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Objective: To provide an updated summary of the literature on dextromethorphan quinidine for the treatment of agitation in dementia., Data Sources: PubMed, Medline, APA PsycINFO, Embase, and Cochrane Collaboration were searched from inception to January 7, 2024 using the keywords dementia , dextromethorphan , and quinidine . The search was limited to the English language and human subjects., Study Selection: Twenty-four articles underwent full-text review. One randomized controlled trial (RCT) and 2 case reports were included. Twenty one studies were excluded because they were editorials or commentaries, were not treatment studies, or were assessing outcomes other than agitation., Data Extraction: The 3 included studies underwent full-text review. A qualitative analysis of the data was performed, and abstracted data included patient diagnosis and symptoms, treatment dose and duration of dextromethorphan-quinidine, and symptom response., Data Synthesis: One RCT and 2 case reports showed an improvement in dementia-related agitation with dextromethorphan-quinidine treatment; however, the data are limited., Conclusion: Though all the identified studies demonstrated that treatment with dextromethorphan improved agitation, more evidence is needed to establish its potential efficacy and associated risks for this patient population. Future studies should include diverse types of dementia, a variety of treatment settings, and longer duration of treatment., Prim Care Companion CNS Disord 2024;26(6):24nr03737 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

When discussing neurotransmitters whose signaling plays an important role in psychiatric illnesses, serotonin and dopamine may be the first that come to mind. Although serotonin and dopamine have significant roles, the impact of norepinephrine signaling is often overlooked. A growing body of evidence suggests that hyperactivity of norepinephrine signaling is an underlying issue in psychiatric disorders; conversely, there is evidence to suggest that deficits in the noradrenergic system are just as significant. Hence, alterations in noradrenergic activity are better characterized as dysregulation rather than a reductive, outdated formulation of "too much" or "too little" activity. Therefore, symptoms such as agitation, irritability, hyperarousal, and insomnia could be treated by targeting the underlying pathophysiology related to noradrenergic dysregulation with targeted treatments. In a recent consensus panel meeting, 5 experts reviewed the available evidence of altered noradrenergic activity and its potential role in some of the most common psychiatric disorders. This Academic Highlights article summarizes their discussion and presents the panel's conclusions., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Introduction: We evaluated the efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia (AAD) in Japanese patients., Methods: This was a phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients with AAD were randomized to receive brexpiprazole 1 mg/day or 2 mg/day, or placebo (3:4:4) for 10 weeks., Results: For the primary endpoint (change in Cohen-Mansfield Agitation Inventory [CMAI] total score from baseline to Week 10), both brexpiprazole 1 mg and 2 mg groups demonstrated statistically significant improvement versus placebo (2 mg: least squares [LS] mean difference -7.2 [95% confidence interval (CI): -10.0 to -4.3], p-value < 0.0001, 1 mg: LS mean difference -3.7 [95% CI: -6.8 to -0.7], p-value = 0.0175). The incidences of treatment-emergent adverse events reported in the brexpiprazole 1 mg, 2 mg, and placebo groups were 76.8%, 84.6%, and 73.8%, respectively., Discussion: Brexpiprazole 1 mg/day and 2 mg/day for 10 weeks was efficacious and well tolerated., Highlights: Brexpiprazole treatment for 10 weeks improved agitation in Alzheimer's dementia. The efficacy of brexpiprazole 1 mg/day has been confirmed for the first time. The incidence of adverse events was higher compared to the previous studies. Both brexpiprazole 1 mg/day and 2 mg/day were generally well tolerated., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: In patients presenting to the emergency department (ED) with acute respiratory failure, non-invasive mechanical ventilation (NIMV) is applied when conventional oxygen support is not sufficient. Patients who are agitated often have very low NIMV compliance and a transition to invasive mechanical ventilation (IMV) is often required. To avoid IMV, a suitable sedative agent can be utilized. The aim of this research is to investigate the relationship between ketamine administration to patients who are non-compliant with NIMV due to agitation and the outcome of their intubation., Methods: This retrospective study included patients with acute respiratory failure who were admitted to the ED from 2021 to 2022 and used Richmond Agitation Sedation Scale (RASS) to identify agitation level of patients. The relationship between ketamine administration in this patient group and NIMV compliance and intubation rate was evaluated., Results: A total of 81 patients, including 35 (43.2%) men and 46 (56.8%) women, were included in the study. Of these patients, 46 (56.8%) were intubated despite ketamine administration, while 35 (43.2%) were compliant with NIMV and were not intubated. When evaluating the RASS, which shows the agitation levels of the patients, the non-intubated group was found to be 2.17 ± 0.68, while the intubated group was 2.66 ± 0.73, and it was statistically significant that the NIMV intubated group was higher (p = 0.003)., Conclusion: This study showed that agitation can impair NIMV compliance in patients with acute respiratory failure. However, a significant proportion of this patient group can be avoided through IMV with proper sedative agents., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT 1A and dopamine D 2 receptor agonist activity and serotonin 5-HT 2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials., Competing Interests: Disclosures E.D.C. reports personal fees from Genomadix Inc and a grant to her institution from Alzheon. A.P.P. reports personal fees from Acadia Pharmaceuticals, Athira, BMS, Cognitive Research Corp, Eisai, IQVIA, Lundbeck, Novartis, ONO Pharmaceuticals, WCG, WebMD, and Xenon; and grants to his institution from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD. He is a member of the Scientific Advisory Board of Alzheon. D.L. and I.M.A. declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I 2  = 19%) and at 2 mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I 2  = 0%) over 12 weeks. Brexpiprazole at any dose and 2 mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12 weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I 2  = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I 2  = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I 2  = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Sedation at the end of life is used to relieve distressing symptoms including agitation and delirium. Standard care may include infused benzodiazepines or antipsychotics. These agents often result in deep sedation with loss of interaction with loved ones, which may be distressing., Objective: The DREAMS (Dexmedetomidine for the Reduction of End-of-life Agitation and for optiMised Sedation) trial aimed to compare the sedative and antidelirium effects of the alpha-2 agonist dexmedetomidine, a novel palliative care sedative, compared with midazolam, a benzodiazepine when administered by subcutaneous infusion at the end of life, with doses of both agents targeting lighter, or potentially interactive sedation., Methods: Participants were recruited from adult inpatients admitted for end-of-life care under a palliative care team in regional New South Wales, Australia. Inclusion criteria included patients older than 18 years, with a preference for lighter sedation at the end of life. Exclusion criteria included severe cardiac dysfunction (contraindication to dexmedetomidine). Participants consented and were placed on a treatment-pending list. Upon experiencing terminal deterioration, patients were randomized to either arm 1 (dexmedetomidine) or arm 2 (midazolam) as their treatment arm. These treatments were administered by continuous subcutaneous infusion. The level of consciousness and agitation of the patients were measured by the Richmond Agitation-Sedation Scale-Palliative version and the Memorial Delirium Assessment Score. Richmond Agitation-Sedation Scale-Palliative version assessments were performed by both nursing and medical staff, while Memorial Delirium Assessment Score assessments were carried out by medical staff only. Families and patients were asked to complete, as able, a patient comfort assessment form, to gauge perceptions of distress. Data were collected and matched with the breakthrough medication doses administered, along with qualitative comments in the medical record. In addition, the study tracked symptoms and patient functional status that were recorded as part of the Palliative Care Outcomes Collaborative, a national tracking project for monitoring symptom outcomes in palliative care., Results: The DREAMS trial was funded in May 2020, approved by the ethics committee in November 2020, and started recruiting participants in May 2021. Data collection commenced in May 2021 and is anticipated to continue until December 2024. Publication of results is anticipated from 2024 to 2026., Conclusions: The evidence base for sedative dosing in palliative care for distress and agitation is not robust, with standard care based primarily on clinical experience and not robust scientific evidence. This study is important because it will compare a standard and a novel sedative used in end-of-life treatment. By assessing the potential efficacy and benefits of both, it seeks to optimize the quality of dying by providing targeted sedation that can improve the communication between dying patients and their loved ones., Trial Registration: Australia New Zealand Clinical Trials Register ACTRN12621000052831; https://uat.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380889., International Registered Report Identifier (irrid): DERR1-10.2196/55129., (©Benjamin Thomas, Greg Barclay, Wing-Shan Angela Lo, Judy Mullan, Kylie Mansfield. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 04.09.2024.)

