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Biomedicine & Pharmacotherapy =... Jun 2024Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome...
BACKGROUND
Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia.
METHODS
Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes.
RESULTS
The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na/Ca exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1β, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone.
CONCLUSIONS
Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.
Topics: Animals; Atrial Fibrillation; TOR Serine-Threonine Kinases; Inflammasomes; Signal Transduction; Proto-Oncogene Proteins c-akt; Myocytes, Cardiac; Rabbits; Reactive Oxygen Species; Piperazines; Male; Phosphatidylinositol 3-Kinases; Thiazoles; Heart Atria; Action Potentials; Antipsychotic Agents
PubMed: 38692059
DOI: 10.1016/j.biopha.2024.116649 -
Pharmacology, Biochemistry, and Behavior Jul 2024The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders...
The 5-HT receptor antagonist SB 269970 ameliorates maternal fluoxetine exposure-induced impairment of synaptic plasticity in the prefrontal cortex of the offspring female mice.
The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders and cognitive symptoms in progeny. In animal models, maternal exposure to fluoxetine throughout gestation and lactation negatively affects the behavior of the offspring. Little is known about the effects of maternal fluoxetine on synaptic transmission and plasticity in the offspring cerebral cortex. During pregnancy and lactation C57BL/6J mouse dams received fluoxetine (7.5 mg/kg/day) with drinking water. Female offspring mice received intraperitoneal injections of the selective 5-HT receptor antagonist SB 269970 (2.5 mg/kg) for 7 days. Whole-cell and field potential electrophysiological recordings were performed in the medial prefrontal cortex (mPFC) ex vivo brain slices. Perinatal exposure to fluoxetine resulted in decreased field potentials and impaired long-term potentiation (LTP) in layer II/III of the mPFC of female young adult offspring. Neither the intrinsic excitability nor spontaneous excitatory postsynaptic currents were altered in layer II/III mPFC pyramidal neurons. In mPFC slices obtained from fluoxetine-treated mice that were administered SB 269970 both field potentials and LTP magnitude were restored and did not differ from controls. Treatment of fluoxetine-exposed mice with a selective 5-HT receptor antagonist, SB 269970, normalizes synaptic transmission and restores the potential for plasticity in the mPFC of mice exposed in utero and postnatally to fluoxetine.
Topics: Animals; Fluoxetine; Female; Mice; Prefrontal Cortex; Receptors, Serotonin; Pregnancy; Neuronal Plasticity; Mice, Inbred C57BL; Phenols; Sulfonamides; Prenatal Exposure Delayed Effects; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Long-Term Potentiation
PubMed: 38688436
DOI: 10.1016/j.pbb.2024.173779 -
Scientific Reports Apr 2024Lung cancer, a global mortality leader, often necessitates Video-Assisted Thoracoscopic (VATS) surgery. However, post-operative nausea and vomiting (PONV) is common,... (Comparative Study)
Comparative Study
Lung cancer, a global mortality leader, often necessitates Video-Assisted Thoracoscopic (VATS) surgery. However, post-operative nausea and vomiting (PONV) is common, highlighting a need for effective management and prevention strategies in this context. A retrospective case-control study at Fujian Medical University Union Hospital evaluated patients undergoing VATS radical resection of lung cancer between May and September 2022. Patients were categorized based on PONV prevention methods, and data encompassing demographics, surgical history, and postoperative adverse events s were analyzed to assess the association between prophylactic protocols and PONV incidence. The Netupitant and Palonosetron Hydrochloride (NEPA) group showed a significant reduction in PONV occurrences post-surgery compared to Ondansetron (ONDA) and Control groups, emphasizing NEPA's efficacy in alleviating PONV symptoms (P < 0.05). Furthermore, following VATS radical resection of lung cancer, NEPA markedly reduced the intensity of PONV symptoms in patients. Both univariate and multivariate logistic analyses corroborated that NEPA independently reduces PONV risk, with its protective effect also apparent in susceptible populations like females and non-smokers. NEPA utilization markedly reduced both the incidence and severity of PONV in patients undergoing VATS radical resection of lung cancer, serving as an independent protective factor in mitigating PONV risk post-surgery.
Topics: Humans; Female; Thoracic Surgery, Video-Assisted; Male; Lung Neoplasms; Postoperative Nausea and Vomiting; Middle Aged; Retrospective Studies; Aged; Case-Control Studies; Antiemetics; Ondansetron; Palonosetron
PubMed: 38684769
DOI: 10.1038/s41598-024-59687-z -
Journal of Integrative Neuroscience Apr 2024Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic... (Review)
Review
Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.
