Pharmacokinetic interaction of quetiapine and lamotrigine - victim and perpetrator?

OBJECTIVE: We aimed to investigate the ambiguous findings of earlier research regarding the reduction of quetiapine plasma levels when combined with lamotrigine, most likely via UDP-glucuronosyltransferase induction by lamotrigine. METHODS: One thousand one hundred and fifty samples, divided into four groups of patients receiving either quetiapine immediate- (IR) or extended-release (XR) without or in combination with lamotrigine were compared regarding absolute and dose-adjusted plasma concentrations. Furthermore, samples of intra-individual controls were analyzed. RESULTS: Patients receiving quetiapine IR in combination with lamotrigine showed 31% lower plasma (p = 0.002) and 23% lower dose-adjusted plasma concentrations (p = 0.004) compared to those receiving IR monotherapy. The proportion of patients with quetiapine plasma concentrations below the lower limit of the therapeutic reference range was 50% and 30% in the combination group and in patients receiving monotherapy, respectively (p = 0.03). However, no significant differences regarding plasma concentration (p = 0.13) and dose-adjusted plasma concentration (p = 0.42) were observed in patients with combination vs. monotherapy with the XR formulation of quetiapine. In the intra-individual controls, no trends could be identified, possibly due to insufficient number of samples (p > 0.05). CONCLUSIONS: The combination of quetiapine IR with lamotrigine is associated with significantly lower drug concentrations of quetiapine, potentially impacting quetiapine effectiveness. For quetiapine ER, a significant interaction is less likely.

Evaluation of the Impact of the Addition of Atypical Antipsychotics to Continuous Infusion Propofol Therapy.

Purpose: The administration of sedatives to critically ill patients is a common practice in intensive care units (ICU) and has been associated with negative outcomes. To mitigate this, atypical antipsychotics are utilized as adjunctive therapy. This study aims to review and quantify overall effectiveness of the atypical antipsychotics quetiapine, risperidone, and olanzapine on reduction in the amount of continuous infusion propofol utilized in the ICU. Methods: This was an observational study that took place from February 27, 2021 to December 31, 2022. The primary outcome of this study was the percentage change in average propofol infusion rate (mcg/kg/min) from baseline to the greater than 24 to 48 hours period after atypical antipsychotic initiation. Secondary outcomes included ICU length of stay, duration of mechanical ventilation, QTc interval monitoring, and continuation of the antipsychotic without a valid indication. Descriptive statistics were utilized for the statistical analysis. Results: A total of 47 patients were included in the study. The average baseline propofol rate was 31 mcg/kg/min, which reduced 8.6% to 28.35 mcg/kg/min over the 0 to 24 hours period, was reduced by 19.4% compared to baseline to a rate of 25 mcg/kg/min during the greater than 24 to 48 hours period, and finally a percent reduction of 54.2% seen during the greater than 48 to 72 hours period to a rate of 14 mcg/kg/min. Conclusions: Patients who received an adjunctive antipsychotic saw resulting propofol rate reductions of 8.6% at 24 hours, 19.4% at 48 hours, and 54.2% at 72 hours. However, research on this topic should not end here, as further investigation with higher-level study design is needed to determine the true impact of these agents for this indication.

Long-term stability of five atypical antipsychotics (risperidone, olanzapine, paliperidone, clozapine, quetiapine) and the antidepressant mirtazapine in human serum assessed by a validated SPE LC-MS/MS method.

Long-term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid-phase extraction and liquid chromatography-tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation. We assessed analyte stability on long-term storage in serum samples at 25°C, 5°C, -20°C and -80°C, and during five freeze-thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at -20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at -80°C. Furthermore, all analytes were stable for five freeze-thaw cycles. We recommend storage at -80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of -20°C is sufficient for storage less than 60 days.

Comparison of oven drying and freeze drying methods for the production of fast melt films containing quetiapine fumarate.

