Effects of Antipsychotics on the Hypothalamus-Pituitary-Adrenal Axis in a Phencyclidine Animal Model of Schizophrenia.

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11ß-Hydroxysteroid dehydrogenase-11ß-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH.

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

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

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

Lipid-Conjugated Reduced Haloperidol in Association with Glucose-Based Nanospheres: A Strategy for Glioma Treatment.

Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect. Hypothetically, ±RHPC8 would act simultaneously as an SR-targeting ligand and anticancer agent. As the blood-brain barrier (BBB) obstructs direct targeting of in situ glioma, we used BBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8 within the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP nanoconjugate targeted SR-expressing glioma cells. In both orthotopic and subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival and regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP was significantly taken up by SR-expressing TAMs thus resulting in macrophage polarization from M2 to M1, as exhibited by markedly reduced expression of immunosuppressive cytokines released by TAMs, including TGF-ß, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP nanoconjugate presented an effective nanodrug delivery system for brain cancer treatment.

Vitexin Mitigates Haloperidol-Induced Orofacial Dyskinesia in Rats through Activation of the Nrf2 Pathway.

Vitexin (VTX), a C-glycosylated flavone found in various medicinal herbs, is known for its antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the protective effects of VTX against orofacial dyskinesia (OD) in rats, induced by haloperidol (HPD), along with the neuroprotective mechanisms underlying these effects. OD was induced by administering HPD (1 mg/kg i.p.) to rats for 21 days, which led to an increase in the frequency of vacuous chewing movements (VCMs) and tongue protrusion (TP). VTX (10 and 30 mg/kg) was given intraperitoneally 60 min after each HPD injection during the same period. On the 21st day, following assessments of OD, the rats were sacrificed, and nitrosative and oxidative stress, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptosis markers in the striatum were measured. HPD effectively induced OD, while VTX significantly reduced HPD-induced OD, decreased oxidative stress, enhanced antioxidant capacity, prevented mitochondrial dysfunction, and reduced neuroinflammatory and apoptotic markers in the striatum, and the protective effects of VTX on both behavioral and biochemical aspects of HPD-induced OD were significantly reduced when trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated pathway, was administered. These findings suggest that VTX provides neuroprotection against HPD-induced OD, potentially through the Nrf2 pathway, indicating its potential as a therapeutic candidate for the prevention or treatment of tardive dyskinesia (TD) in clinical settings. However, further detailed research is required to confirm these preclinical findings and fully elucidate VTX's therapeutic potential in human studies.

PVA-based formulations as a design-technology platform for orally disintegrating film matrices.

In the majority of pharmaceutical applications, polymers are employed extensively in a diverse range of pharmaceutical products, serving as indispensable components of contemporary solid oral dosage forms. A comprehensive understanding of the properties of polymers and selection the appropriate methods of characterization is essential for the design and development of novel drug delivery systems and manufacturing processes. Orally disintegrating film (ODF) formulations are considered to be a potential substitute to traditional oral dosage forms and an alternative method of drug administration for children and uncooperative adult patients, including those with swallowing difficulties. A multitude of pharmaceutical formulations with varying mechanical and biopharmaceutical properties have emerged from the modification of the original polymeric bulk. Here we propose different formulation approaches, i.e. solvent casting (SC), 3D printing (3DP), electrospinning (ES), and lyophilization (LP) that enabled us to adjust the disintegration time and the release profile of poorly water soluble haloperidol (HAL, BCS class II) from PVA (polyvinyl alcohol) based polymer films while maintaining similar hydrogel composition. In this study, the solubility of haloperidol in aqueous solution was improved by the addition of lactic acid. The prepared films were evaluated for their morphology (SEM, micro-CT), physicochemical and biopharmaceutical properties. TMDSC, TGA and PXRD were employed for extensive thermal and structural analysis of fabricated materials and their stability. These results allowed us to establish correlations between preparation technology, structural characteristics and properties of PVA films and to adapt the suitable manufacturing technique of the ODFs to achieve appropriate HAL dissolution behaviour.

Breaking barriers in pharmaceutical analysis: Streamlined UV spectrometric quantification and stability profiling of haloperidol and methylparaben in liquid formulations.