Aim: Brexpiprazole is the first FDA-approved treatment for agitation associated with dementia due to Alzheimer's disease. Agitation in Alzheimer's dementia (AAD) occurs in high prevalence and is a great burden for patients and caregivers. Efficacy, safety, and tolerability of brexpiprazole were demonstrated in the AAD clinical trials. To demonstrate the agitation-ameliorating effect of brexpiprazole in animals, we evaluated brexpiprazole in two AAD mouse models., Methods: The resident-intruder test was conducted in 5- to 6-month-old Tg2576 mice, given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally 1 h before the test. Locomotor activity was measured in 6-month-old APPSL-Tg mice given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally the evening before the start of locomotor measurement for 3 days., Results: In the resident-intruder test, Tg2576 mice showed significantly higher attack number and shorter latency to first attack compared to non-Tg mice. In the Tg mice, brexpiprazole treatment (0.03 mg/kg) significantly delayed the latency to first attack and showed a trend toward a decrease in attack number. APPSL-Tg mice (≧6 months old) showed significantly higher locomotion during dark period Phase II (Zeitgeber time [ZT] 16-20) and Phase III (ZT20-24) compared to non-Tg mice, correlating with the clinical observations of late afternoon agitation in Alzheimer's disease. Brexpiprazole treatment (0.01 and 0.03 mg/kg) significantly decreased hyperlocomotion during the Phase III in APPSL-Tg mice., Conclusion: The suppression of attack behavior and the reduction of nocturnal hyperlocomotion in these Tg mice may be indicative of the therapeutic effect of brexpiprazole on AAD, as demonstrated in the clinical trials., (© 2024 Otsuka Pharmaceutical Co., Ltd. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Introduction: Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS., Areas Covered: This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD., Expert Opinion: Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis, while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.