BACKGROUND: Quetiapine fumarate (QTP) is commonly prescribed for schizophrenic patient, typically available in tablet or oral suspension form, presenting challenges such as administration difficulties, fear of choking and distaste for its bitter taste. Fast melt films (FMF) offer an alternative dosage form with a simple development process, ease of administration and rapid drug absorption and action onset. OBJECTIVE: This study aims to prepare FMF with different formulations using solvent casting methods and to compare the effects of different drying methods, including oven drying and freeze drying, on the properties of the films. METHODS: Various formulations were created by manipulating polymer types (starch, hydroxypropyl methylcellulose (HPMC) and guar gum) at different concentrations, along with fixed concentrations of QTP and other excipients. Characterization tests including surface morphology, weight, thickness, pH, tensile strength, elongation length, Young's modulus, folding endurance and disintegration time were conducted. The optimal FMF formulation was identified and further evaluated for moisture and drug content, dissolution behavior, accelerated stability, X-ray diffraction (XRD), and palatability. RESULTS: FMF containing 10 mg guar gum/film developed using oven drying emerged as the optimum choice, exhibiting desirable film appearance, ultra-thin thickness (0.453 ± 0.002 mm), appropriate pH for oral intake (pH 5.0), optimal moisture content of 11.810%, rapid disintegration (52.67 ± 1.53 s), high flexibility (folding endurance > 300 times) and lower Young's modulus (1.308 ± 0.214). CONCLUSION: Oven drying method has been proven to be favorable for developing FMF containing QTP, meeting all testing criteria and providing an alternative option for QTP prescription.

Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performance.

Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg-1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency.

Doses, serum concentrations and diagnoses of Norwegian quetiapine users 2001-2019 in a therapeutic drug monitoring material.

Over the past decade, increasing off-label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001-2019 were obtained and analysed for age, gender, trends in quetiapine doses, serum concentrations and indicators of diagnoses. There were 19 759 requisitions from 7459 individuals. Daily doses of quetiapine decreased by 24 mg per year (95% CI: -25.61 to -21.48, p < 0.001, N = 4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use was 13% for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results signal a trend towards lower prescribed doses of quetiapine, possibly reflecting drug repurposing and/or off-label use. The discrepancy in the decrease of doses versus serum concentrations may reflect the intake of higher doses than prescribed and/or inappropriate TDM sampling. Our findings show that TDM data have limitations when it comes to making inferences about the use of quetiapine based on serum concentrations and clinical information on the requisitions.

Association of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine versus patients treated with olanzapine, risperidone, or quetiapine: A systematic review and meta-analysis.

INTRODUCTION: Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. METHODS: We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. RESULTS: We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82-1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09-1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92-2.25]). CONCLUSION: In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs.

Dissolving Microneedles Patch: A Promising Approach for Advancing Transdermal Delivery of Antischizophrenic Drug.

OBJECTIVE: Microneedles (MNs) are minimally invasive transdermal drug delivery systems capable of penetrating the stratum corneum to overcome the barrier properties. The primary objective of this research was to prepare dissolving microneedle patches (DMNP) loaded with quetiapine (QTP). METHODS: DMNP were fabricated employing the solvent casting technique, utilizing various polymer feed ratios including polyvinyl alcohol (PVA), polyvinylpyrrolidone K30 (PVP-K30), and polylactide-co-glycolide (PLGA) polymers. The loaded DMNP with QTP underwent a comprehensive characterization process encompassing assessments for compatibility, thickness, insertion potential, morphology, thermal behavior, X-ray diffraction, ex-vivo permeation, skin irritation, and histopathological changes. RESULTS: FTIR studies confirmed the compatibility of QTP with the microneedle patch composites. The thickness of the drug-loaded DMNP ranged from 0.67 mm to 0.97 mm. These microneedles exhibited an impressive penetration depth of 480 µm, with over 80% of the needles maintaining their original shape after piercing Parafilm-M. SEM analysis of the optimized DMNP-2 revealed the formation of sharp-tipped and uniformly surfaced needles, measuring 570 µm in length. Remarkably, the microneedles did not elicit any signs of irritation upon application of the prepared DMNP. The DMNP-2 showcased an impressive cumulative ex-vivo permeation of QTP, reaching 17.82 µg/cm2/hr. Additionally, histopathological assessment of vital organs in rabbits attested to the safety profile of the formulated microneedle patches. CONCLUSIONS: In conclusion, the developed microneedle patch represents a promising strategy for enhancing the transdermal delivery of QTP. This innovative approach has the potential to increase patient compliance, offering a more efficient and patient-friendly method of administering QTP.

Pharmacobezoar Associated Prolonged Clinical Course in a Patient with Immediate Release Quetiapine Overdose.

