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Molecular Pharmacology May 2024Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical...
Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin (5-HT) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT receptors and blocks sodium current. The new compound, -(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, G-mediated, calcium flux at 5-HT receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT, 5-HT, and 5-HT receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT receptors and voltage-gated sodium channels (VGSCs), in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.
PubMed: 38821630
DOI: 10.1124/molpharm.123.000837 -
Journal of Psychiatric Practice May 2024Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence...
OBJECTIVE
Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence that prescribers consider before using these agents is lacking. While empirical literature on the long-term safety and efficacy of these medications is available, the literature concerning their use in these younger age groups is relatively sparse. In this study, we examined the current prescribing patterns of medical professionals employed by a public health service in Australia.
METHODS
A survey examining their current practice when prescribing atypical antipsychotics to children and adolescents was completed by 103 physicians. Questions were asked about commonly prescribed atypical antipsychotics, indications, dose ranges, target symptoms, duration of treatment, and the evidence base(s) used when making treatment decisions.
RESULTS
Physicians prescribed atypical antipsychotics for a wide range of indications in this age group, with the most common agents being risperidone, quetiapine, and olanzapine. Adverse effects were reported as the main reason for treatment discontinuation. More than half of the respondents indicated that the most common source of guidance/evidence they referred to when initiating prescriptions were peers or expert opinion.
CONCLUSIONS
Children and adolescents were prescribed a number of atypical antipsychotics for a variety of indications, with variable perceived confidence and a relatively heavy reliance on "own or peer experience" as opposed to good quality evidence. Challenges exist for both prescribers and policymakers, and further "head-to-head" studies are needed in this age group to ensure that a balance is maintained between therapeutic benefit and safety.
Topics: Humans; Antipsychotic Agents; Adolescent; Practice Patterns, Physicians'; Australia; Child; Male; Female; Drug Prescriptions; Risperidone; Surveys and Questionnaires; Olanzapine
PubMed: 38819247
DOI: 10.1097/PRA.0000000000000785 -
Journal of Psychiatric Practice May 2024Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin...
OBJECTIVE
Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms.
METHODS
This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included.
RESULTS
Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment.
CONCLUSIONS
Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.
Topics: Humans; Prolactinoma; Pituitary Neoplasms; Mental Disorders; Dopamine Agonists; Antipsychotic Agents; Dopamine Antagonists
PubMed: 38819244
DOI: 10.1097/PRA.0000000000000783 -
Federal Practitioner : For the Health... Apr 2024Acute agitation frequently occurs in the emergency department. Appropriate management is critical for the safety of all parties involved. Benzodiazepines and...
BACKGROUND
Acute agitation frequently occurs in the emergency department. Appropriate management is critical for the safety of all parties involved. Benzodiazepines and antipsychotics are commonly used for agitation, but safety concerns exist with these medications in older adults, even with acute use. The purpose of this study was to compare prescribing practices of anti-agitation medications between adults aged 18 to 64 years and those aged ≥ 65 years.
METHODS
This study was a retrospective chart review of patients who presented to the Veteran Affairs Southern Nevada Healthcare System emergency department and received haloperidol, droperidol, lorazepam, olanzapine, or ziprasidone from August 1, 2019, to July 31, 2022. Veterans were excluded if they had alcohol intoxication, alcohol withdrawal, benzodiazepine withdrawal, or medication administration unrelated to agitation. Safety outcomes included oxygen saturation < 95%, supplemental oxygen use, intubation, QTc prolongation, and new hypotension within 1 hour of medication administration.
RESULTS
For the 232 patients who met inclusion criteria, baseline characteristics differed significantly. When comparing patients aged 18 to 64 years and those aged ≥ 65 years, the younger cohort had higher rates of substance use disorder diagnosis (55.3% vs 27.5%, < .001), positive urine drug screen (69.7% vs 22.5%, < .001), and 72-hour legal hold (59.9% vs 32.5%, < .001), and lower rates of cognitive impairment or dementia (0.7% vs 48.8%, < .001), and altered mental status-related diagnosis (2.0% vs 18.8%, < .001). Anti-agitation medication selection significantly differed based on age ( = .02). Other than lorazepam ( = .007), no significant differences were noted in the dose ordered. No significant differences were observed for safety outcomes or additional anti-agitation doses.
CONCLUSIONS
Anti-agitation prescribing practices may differ between adults aged 18 to 64 years and those aged ≥ 65 years. The findings of this study also suggest that the most common agitation etiologies may differ based on patient age. Additional higher-quality studies are needed to further explore acute agitation in older adults.
PubMed: 38813266
DOI: 10.12788/fp.0456 -
Journal of Cancer Research and Clinical... May 2024The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with... (Randomized Controlled Trial)
Randomized Controlled Trial
A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.
OBJECTIVE
The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors.
METHODS
Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions.
RESULTS
1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05).
CONCLUSION
Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.
Topics: Humans; Olanzapine; Female; Middle Aged; Nausea; Vomiting; Antineoplastic Combined Chemotherapy Protocols; Prospective Studies; Oxaliplatin; Irinotecan; Aged; Adult; Antiemetics; Gastrointestinal Neoplasms; Palonosetron; Quality of Life; Dexamethasone
PubMed: 38806870
DOI: 10.1007/s00432-024-05712-7 -
Biomedicine & Pharmacotherapy =... Jul 2024Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related...
BACKGROUND
Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects.
METHODS
To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels.
RESULTS
Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol.
CONCLUSIONS
A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
Topics: Animals; Immunoglobulin Fc Fragments; Glucagon-Like Peptides; Olanzapine; Rats, Sprague-Dawley; Female; Recombinant Fusion Proteins; Rats; Antipsychotic Agents; Eating; Glucagon-Like Peptide-1 Receptor; Weight Gain; Disease Models, Animal; Benzodiazepines; Body Weight; Caloric Restriction
PubMed: 38805968
DOI: 10.1016/j.biopha.2024.116763 -
Frontiers in Cardiovascular Medicine 2024To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT...