Background: Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision., Methods: We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach., Discussion: This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments., Systematic Review Registration: PROSPERO CRD42023402365., (© 2024. The Author(s).)

Background: Hostility, irritability, and agitation are common in patients with bipolar I disorder. Post hoc analyses evaluated the effect of cariprazine on these symptoms in patients with bipolar I mania., Methods: Data were pooled from three randomized, double-blind, placebo-controlled phase 3 cariprazine trials in adults with bipolar I manic/mixed episodes (NCT00488618, NCT01058096, NCT01058668); pooled cariprazine doses (3-12 mg/d) were analyzed. Patients were categorized into hostility/irritability and agitation subgroups by baseline scores: Young Mania Rating Scale (YMRS) irritability and disruptive-aggressive behavior items score ≥ 2; Positive and Negative Syndrome Scale (PANSS) hostility item ≥ 2; PANSS-Excited Component (PANSS-EC) total score ≥ 14 and score ≥ 4 on ≥ 1 individual item. Changes from baseline to week 3 in hostility/irritability- and agitation-related outcomes were evaluated. Adjustments were made for the presence of other manic symptoms, sedation, and akathisia., Results: Most patients met subgroup inclusion criteria (YMRS hostility = 930; PANSS hostility = 841, PANSS-EC agitation = 486). In the YMRS subgroup, least squares mean differences in change from baseline were statistically significant for cariprazine versus placebo on YMRS hostility/irritability-related items (irritability [-0.93], disruptive-aggressive behavior [-0.79], combined [-1.75]; P ≤ 0.001 each), YMRS total score (-5.92, P ≤ 0.0001), and all individual YMRS items (-0.25 to -0.93, P ≤ 0.0001); differences remained significant after adjustment for other manic symptoms, sedation, and akathisia. Differences in PANSS hostility and PANSS-EC subgroups were significant for cariprazine versus placebo (P ≤ 0.001)., Limitations: Post hoc analysis., Conclusion: Cariprazine demonstrated specific antihostility/irritability and anti-agitation effects in patients with manic/mixed episodes of bipolar I disorder and baseline hostility, irritability, or agitation., Competing Interests: Declaration of competing interest L. Citrome has served as a consultant for AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. He has served as a speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, and Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies. He owns stock options of Reviva and stock (a small number of shares of common stock) of Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer, purchased >10 years ago. He has received royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), and Elsevier (topic editor, Psychiatry, Clinical Therapeutics). C. Li, J. Yu, and H.-B. Nguyen are employees of AbbVie and may hold stock. K. Kramer was an employee of AbbVie at the time of the study and may hold stock., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To investigate the effects of nalbuphine on emergency agitation (EA), which affects up to 80% of the children following otolaryngology procedures, in children undergoing cochlear implantation., Methods: A prospective double-blinded randomized controlled clinical trial was conducted between November 2020 and October 2022. Eligible children, aged 6 months to 3 years old, were randomly assigned to either 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg nalbuphine or 0.9% saline groups. EA was defined by the Pediatric Anesthesia Emergence Delirium (PAED) score ≥10. Extubation time, post-anesthesia care unit (PACU) length of stay, severe EA (PAED ≥ 15), peak PAED score, the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale, Ramsay sedation score, and adverse events were also recorded., Results: A total of 104 children were enrolled, with 26 children in each group. Nalbuphine significantly reduced the EA occurrence from 73.1% in the saline group to 38.5%, 30.8%, and 26.9% in the 0.1 mg/kg, 0.15 mg/kg, and 0.2 mg/kg nalbuphine groups, respectively ( P < 0.001), without affecting the extubation time and PACU length of stay. More children (34.6%) in the 0.9% saline group experienced severe EA. Higher dose nalbuphine (0.15 mg/kg, 0.2 mg/kg) showed lower peak PAED score, better analgesia and sedation effect compared with 0.1 mg/kg nalbuphine and saline groups. However, 0.2mg/kg nalbuphine caused undesired over-sedation in two (7.7%) children. No other adverse events were reported., Conclusion: Young children undergoing cochlear implantation surgery were at a high risk of EA and postoperative pain, while 0.2 mg/kg nalbuphine might be an ideal candidate for EA and pain prevention when used under close monitoring., Trial Registration: ChiCTR2000040407., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Background and Objectives: Patient monitoring systems provide critical information but often produce loud, frequent alarms that worsen patient agitation and stress. This may increase the use of physical and chemical restraints with implications for patient morbidity and autonomy. This study analyzes how augmenting alarm thresholds affects the proportion of alarm-free time and the frequency of medications administered to treat acute agitation., Methods: Our emergency department's patient monitoring system was modified on June 28, 2022 to increase the tachycardia alarm threshold from 130 to 150 and to remove alarm sounds for several arrhythmias, including bigeminy and premature ventricular beats. A pre-post study was performed lasting 55 days before and 55 days after this intervention. The primary outcome was change in number of daily patient alarms. The secondary outcomes were alarm-free time per day and median number of antipsychotic and benzodiazepine medications administered per day. The safety outcome was the median number of patients transferred daily to the resuscitation area. We used quantile regression to compare outcomes between the pre- and post-intervention period and linear regression to correlate alarm-free time with the number of sedating medications administered., Results: Between the pre- and post-intervention period, the median number of alarms per day decreased from 1332 to 845 (-37%). This was primarily driven by reduced low-priority arrhythmia alarms from 262 to 21 (-92%), while the median daily census was unchanged (33 vs 32). Median hours per day free from alarms increased from 1.0 to 2.4 (difference 1.4, 95% CI 0.8-2.1). The median number of sedating medications administered per day decreased from 14 to 10 (difference - 4, 95% CI -1 to -7) while the number of escalations in level of care to our resuscitation care area did not change significantly. Multivariable linear regression showed a 60-min increase of alarm-free time per day was associated with 0.8 (95% CI 0.1-1.4) fewer administrations of sedating medication while an additional patient on the behavioral health census was associated with 0.5 (95% CI 0.0-1.1) more administrations of sedating medication., Conclusion: A reasonable change in alarm parameter settings may increase the time patients and healthcare workers spend in the emergency department without alarm noise, which in this study was associated with fewer doses of sedating medications administered., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA., Methods: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events., Results: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation., Conclusion: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alpha-2 agonists are under-recognized for their class effects yet offer potential benefit in specialty palliative care via decreasing sympathetic output, inducing sedation, and modulating pain. Especially in clinical contexts where agitation predominates and patients are intolerant of oral medication route, transdermal medication delivery is advantageous. We report a case of agitated behaviors in setting of mixed Alzheimer/vascular-type dementia limiting hospital discharge to nursing facility that were ameliorated with transdermal clonidine. We suggest palliative clinicians routinely conceptualize the seemingly disparate alpha-2 agonists as a class for effective symptom palliation especially as new clinical evidence becomes available.