INTRODUCTION: Quetiapine is available in both immediate-release (IR) and extended-release (XR) formulations. Quetiapine XR overdose is known to cause delayed increase in serum quetiapine concentrations. However, it is not certain whether quetiapine IR overdose would similarly cause a delayed increase in serum quetiapine concentrations. CASE REPORT: A 57-year-old woman with depression who was taking half a tablet of 25 mg quetiapine IR daily was transported to our emergency department with a complaint of disturbance of consciousness 12 h after a quetiapine IR overdose. On arrival, her initial vital signs were heart rate of 116 beats per minute, blood pressure of 77/43 mm Hg, and oxygen saturation of 91% under 10 L oxygen administration. Whole body plain computed tomography showed a large amount of gastric hyperdense content suggesting pharmacobezoar with a volume of 71.2 ml. After treatment with respiratory and circulatory support, gastric lavage was performed. Her disturbance of consciousness persisted until day 5, and she was extubated on day 7. The serum concentrations of quetiapine were 2690 ng/mL at 12 h after overdose, 5940 ng/mL at 40 h, and 350 ng/mL at 124 h after overdose. Serum concentrations of other co-ingestions were all below lethal levels. CONCLUSION: A massive quetiapine IR overdose with pharmacobezoars can cause a delayed increase in serum quetiapine concentrations.

Clozapine Safety in Pregnancy: A Clinical Study.

BACKGROUND AND HYPOTHESIS: Pregnant women with persistent schizophrenia and related disorders may require ongoing antipsychotic treatment, including clozapine. However, the potential risks of using clozapine during pregnancy and the postnatal period remain uncertain. STUDY DESIGN: We conducted a nested case-control study using the National Register of Antipsychotic Medication in Pregnancy (NRAMP) database. Our study assessed pregnancy outcomes among Australian women diagnosed with schizophrenia spectrum disorder and treated with clozapine (n = 14) during the first trimester. These women were compared to 2 subgroups: those treated with quetiapine (n = 53) and those not taking any medication (n = 24) during pregnancy. STUDY RESULTS: We observed higher rates of miscarriage in the clozapine group compared to the quetiapine and drug-free groups. The clozapine group had a higher early pregnancy body mass index but lower overall pregnancy weight gain than the other groups. The prevalence of gestational diabetes was significantly higher in the clozapine group. The percentage of vaginal delivery was higher in the clozapine group than in the other 2 groups. Neonatal outcomes such as gestational age, and Apgar scores were similar across groups. The birth weight was lower in the clozapine group compared to the other 2 groups. CONCLUSIONS: This study suggests that pregnant women taking clozapine and their babies have greater adverse outcomes compared to other groups. Clozapine appears to be associated with a greater risk of miscarriages, maternal gestational diabetes, and lower birth weight. However, the gestational age, Apgar scores, and admission to NICU/SCN were comparable between all groups.

Quetiapine, Clozapine, and Pimavanserin Treatment Response in Monogenic Parkinson's Disease Psychosis: A Systematic Review.

Psychotic symptoms frequently occur in idiopathic Parkinson's disease (PD) and often require treatment with antipsychotic therapy. Most antipsychotics have the potential to worsen the motor symptoms of PD; quetiapine, clozapine, and pimavanserin are commonly used for the treatment of idiopathic PD because these medications tend to be comparatively well tolerated. Although psychotic symptoms may also occur in monogenic forms of PD, no reviews have focused on the use of antipsychotic medications in this context. The objective of the present systematic review was to characterize the effectiveness and tolerability of quetiapine, clozapine, and pimavanserin in monogenic PD-associated psychosis. A literature search was performed with PubMed, Scopus, and Embase. The search yielded 24 eligible articles describing 30 individuals, although treatment response with respect to psychotic symptoms was described in only 11 cases; of these, six individuals experienced symptomatic improvement or remission (four with clozapine and two with quetiapine), two exhibited a poor therapeutic response (one to clozapine and one to quetiapine), and the other three responded initially to antipsychotic therapy before experiencing a recurrence of symptoms. The use of quetiapine and clozapine in GBA variant-associated PD is briefly reviewed separately. Notably, no reports of pimavanserin therapy were identified. In keeping with the idiopathic PD literature, relatively low doses of medication were used in most cases. Lastly, side effects were rarely reported. Although quetiapine and particularly clozapine may be effective and well tolerated in the treatment of monogenic PD psychosis, this review highlights the paucity of available evidence to guide clinical decision making in this context.