This study aims to quantify haloperidol and methylparaben in a liquid pharmaceutical formulation (2 mg/ml) using UV spectrometry and the simultaneous equations method. Additionally, we explored the stability of haloperidol under various stress conditions. The UV analysis revealed maximum absorption peaks at 248 nm for haloperidol and 256 nm for methylparaben, using a 1 % (v/v) lactic acid solution as the solvent. Method validation, conducted according to ICH guidelines, affirmed the method's reliability, showing excellent results in terms of linearity, precision, accuracy, and sensitivity. The method allows direct application to finished products, enabling simultaneous quantification without extractions. Its simplicity, speed, and cost-effectiveness make it ideal for routine controls in pharmaceutical industry haloperidol solution analyses. The method extends to monitoring forced degradation, indicating photolytic and hydrolytic degradation under acidic and basic conditions, while affirming thermal and oxidative stability. This proposed UV spectrometric method serves as a compelling alternative to pharmacopeia-recommended techniques, simplifying simultaneous determination of the active ingredient and preservative. This streamlines analysis, reducing time and costs. Additionally, it proves valuable in small industries lacking sophisticated instrumentation, offering insights into active ingredient behavior during forced degradation.

Haloperidol for Pain Management: A Narrative Review.

The use of haloperidol in pain management has been a topic of interest for several decades. Haloperidol is a widely used antipsychotic medication with unique pharmacologic properties that make it a potential candidate for pain management. However, the efficacy and safety of haloperidol for pain management remain controversial. This narrative review provides a summary of the current literature on the use of haloperidol for pain management, including its pharmacology, clinical effectiveness, adverse effects, and dosing regimens. We performed a comprehensive search of the literature for this review. The most robust clinical data from the past decade suggest that haloperidol has good efficacy in the treatment of pain related to gastroparesis and migraines and has shown promise for opioid use reduction in patients with chronic pain or receiving palliative care. The overall side effect profile is excellent, with zero reported events of QT-related cardiac arrest and minimal reports of sedation and transient extrapyramidal effects such as akathisia. Dosing regimens used were heterogeneous, with most ranging from 1 to 5 mg per dose via intravenous, intramuscular, or oral route. Studies with designs that isolated the effects of haloperidol from combinations of other drugs were extremely limited. Further high-quality prospective studies are needed to determine the ideal role of haloperidol in the routine clinical management of painful conditions.

Investigating the cardiotoxicity of N-n-butyl haloperidol iodide: Inhibition mechanisms on hERG channels.

The human Ether-à-go-go-Related Gene (hERG) encodes a protein responsible for forming the alpha subunit of the IKr channel, which plays a crucial role in cardiac repolarization. The proper functioning of hERG channels is paramount in maintaining a normal cardiac rhythm. Inhibition of these channels can result in the prolongation of the QT interval and potentially life-threatening arrhythmias. Cardiotoxicity is a primary concern in the field of drug development. N-n-Butyl haloperidol iodide (F2), a derivative of haloperidol, has been investigated for its therapeutic potential. However, the impact of this compound on cardiac toxicity, specifically on hERG channels, remains uncertain. This study employs computational and experimental methodologies to examine the inhibitory mechanisms of F2 on hERG channels. Molecular docking and molecular dynamics simulations commonly used techniques in computational biology to predict protein-ligand complexes' binding interactions and stability. In the context of the F2-hERG complex, these methods can provide valuable insights into the potential binding modes and strength of interaction between F2 and the hERG protein. On the other hand, electrophysiological assays are experimental techniques used to characterize the extent and nature of hERG channel inhibition caused by various compounds. By measuring the electrical activity of the hERG channel in response to different stimuli, these assays can provide important information about the functional effects of ligand binding to the channel. The study's key findings indicate that F2 interacts with the hERG channel by forming hydrogen bonding, π-cation interactions, and hydrophobic forces. This interaction leads to the inhibition of hERG currents in a concentration-dependent manner, with an IC50 of 3.75 µM. The results presented in this study demonstrate the potential cardiotoxicity of F2 and underscore the significance of considering hERG channel interactions during its clinical development. This study aims to provide comprehensive insights into the interaction between F2 and hERG, which will may guid us in the safe use of F2 and in the development of new derivatives with high efficiency while low toxicity.

Opposite regulation by L-DOPA receptor GPR143 of the long and short forms of the dopamine D2 receptors.

Dopamine (DA) D2 receptors (D2Rs) have 2 isoforms, a long form (D2L) and a short form (D2S). D2L is predominantly postsynaptic in the striatal medium spiny neurons and cholinergic interneurons. D2S is principally presynaptic autoreceptors in the nigrostriatal DA neurons. Recently, we demonstrated that L-3,4-dihydroxyphenylalanine (L-DOPA) augments D2L function through the coupling between D2L and GPR143, a receptor of L-DOPA that was originally identified as the gene product of ocular albinism 1. Here we show that GPR143 modifies the functions of D2L and D2S in an opposite manner. Haloperidol-induced catalepsy was attenuated in DA neuron-specific Gpr143 gene-deficient (Dat-cre;Gpr143flox/y) mice, compared with wild-type (Wt) mice. Haloperidol increased in vivo DA release from the dorsolateral striatum, and this increase was augmented in Gpr143-/y mice compared with Wt mice. A D2R agonist quinpirole-induced increase in the phosphorylation of GSK3ß(pGSK3ß(S9)) was enhanced in Chinese hamster ovary (CHO) cells coexpressing D2L and GPR143 compared with cells expressing D2L alone, while it was suppressed in cells coexpressing D2S and GPR143 compared with D2S alone, suggesting that GPR143 differentially modifies D2R functions depending on its isoforms of D2L and D2S.