PURPOSE
To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation.
METHODS
We employed the preferred term (PT) "electrocardiogram QT prolonged" from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004-2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs.
RESULTS
We listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system ( = 19, 47.50%) and antiinfectives for systemic use ( = 7, 17.50%). Patients with missing gender ( = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis.
CONCLUSIONS
Our study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.
PubMed: 38803662
DOI: 10.3389/fcvm.2024.1363382 -
Journal of Cutaneous and Aesthetic... 2024Facial pigmentation is a common presentation of patients attending dermatology out patient department (OPD) and is of great concern to patients. Facial pigmentation may...
INTRODUCTION
Facial pigmentation is a common presentation of patients attending dermatology out patient department (OPD) and is of great concern to patients. Facial pigmentation may be multifactorial and is only rarely diagnosed accurately by a detailed history and clinical examination. Pigmentary disorders cause psychological distress and negatively impact the quality of life of an individual.
AIMS AND OBJECTIVES
(1) To study different dermoscopic patterns in facial melanosis. (2) To estimate the frequency of different dermoscopic patterns.
MATERIALS AND METHODS
Patients with facial hyperpigmentation attending the dermatology OPD were recruited after taking their written consent. A detailed history was taken to collect demographic data. Clinical examination and dermoscopy were done in all patients. Biopsy was done as and when required. Descriptive statistics has been used to describe the quantitative data. Qualitative data were presented as frequency and percentage for clinical and dermoscopic patterns.
RESULTS
The study included 100 patients with 15 different facial melanoses. The most common age group affected was 21-40 years in 53 (53%) cases. The female-to-male ratio was 1.63:1. Melasma was reported as the most common cause of facial melanosis constituting 49 (49%) of the total cases. Out of the total melasma cases, epidermal melasma constituted 22 (45%) cases, dermal melasma constituted four (4%) cases and mixed melasma constituted 23 (47%) cases. Other cases included were lichen planus pigmentosus (14; 14%), facial acanthosis nigricans (14; 14%), periorbital hyperpigmentation (7; 7%), post-inflammatory hyperpigmentation (4; 4%), exogenous ochronosis (2; 2%), lentigines (2; 2%), frictional melanosis (2;2%), and one case each of Becker's nevus, nevus of Ota, olanzapine-induced hyperpigmentation, Riehl's melanosis, macular amyloidosis, and tanning.
CONCLUSIONS
Melasma was reported as the most common cause of facial melanosis. The most common dermoscopic feature was accentuated pseudopigment network. The study is beneficial in understanding the different clinical and dermoscopic patterns of facial melanosis, thus helping the physician to effectively manage the conditions and reduce the need of biopsy.
LIMITATIONS
(1) A small sample size. (2) Histopathological correlation was not done in all cases.
PubMed: 38800811
DOI: 10.4103/JCAS.JCAS_48_23 -
International Journal of Dermatology May 2024Trichotillomania, also known as hair-pulling disorder, is a chronic psychiatric condition with a fluctuating course in which an individual pulls out their hair, leading...
BACKGROUND
Trichotillomania, also known as hair-pulling disorder, is a chronic psychiatric condition with a fluctuating course in which an individual pulls out their hair, leading to visible hair loss and psychosocial sequelae. Due to the unknown pathogenesis, the treatment of this disorder is complex and remains a challenge for dermatologists and psychiatrists. Since guidelines for treating trichotillomania are lacking and, consequently, no common treatment strategy exists, we decided to perform a large-scale, global retrospective cohort study to assess the characterized real-world prescription patterns in treating trichotillomania.
METHODS
The research used the TrinetX database for patients with trichotillomania (ICD 10 - F63.3) within the European and the United States Collaborative Network (EC and UC, respectively). After consulting with a psychodermatology expert, a list of 25 medications was investigated.
RESULTS
Data on the prescription drugs of 1,275 patients from the EC and 109,741 patients from the UC were collected. In both the EC and UC cohorts, benzodiazepine derivatives, particularly lorazepam and midazolam, were the most commonly prescribed sedatives/hypnotics. Antipsychotic prescriptions, primarily haloperidol, followed benzodiazepines. After the trichotillomania diagnosis, notable changes in drug prescriptions for the EC cohort, including an increased likelihood of receiving acetylcysteine, haloperidol, quetiapine, sertraline, olanzapine, and risperidone were observed. The UC cohort showed minimal changes. Overall, both cohorts leaned toward benzodiazepine prescriptions (37% UC, 21% EC) and had limited antidepressant usage. Haloperidol (19.3%) and quetiapine (15.1%) were commonly prescribed in both cohorts.
CONCLUSIONS
The results of our study indicate that the real-world prescription patterns for trichotillomania differ significantly from the expert-proposed therapeutic approach and point toward the necessity of creating standards of pharmacological care and better education.
PubMed: 38797877
DOI: 10.1111/ijd.17269 -
Journal of Pharmacological and... 2024Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an...
Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry.
Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D), histamine 1 (H), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D, H and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D, H, and mACh receptor occupancy is possible using LC-MS/MS.
Topics: Animals; Tandem Mass Spectrometry; Rats; Male; Antipsychotic Agents; Chromatography, Liquid; Receptors, Dopamine D2; Rats, Sprague-Dawley; Receptors, Muscarinic; Receptors, Histamine H1; Olanzapine; Brain; Benzodiazepines; Raclopride; Doxepin; Quinuclidinyl Benzilate; Dose-Response Relationship, Drug
PubMed: 38797366
DOI: 10.1016/j.vascn.2024.107518