with terminal illnesses., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is slowly developing neurodegenerative disorder associated with gradual decline in cerebration and laboriousness to perform routine piece of work. PD imposed a social burden on society through higher medical cost and by loss of social productivity in current era. The available treatment options are expensive and associated with serious adverse effect after long term use. Therefore, there is a critical clinical need to develop alternative pharmacotherapies from natural sources to prevent and cure the pathological hall marks of PD with minimal cost. Our study aimed to scrutinize the antiparkinsonian potential of curcuminoids-rich extract and its binary and ternary inclusion complexes. In healthy rats, 1 mg/kg haloperidol daily intraperitoneally, for 3 weeks was used to provoke Parkinsonism like symptoms except control group. Curcuminoids rich extract, binary and ternary inclusion complexes formulations 15-30 mg/kg, L-dopa and carbidopa (100 + 25 mg/kg) were orally administered on each day for 3 weeks. Biochemical, histopathological and RT-qPCR analyses were conducted after neurobehavioral observations. Findings of current study indicated that all curcuminoids formulations markedly mitigated the behavioral abnormalities, recovered the level of antioxidant enzymes, acetylcholinesterase inhibitory activity and neurotransmitters. Histological analysis revealed that curcuminoids supplements stabilized the neuronal loss, pigmentation and Lewy bodies' formation. The mRNA expressions of neuro-inflammatory and specific PD pathological biomarkers were downregulated by treatment with curcuminoids formulations. Therefore, it is suggested that these curcuminoids rich extract, binary and ternary supplements should be considered as promising therapeutic agents in development of modern anti-Parkinson's disease medications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Source Citation: Andersen-Ranberg NC, Poulsen LM, Perner A, et al. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022;387:2425-35. 36286254.

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.)