The aim of this short narrative review was to evaluate the existing literature regarding the clinical use of ketamine among individuals with dementia, especially those with behavioral disturbances. PubMed, Cochrane, and Ovid (Embase, APA PsycINFO, and MEDLINE) databases were searched for abstracts using the search terms "ketamine" AND "dementia." Only articles describing the use of ketamine in individuals with dementia were included. Articles that did not include individuals with dementia, did not use ketamine, were published in a non-English language, primarily described animal studies, or were reviews were excluded. Three case reports met the inclusion criteria. One described the use of subcutaneous ketamine for depression, one described the use of intramuscular ketamine for acute agitation, and one described the use of S-ketamine as anesthesia during electroconvulsive therapy for depression and catatonia. No significant adverse effects were reported in any of the cases. Although the use of ketamine in the treatment of depression and agitation associated with dementia has potential, the current evidence remains limited. High-quality prospective studies are needed to confirm the observations of these case reports before ketamine can be used to treat behavioral disturbances in individuals with dementia., Competing Interests: Declaration of conflicting interestsThe authors declare that there is no conflict of interest.

Purpose/background: It is still not well known whether antipsychotic monotherapy versus polypharmacy differs in terms of efficacy in the emergency department (ED) utilization, presentation with agitation/aggression, and rehospitalization in schizophrenia spectrum disorders (SSD) patients. This study aimed to determine the effectiveness of antipsychotic monotherapy and polypharmacy for these outcomes in the real world., Methods/procedures: The study was conducted with electronic health records of 669 SSD patients admitted to the ED. Patients were evaluated in 4 groups according to antipsychotic use at the first admission to ED: antipsychotic noncompliance for more than 90 days, antipsychotic noncompliance for 15 to 90 days, antipsychotic monotherapy, and polypharmacy. All patients followed up for at least 1 year after index admission. The primary outcomes determined an association between antipsychotic monotherapy versus polypharmacy and all-cause psychiatric hospitalization between the groups after index admission in the SSD., Findings/results: The groups, including patients with antipsychotic noncompliance, had higher ED visits, more hospitalizations, and more admissions with agitation/aggression compared with antipsychotic monotherapy or polypharmacy. However, no differences were found between monotherapy and polypharmacy groups regarding these outcomes. In addition, there was no difference in the risk of hospitalization in monotherapy antipsychotic users compared with polypharmacy users. Patients discharged with monotherapy or polypharmacy also had similar rehospitalization rates at follow-up., Implications/conclusions: There is no positive evidence that recommending polypharmacy over antipsychotic monotherapy is superior with regard to the resulting frequency of ED visits, ED admissions with agitation/aggression, hospitalization, and rehospitalization. In this context, antipsychotic monotherapy may be preferred over polypharmacy in patients who are not resistant to treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Acute disturbance is a broad term referring to escalating behaviors secondary to a change in mental state, such as agitation, aggression, and violence. Available management options include de-escalation techniques and rapid tranquilization, mostly via parenteral formulations of medication. While the intramuscular route has been extensively studied in a range of clinical settings, the same cannot be said for intravenous (IV); this is despite potential benefits, including rapid absorption and complete bioavailability. This systematic review analyzed existing evidence for effectiveness and safety of IV medication for management of acute disturbances. It followed a preregistered protocol (PROSPERO identification CRD42020216456) and is reported following the guidelines set by Preferred Reporting Items for Systematic Review and Meta-Analysis. APA PsycINFO, MEDLINE, and EMBASE databases were searched for eligible interventional studies up until May 30th, 2023. Data analysis was limited to narrative synthesis since primary outcome measures varied significantly. Results showed mixed but positive results for the effectiveness of IV dexmedetomidine, lorazepam, droperidol, and olanzapine. Evidence was more limited for IV haloperidol, ketamine, midazolam, chlorpromazine, and valproate. There was no eligible data on the use of IV clonazepam, clonidine, diazepam, diphenhydramine, propranolol, ziprasidone, fluphenazine, carbamazepine, or promethazine. Most studies reported favorable adverse event profiles, though they are unlikely to have been sufficiently powered to pick up rare serious events. In most cases, evidence was of low or mixed quality, accentuating the need for further standardized, large-scale, multi-arm randomized controlled trials with homogeneous outcome measures. Overall, this review suggests that IV medications may offer an effective alternative parenteral route of administration in acute disturbance, particularly in general hospital settings., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually., (© 2024. The Author(s).)