A Comparative Analysis of the Effects of Haloperidol and Dexmedetomidine on QTc Interval Prolongation during Delirium Treatment in Intensive Care Units.

Background: Haloperidol and dexmedetomidine are used to treat delirium in the intensive care unit (ICU). The effects of these drugs on the corrected QT (QTc) interval have not been compared before. It was aimed to compare the effects of haloperidol and dexmedetomidine treatment on QTc intervals in patients who developed delirium during ICU follow-up. Method: The study is single-center, randomized, and prospective. Half of the patients diagnosed with delirium in the ICU were treated with haloperidol and the other half with dexmedetomidine. The QTc interval was measured in the treatment groups before and after drug treatment. The study's primary endpoints were maximal QT and QTc interval changes after drug administration. Results: 90 patients were included in the study, the mean age was 75.2±12.9 years, and half were women. The mean time to delirium was 142+173.8 hours, and 53.3% of the patients died during their ICU follow-up. The most common reason for hospitalization in the ICU was sepsis (%37.8.). There was no significant change in QT and QTc interval after dexmedetomidine treatment (QT: 360.5±81.7, 352.0±67.0, p= 0.491; QTc: 409.4±63.1, 409.8±49.7, p=0.974). There was a significant increase in both QT and QTc interval after haloperidol treatment (QT: 363.2±51.1, 384.6±59.2, p=0.028; QTc: 409.4±50.9, 427.3±45.9, p=0.020). Conclusions: Based on the results obtained from the study, it can be concluded that the administration of haloperidol was associated with a significant increase in QT and QTc interval. In contrast, the administration of dexmedetomidine did not cause a significant change in QT and QTc interval.

Comparison of intramuscular haloperidol and other short-acting injectable antipsychotics for management of acute agitation in an adult inpatient psychiatry unit.

Introduction: There is no consensus on the optimal antipsychotic for acute agitation. Whereas haloperidol is frequently used and has proven efficacy, second generation antipsychotics show similar efficacy and improved safety and tolerability. This study aimed to determine the effectiveness of short-acting intramuscular (IM) haloperidol versus other IM antipsychotics for acute agitation in adults admitted to an inpatient psychiatry unit. Methods: This was a retrospective medical record review of patients who received 1 or more doses of a short-acting IM antipsychotic, including chlorpromazine, haloperidol, olanzapine, or ziprasidone. The primary endpoint was the need for subsequent IM antipsychotic(s) or physical restraint within 2 hours of the initial IM antipsychotic. Secondary endpoints assessed outcomes at 24 hours and adverse events. Results: One hundred six patients were included. Four patients in the haloperidol group and 0 patients in the other antipsychotic group received an additional IM antipsychotic or required physical restraints within 2 hours (5.3% versus 0%, p = .319). More patients in the other antipsychotic group required an additional dose of IM antipsychotic within 24 hours compared with the haloperidol group (p = .0096). More adverse events were seen in patients who received haloperidol. Discussion: Haloperidol was used more frequently than other short-acting IM antipsychotics. Whereas the effectiveness at 2 hours was not significantly different between groups, patients who received haloperidol were more likely to experience adverse events and were more often subjected to polypharmacy with benzodiazepines and/or diphenhydramine. This study further supports the use of olanzapine and ziprasidone for acute agitation in patients hospitalized in inpatient psychiatry.

Novel drug treatments for pain in advanced cancer and serious illness: a focus on neuropathic pain and chemotherapy-induced peripheral neuropathy.

Drugs that are commercially available but have novel mechanisms of action should be explored as analgesics. This review will discuss haloperidol, miragabalin, palmitoylethanolamide (PEA), and clonidine as adjuvant analgesics or analgesics. Haloperidol is a sigma-1 receptor antagonist. Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels. Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain. Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019. In randomized trials, patients with diabetic neuropathy have responded to miragabalin. Its long binding half-life on the calcium channel subunit may provide an advantage over other gabapentinoids. PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes in particular non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation. Multiple randomized trials and meta-analyses have demonstrated PEA's effectiveness in reducing pain severity arising from diverse pain phenotypes. Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette's syndrome, adjunctive therapy for cancer-related pain, and hypertension. Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic Adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia. Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of dopamine-receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting.