Topics: Humans; Antipsychotic Agents; Clozapine; Hallucinations; Parkinson Disease; Piperidines; Quetiapine Fumarate; Urea
PubMed: 38682215
DOI: 10.31083/j.jin2304080 -
Case Reports in Critical Care 2024Trazodone is a serotonin receptor antagonist and reuptake inhibitor commonly used to treat major depression disorder (MDD), anxiety, and sleep disorders. It is...
INTRODUCTION
Trazodone is a serotonin receptor antagonist and reuptake inhibitor commonly used to treat major depression disorder (MDD), anxiety, and sleep disorders. It is considered safe for the heart due to minimal anticholinergic effects. Prolonged QT intervals can cause polymorphic ventricular tachycardia, known as torsades de pointe (TdP). We present a case of a 67-year-old female with a history of MDD who developed trazodone-induced TdP. . The patient was referred to a tertiary hospital with a ten-hour history of nausea and vomiting. Trazodone (50 mg daily) was started for her six days ago due to her past medical history of MDD. The initial electrocardiography (ECG) revealed a prolonged corrected QT interval (QTc = 586 ms) due to a long ST segment and generalized T wave inversion. A few moments after admission to the intensive care unit, she suddenly lost consciousness. ECG monitoring showed a TdP, which terminated immediately with the asynchronous defibrillation. A temporary pacemaker was implanted due to repeated arrhythmias and bradycardia. Arrhythmia did not recur for hours and days later. After four days of stopping trazodone, all abnormal ECG findings were resolved, and she was discharged with a normal ECG. She was followed up six months later; the ECG was normal, and she had no complaints.
CONCLUSION
Trazodone may lead to QTc prolongation and TdP, potentially fatal even without risk factors for QTc prolongation. Close monitoring is essential to prevent adverse complications in trazodone users.
PubMed: 38680420
DOI: 10.1155/2024/5759229 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024Mirtazapine blocks 5-hydroxytryptamine type (5-HT), 5-HT, 5-HT and histamine H receptors, similarly to olanzapine. This study aimed to investigate the efficacy and...
BACKGROUND
Mirtazapine blocks 5-hydroxytryptamine type (5-HT), 5-HT, 5-HT and histamine H receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers.
METHODS
We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h).
RESULTS
Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0.
CONCLUSIONS
Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute.
Topics: Humans; Granisetron; Male; Mirtazapine; Female; Dexamethasone; Middle Aged; Aged; Nausea; Vomiting; Prospective Studies; Carboplatin; Antiemetics; Thoracic Neoplasms; Adult; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Japan; Drug Therapy, Combination
PubMed: 38678830
DOI: 10.1016/j.lungcan.2024.107801 -
International Journal of Molecular... Apr 2024According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of...
According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response.
Topics: Animals; Dopaminergic Neurons; Male; Mice; Social Behavior; Humans; Clozapine; Raphe Nuclei; Behavior, Animal; Dopamine; Mice, Inbred C57BL
PubMed: 38673899
DOI: 10.3390/ijms25084315 -
PloS One 2024To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVES
To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD).
METHODS
We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events.
RESULTS
Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies.
CONCLUSIONS
A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.
Topics: Aripiprazole; Bupropion; Humans; Depressive Disorder, Major; Randomized Controlled Trials as Topic; Depressive Disorder, Treatment-Resistant; Treatment Outcome; Drug Therapy, Combination
PubMed: 38669232
DOI: 10.1371/journal.pone.0299020 -
Cells Apr 2024Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor...
Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain.
Topics: Animals; Receptors, Opioid, kappa; Neuralgia; Neurons; Mice; Amygdala; Mice, Transgenic; Behavior, Animal; Male; Clozapine; Central Amygdaloid Nucleus
PubMed: 38667320
DOI: 10.3390/cells13080705 -
The British Journal of Psychiatry : the... May 2024A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. (Observational Study)
Observational Study
BACKGROUND
A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood.
AIMS
To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS).
METHOD
Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.
RESULTS
A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions ( = 0.07, 95% CI 0.04-0.09; < 0.001). No direct effect of psychosis on checking was identified ( = -0.28, 95% CI -0.09 to 0.03; = 0.340). After psychosis remission ( = 65), checking compulsions correlated with both clozapine plasma levels ( = 0.35; = 0.004) and dose ( = 0.38; = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction.
CONCLUSIONS
We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.
Topics: Humans; Clozapine; Male; Female; Adult; Antipsychotic Agents; Longitudinal Studies; Psychotic Disorders; Schizophrenia, Treatment-Resistant; Middle Aged; Compulsive Behavior; Obsessive-Compulsive Disorder; Schizophrenia
PubMed: 38652060
DOI: 10.1192/bjp.2024.30