Introduction: iWHELD is a digital person-centered care program for people with dementia in nursing homes adapted for remote delivery during the COVID-19 pandemic., Methods: A 16-week two-arm cluster-randomized controlled trial in 149 UK nursing homes compared iWHELD with treatment as usual (TAU). Primary outcome was the overall quality of life with secondary outcomes of agitation and psychotropic use., Results: iWHELD conferred benefit to quality of life on the primary (F = 4.3, p = 0.04) and secondary measures of quality of life (F = 6.45, p = 0.01) and reduced psychotropic medication use (χ 2  = 4.08, p = 0.04) with no worsening of agitation. Benefit was seen in participants who contracted COVID-19, those with agitation at baseline, and those taking psychotropic medications., Discussion: iWHELD confers benefits to quality of life and key measures of well-being, can be delivered during the challenging conditions of a pandemic, and should be considered for use alongside any emerging pharmacological treatment for neuropsychiatric symptoms., Highlights: iWHELD is the only remote, digital delivery nursing home training programme for dementia care iWHELD improved quality of life in people with dementia and reduced antipsychotic use without worsening of agitation Residents who contracted Covid-19 during the study also experienced benefits from iWHELD iWHELD offers a valuable, pandemic-safe tool for improving dementia care., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes ( CYP2C19 or CYP2D6 ), the serotonin transporter ( SLC6A4 ), and the serotonin receptor 2A subtype ( HTR2A ). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC 0-24 ; p  = 0.025), trough concentrations (C trough ; p  = 0.013), and elimination half-lives (t 1/2 ; p  < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia ( p  = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores ( p  = 0.017). Escitalopram maximum concentration, AUC 0-24 , CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

The acutely agitated patient should be managed in a step-wise fashion, beginning with non-coercive de-escalation strategies and moving on to pharmacologic interventions and physical restraints as necessary. Face-to-face examination, monitoring, and documentation by the physician are essential. The emergency physician should be familiar with multiple pharmaceutical options, tailored to the individual patient. Use of ketamine, benzodiazepines and antipsychotics should be considered. Patient autonomy, safety, and medical well-being are paramount., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Agitation is a common clinical problem encountered in the intensive care unit (ICU). Treatment options are based on clinical experience and sparse quality literature., Aim: The aim of this study was to describe the effect of valproic acid (VPA) as adjuvant treatment for agitation in the ICU, identify predictors of response to VPA and evaluate the independent effect of VPA on agitation compared to standard of care (SOC)., Method: This retrospective single center observational study evaluated adult patients admitted to the ICU for whom a psychiatric consultation was requested for agitation management, with agitation defined as a Richmond Agitation Sedation Score of 2 or greater. A descriptive analysis of the proportion of agitation-free patients per day of follow-up, the incidence of agitation-related-events, as well as the evolution of co-medications use over time are presented. A logistic regression model was used to assess predictors of VPA response, defined as being agitation-free on Day 7 and generalized estimating equations were used to evaluate the independent effect of VPA as adjuvant therapy for agitation in the critically ill., Results: One hundred seventy-five patients were included in the study with 78 receiving VPA. The percentage of agitation-free patients on VPA was 6.5% (5/77) on Day 1, 14.1% (11/78) on Day 3 and 39.5% (30/76) on Day 7. Multivariate regression model for clinical and demographic variables identified female gender as predictor of response on Day 7 (OR 6.10 [1.18-31.64], p = 0.03). The independent effect of VPA was non-significant when compared to SOC., Conclusion: Although VPA used as adjuvant treatment was associated with a decrease in agitation, its effect when compared to SOC did not yield significant results., (© 2023. Crown.)