INTRODUCTION: Dopamine (D)2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). AREAS COVERED: Eight D2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects. EXPERT OPINION: Since the introduction of D2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)3-RAs and neurokinin (NK)1-RAs have been developed. The classical D2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT3-RA, dexamethasone and a NK1-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.

Prenatal stress alters transcription of NMDA-type glutamate receptors in the hippocampus.

Prenatal stress increases the risk of neurodevelopmental disorders. NMDA-type glutamate receptor (NMDAR) activity plays an important pathophysiological role in the cortico-hippocampal circuit in these disorders. We tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex (FCx) and hippocampus after exposure to prenatal restraint stress (PRS) in mice. At 10 weeks of age, male PRS offspring (n = 20) and non-stressed controls (NS, n = 20) were treated with haloperidol (1 mg/kg), clozapine (5 mg/kg) or saline twice daily for 5 days, before measuring social approach (SOC). Saline-treated and haloperidol-treated PRS mice had reduced SOC relative to NS (P < 0.01), but clozapine-treated PRS mice had similar SOC to NS mice. These effects of PRS were associated with increased transcription of NMDAR subunits encoded by GRIN2A and GRIN2B genes in the hippocampus but not FCx. GRIN transcription in FCx correlated positively with SOC, but hippocampal GRIN transcription had negative correlation with SOC. The ratio of GRIN2A/GRIN2B transcription is known to increase during development but was lower in PRS mice. These results suggest that GRIN2A and GRIN2B transcript levels are modified in the hippocampus by PRS, leading to life-long deficits in social behavior. These data have some overlap with the molecular pathophysiology of schizophrenia. Similar to PRS in mice, schizophrenia, has been associated with social withdrawal, with increased GRIN2 expression in the hippocampus, and reduced GRIN2A/GRIN2B expression ratios in the hippocampus. These findings suggest that PRS in mice may have construct validity as a preclinical model for antipsychotic drug development.

Adenosine A2A and dopamine D2 receptor interaction controls fatigue resistance.

Introduction: Caffeine and the selective A2A receptor antagonist SCH58261 both have ergogenic properties, effectively reducing fatigue and enhancing exercise capacity. This study investigates in male Swiss mice the interaction between adenosine A2A receptors and dopamine D2 receptors controlling central fatigue, with a focus on the striatum where these receptors are most abundant. Methods: We employed DPCPX and SCH58261 to antagonize A1 and A2A receptors, caffeine as a non-competitive antagonist for both receptors, and haloperidol as a D2 receptor antagonist; all compounds were tested upon systemic application and caffeine and SCH58261 were also directly applied in the striatum. Behavioral assessments using the open field, grip strength, and treadmill tests allowed estimating the effect of treatments on fatigue. Results and discussion: The results suggested a complex interplay between the dopamine and adenosine systems. While systemic DPCPX had little effect on motor performance or fatigue, the application of either caffeine or SCH58261 was ergogenic, and these effects were attenuated by haloperidol. The intra-striatal administration of caffeine or SCH58261 was also ergogenic, but these effects were unaffected by haloperidol. These findings confirm a role of striatal A2A receptors in the control of central fatigue but suggest that the D2 receptor-mediated control of the ergogenic effects of caffeine and of A2A receptor antagonists might occur outside the striatum. This prompts the need of additional efforts to unveil the role of different brain regions in the control of fatigue.

Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.

The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE-4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE-4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [low to very low certainty of evidence]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [very low certainty of evidence]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [low certainty of evidence]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [low certainty of evidence]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [very low certainty of evidence]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence].

Haloperidol-induced painless legs and moving toe syndrome in a schizophrenia patient: a case report.

Painless legs and moving toe syndrome (PoLMT) is a rare syndrome characterized by involuntary movements of the toe without pain. The exact etiology of the patient's PoLMT is unknown. We present a case of PoLMT in 45-year-old woman with a history of haloperidol intake for 10 months. Haloperidol was discontinued, and aripiprazole (15 mg) was initiated. After this switch, a reduction in movement was observed in the third and fourth toes; however, the second toe showed no discernible change.

Painless Legs and Moving Toe Syndrome (PoLMT) is a rare condition in which the toe moves on its own without any pain. No one knows for sure what causes PoLMT in patients. In this case report, we discuss a 45-year-old woman with PoLMT who was taking a drug called haloperidol for 10 months prior to their visit to hospital. Another drug, aripiprazole, was started after haloperidol was stopped. It was noticed that the third and fourth toes moved less after this switch in medication, but no change was noticed in the second toe.

Effects of Intracerebral Aminophylline Dosing on Catalepsy and Gait in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A1 and A2A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.

BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

Aripiprazole for treating delirium: A systematic review-Is it a valid yet understudied treatment?

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.