Purpose: Assess the efficacy and safety of valproic acid (VPA) for delirium and agitation in the intensive care unit (ICU) as compared to the use of other antipsychotics. Materials and Methods: This was a retrospective cohort study of patients treated for delirium and agitation in the ICU. Patients were included if they had a Richmond Agitation-Sedation Scale ≥2 and Confusion Assessment Method for the ICU positive. Patients were split into two groups based on their VPA exposure. The primary outcome was delirium free days. Secondary outcomes included agitation free days, ICU length of stay (LOS), mechanical ventilation duration, and mortality. Results: One hundred eight patients were included, 49 patients in the VPA group and 59 patients in the control group. Baseline characteristics were similar between groups. There was no significant difference in the primary outcome (difference -.15, 95% CI: 0.63-.93, P = .70). There were no significant differences in agitation-free days, mortality, mechanical ventilation duration, or ICU LOS. Conclusions: Our findings suggest that VPA is associated with similar delirium and agitation-free days compared to other non-VPA medications, with some adverse effects. Larger prospective studies are needed to validate the routine use of VPA in this setting., 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.

Importance: The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others., Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development., Conclusions and Relevance: Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder., Prim Care Companion CNS Disord 2024;26(1):23nr03596 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Akathisia is a subjective feeling of restlessness that often results in a compulsion to move. Drug-related causes are the most common aetiologies. It can often be confused with restless legs syndrome (RLS). We describe a case of valproate-induced akathisia that improved with drug cessation. This case reports a rare but treatable adverse effect of sodium valproate and highlights the importance of differentiating akathisia from RLS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.

Objective: The objective of this study was to review the available literature for dexmedetomidine sublingual film use in the treatment of acute agitation associated with schizophrenia and bipolar disorders., Data Sources: A literature search of PubMed (January 2017-March 2023) and EMBASE (January 2017-March 2023) was performed using the terms: Igalmi, dexmedetomidine, schizophrenia, bipolar disorder, and agitation. Additional information sources include ClinicalTrials.gov, scientific posters, and articles identified through review of references from clinical trials publications., Study Selection and Data Extraction: Relevant English-language articles conducted in humans were considered, with a preference for phase 3 clinical trials. Trial analyses and articles discussing pharmacology, pharmacokinetics, efficacy, and safety were also evaluated., Data Synthesis: Dexmedetomidine sublingual film was evaluated for use in schizophrenia in the SERENITY 1 pivotal trial and for bipolar disorders in the SERENITY 2 pivotal trial. Both studies found treatment of mild to moderate agitation with dexmedetomidine sublingual film 180 and 120 μg to be superior to placebo in reducing the severity of agitation. Treatment effect was seen as early as 20 minutes. Somnolence was the most common adverse effect in both studies. Cardiovascular adverse effects were mild and transient in most cases., Relevance to Patient Care and Clinical Practice: Dexmedetomidine sublingual film is a new and novel treatment for agitation and gives clinicians an alternative to antipsychotic and benzodiazepine use. It has advantageous properties including its noninvasive route of administration, fast absorption, and rapid onset of effect. Cost may limit its use., Conclusion: Dexmedetomidine sublingual film provides an alternative approach to treatment of acute agitation in adults with schizophrenia and bipolar disorders based on both mechanism of action and route of administration., 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: Leigh Anne Nelson is on the Speaker’s Bureau for Alkermes, Inc, and has received research grants from Boehringer Ingelheim, Alkermes, Inc, and Janssen Scientific Affairs, LLC. Austin R. Campbell is on the Speaker’s Bureau for Sunovion Pharmaceuticals, Inc, a paid coauthor for UpToDate, and has received grant support from Intra-Cellular Therapies and Otsuka Pharmaceutical CO Ltd.

Objective: To assess the efficacy and safety of loxapine in acute agitation., Data Sources: PubMed, Cochrane database, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify relevant articles published in English or French from inception to March 15, 2022. The term "Loxap*" was searched in titles and abstracts., Study Selection and Data Extraction: Interventional studies that compared the effectiveness of loxapine to any other intervention (including another administration route or dosage of loxapine, other drugs, and placebo) in acute agitation were included. From the 1,435 articles initially identified, and after the assessment of 73 full texts, 7 articles were selected, encompassing 1,276 participants. Two reviewers independently extracted data of interest using a predefined form., Results: Among included studies, 5 were double-blind, 2 were open-label, and all were randomized. The risk of bias was low for 2 studies, involving 658 participants. Four articles compared loxapine to placebo, and 3 compared it with haloperidol, aripiprazole, and droperidol. Loxapine was found to be more effective and faster regarding acute agitation control. Also, across included studies, loxapine was well-tolerated, with mildly or moderately severe adverse effects., Conclusions: Notwithstanding methodological limitations of the included studies, this systematic review provides reassuring results regarding the use of loxapine in acute agitation. However, further studies with methodological optimizations might be of interest., Prim Care Companion CNS Disord 2023;25(6):23r03552 ., Author affiliations are listed at the end of this article., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Background: Acute agitation accounts for up to 2.6% of visits to the emergency department (ED). To date, a standard of care for the management of acute agitation has not been established. Few studies have evaluated antipsychotic and benzodiazepine combinations., Objective: The purpose of this study was to evaluate effectiveness and safety of combination therapy for acute agitation with intramuscular (IM) droperidol and midazolam (D+M) compared with IM haloperidol and lorazepam (H+L) in patients in the ED., Methods: This was a single-center, retrospective medical record review of patients presenting to a large, academic ED with acute agitation from July 2020 through October 2021. The primary outcome was percentage of patients requiring additional agitation medication within 60 minutes of combination administration. Secondary outcomes included average time to repeat dose administration and average number of repeat doses required before ED discharge., Results: A total of 306 patients were included for analysis: 102 in the D+M group and 204 in the H+L group. Repeat dose within 60 minutes occurred in 7 (6.9%) and 28 (13.8%) patients in the D+M and H+L groups, respectively ( P = 0.065). A total of 28.4% of D+M patients and 30.9% of H+L patients required any repeat dose during their ED visit. Time to repeat dose was 12 and 24 minutes in the D+M and H+L, respectively ( P = 0.22). The adverse event rate was 2.9% in each group., Conclusion and Relevance: IM D+M resulted in a lower rate of repeat doses of acute agitation medication compared with IM H+L, though this was not statistically significant. Both therapies were safe, and the adverse event rate was low., 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: Ketamine is a noncompetitive N-methyl-D-aspartate-receptor antagonist often used for sedation and management of acute agitation in general hospital settings. Many hospitals now include ketamine as part of their standard agitation protocol, and consultation-liaison psychiatrists frequently find themselves treating patients who have received ketamine, despite lack of clear recommendations for management., Objective: Conduct a nonsystematic narrative review regarding the use of ketamine for agitation and continuous sedation, including benefits and adverse psychiatric effects. Compare ketamine to more traditional agents of agitation control. Provide consultation-liaison psychiatrists with a summary of available knowledge and recommendations for managing patients receiving ketamine., Methods: A literature review was performed using PubMed, querying published articles from inception to March 2023 for articles related to use of ketamine for agitation or continuous sedation and side effects including psychosis and catatonia., Results: A total of 37 articles were included. Ketamine was found to have multiple benefits, including shorter time to adequate sedation for agitated patients when compared to haloperidol ± benzodiazepines and unique advantages for continuous sedation. However, ketamine carries significant medical risks including high rates of intubation. Ketamine appears to induce a syndrome that mimics schizophrenia in healthy controls, and such effects are more pronounced and longer-lasting in patients with schizophrenia. Evidence regarding rates of delirium with ketamine for continuous sedation is mixed and requires further investigation before the agent is widely adopted for this purpose. Finally, the diagnosis of "excited delirium syndrome" and use of ketamine to treat this controversial syndrome warrants critical evaluation., Conclusions: Ketamine carries many potential benefits and can be an appropriate medication for patients with profound undifferentiated agitation. However, intubation rates remain high, and ketamine may worsen underlying psychotic disorders. It is essential that consultation-liaison psychiatrists understand the advantages, disadvantages, biased administration, and areas of limited knowledge regarding ketamine., (Copyright © 2023 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.)

Behavioral symptoms associated with dementia, such as agitation, are frequent and associated with well-known negative consequences for patients, their carers, and their environment. Pharmacological treatments for agitation using sedatives and antipsychotics are known to have several undesirable side effects and modest efficacy. Non-pharmacological alternatives are recommended as first-line options for agitation in persons with dementia with few side effects, but there is limited evidence of efficacy. We developed a novel and simple non-pharmacological alternative for agitation in dementia residents based on a Brazilian intervention using warm water surgical gloves used in patients with COVID-19 in intensive care units during the pandemic. We coined it "Mãos de Conforto" - Hands of Comfort. We report a series of 7 cases in 3 residents with dementia who whore Hands of Comfort.

Background: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats., Methods: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum., Key Findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage., Conclusions: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD., 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 Elsevier B.V. All rights reserved.)

Introduction: Agitation is commonly encountered in people with bipolar disorder, particularly when experiencing a manic episode. The number of approved pharmacological agents to manage acute episodes of agitation in this population is limited., Areas Covered: A search was conducted using the US National Library of Medicine PubMed.gov resource for English-language papers of clinical trials and reviews/meta-analyses, using the text words 'bipolar disorder' AND 'agitation,' as well as any papers with both two text words in the title, without any date restrictions., Expert Opinion: Existing pharmacologic options approved by regulatory authorities for the treatment of acute episodes of agitation associated with bipolar disorder have similar degrees of efficacy but differ in their tolerability profiles and ease of use, giving clinicians an opportunity to individualize treatment. The goal is to treat mild-moderate agitation before it evolves into severe agitation, encouraging noninvasive pharmacologic treatment options. Inhaled loxapine and sublingual dexmedetomidine are newer options with rapid onset of action and may be preferable for patients willing to cooperate with treatment.

Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder resulting from TCF4 gene mutations which is characterized by dysmorphic facial features, psychomotor delay, intellectual disability, breathing anomalies, and seizures. Psychiatric conditions are occasionally seen. We present the case report of a seven-year-old PTHS patient with anxiety, insomnia, and agitation. We discuss the psychopharmacological intervention options for this patient. The present case study reports on a 7-year-old female with PTHS, autism spectrum disorder (ASD), and intellectual disability. She had insomnia, crying spells and agitation complaints. For anxiety symptoms and agitation, risperidone, fluoxetine, and clonazepam treatment were given by the neurologist which caused behavioral disinhibition, paroxysmal agitation and no benefit. After admission to our hospital, aripiprazole and hydroxyzine were prescribed for anxiety and ASD-related irritability. She showed a minimal improvement but hyperventilation attacks were still ongoing. Hydroxyzine was stopped, and quetiapine was given to eliminate sleep disturbance. Her sleep period went up to eleven hours. For the anxiety symptoms, escitalopram was prescribed. She showed improvements in sleep, diminished hyperactivity and decreased frequency of abnormal breathing spells. Also, enhancement of social communication skills like increased eye contact and response to her name was observed. Patients with genetic syndromes may have various psychiatric complaints. Psychopharmacological interventions should be administered carefully for the side effects.

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Acute agitation and violent behavior in the emergency department (ED) can lead to significant patient morbidity and contribute to the growing problem of workplace violence against health care providers. To our knowledge, there is no available literature directly comparing intramuscular ketamine to intramuscular droperidol in ED patients presenting with undifferentiated agitation. The purpose of this investigation was to compare the effectiveness and safety of these agents for acute agitation in the ED., Methods: This was a retrospective observational study conducted at an urban, academic ED. The primary endpoint was time from the first dose of study medication to restraint removal. Safety endpoints included incidence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure., Results: An initial 189 patients were screened, of which, 92 met inclusion criteria. The median time from initial drug administration to restraint removal was 49 min (IQR 30, 168) in the ketamine group and 43 min (IQR 30, 80) in the droperidol group (Median difference 6 min; 95% CI [-7, 26]). There was no significant difference in rates of bradycardia (3% vs 3%, 95% CI [-7%, 8%]), hypotension (0% vs 2%, 95% CI [-5%, 2%]), or hypoxia (7% vs 10%, 95% CI [-15%, 9%]) in the ketamine versus droperidol groups respectively. One patient in the ketamine group was intubated for ongoing agitation, and one patient in the droperidol group was intubated for respiratory failure., Conclusions: Intramuscular droperidol and intramuscular ketamine were associated with similar times from drug administration to restraint removal in patients presenting to the ED with undifferentiated agitation. Prospective studies are warranted to evaluate IM droperidol and IM ketamine head-to-head as first line agents for acute agitation in the ED., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Antipsychotic-induced akathisia is severely distressing. We aimed to investigate relationships between antipsychotic doses and akathisia risk. We searched for randomised controlled trials that investigated monotherapy of 17 antipsychotics in adults with acute schizophrenia until 06 March 2022. The primary outcome was the number of participants with akathisia, which was analysed with odds ratios (ORs). We applied one-stage random-effects dose-response meta-analyses using restricted cubic splines to model the dose-response relationships. We included 98 studies (343 dose arms, 34,225 participants), most of which were short-term and had low-to-moderate risk of bias. We obtained data on all antipsychotics except clozapine and zotepine. In patients with acute exacerbations of chronic schizophrenia, from moderate to high certainty of evidence, our analysis showed that sertindole and quetiapine carried negligible risks for akathisia across examined doses (flat curves), while most of the other antipsychotics had their risks increase initially with increasing doses and then either plateaued (hyperbolic curves) or continued to rise (monotonic curves), with maximum ORs ranging from 1.76 with 95% Confidence Intervals [1.24, 2.52] for risperidone at 5.4 mg/day to OR 11.92 [5.18, 27.43] for lurasidone at 240 mg/day. We found limited or no data on akathisia risk in patients with predominant negative symptoms, first-episode schizophrenia, or elderly patients. In conclusion, liability of akathisia varies between antipsychotics and is dose-related. The dose-response curves for akathisia in most antipsychotics are either monotonic or hyperbolic, indicating that higher doses carry a greater or equal risk compared to lower doses., Competing Interests: Conflict of Interest In the past 3 years, SL has received honoraria as a consultant/advisor and/or for lectures from Angelini, Böhringer Ingelheim, Geodon&Richter, Janssen, Johnson&Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA, Mitsubishi. All the other authors have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)