Stevens-Johnson syndrome-toxic epidermal necrolysis overlap in a patient taking quetiapine and famotidine: a case report.

BACKGROUND: Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TNE) overlap is a rare skin disorder characterized by erythema, blisters, extensive exfoliation, epidermal detachment, the involvement of multiple mucosae, and positive Nikolsky's sign. SJS-TEN has a high mortality rate. Our case involves a rare occurrence of drug-induced Stevens-Johnson syndrome-toxic epidermal necrolysis overlap with a delayed onset in the setting of quetiapine and famotidine therapy. CASE PRESENTATION: An 82-year-old Taiwanese female was admitted to our hospital for decreased urine output, generalized edema, and multiple skin blisters and bedsores. With further spread of the lesions, multiple ruptured bullae with shallow erosions on the face, trunk, and limbs and mucosal involvement affected 20% of the total body surface area. Nikolsky's sign was positive. A diagnosis of Steven-Johnson syndrome was highly suspected. One month prior, she had started famotidine and quetiapine. Intravenous methylprednisolone treatment was initiated, which ameliorated the skin lesions after 3 days. However, new lesions developed after only 1 day of methylprednisolone tapering. The patient died 12 days after admission. CONCLUSION: Stevens-Johnson syndrome-toxic epidermal necrolysis is a rare skin disorder. Although it is mainly acute and has a high mortality rate, delayed onset can still occur. Quetiapine and famotidine are generally safe and effective for treating geriatric and gastrointestinal problems, but rare drug hypersensitivity reactions can lead to debilitating consequences. Therefore, increased clinical awareness and the initiation of supportive care are imperative. Optimal management guidelines are still lacking, and confirmation of developed guidelines through randomized controlled trials is needed. Collaboration for better management strategies is warranted.

Acacia saligna extract alleviates quetiapine-induced sexual toxicity in male albino rats: Insights from UPLC-MS/MS metabolite profiling, structural and PI3K/NF-κB pathway assessments.

Background: Quetiapine (QET) abuse has increased due to its anxiolytic and hedonic effects, necessitating protective adjunct treatments. Acacia saligna (A. saligna) flowers, used in traditional medicine, have potential health benefits. Aim: To investigate the protective role of A. saligna flower extract against QET-induced sexual toxicity, and to elucidate the possible underlying mechanisms through metabolomic and physiological studies. Methods: A. saligna extract was subjected to metabolite profiling via High-Resolution Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-ESI-qTOF-MS). Forty-eight adult male albino rats were assigned into six groups for 30 days. The intracavernosal pressure (ICP), semen, biochemical, hormonal, histological, genetic and Western blot (WB) analyses were determined. Results: A. saligna extract is rich in phenolic compounds, flavonoids, tannins, and unsaturated fatty acids. QET significantly decreased ICP and negatively affected semen parameters. A. saligna mitigated decreased sperm motility and ameliorated overexpressed proinflammatory genes in QET-55 group. A. saligna ameliorated the reduction of the antioxidant biomarkers, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), concurrent with downregulation of the nuclear factor kappa B (NF-κB) protein. A. saligna counteracted the disrupted testicular and prostatic structures revealed by histological examination. Conclusion: The extract from A. saligna, which contains a high concentration of antioxidants and anti-inflammatory chemicals, effectively mitigates sexual toxicity caused by QET. This study provided the first known explanation of the hypothesized processes behind the protective properties of A. saligna through biological, biochemical, and histological parameters. The results emphasize the potential of A. saligna as a safeguarding agent against drug-induced sexual toxicity.

Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression.

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE­TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan­Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD.

Kufor-Rakeb syndrome-associated psychosis: a novel loss-of-function ATP13A2 variant and response to antipsychotic therapy.

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

AIMS: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations. RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations. CONCLUSION: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Dopamine D2 receptor antagonism of antipsychotics and the risk of death due to choking.

The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMRchoking). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMRchoking was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.

Chronic Caffeine Consumption, Alone or Combined with Agomelatine or Quetiapine, Reduces the Maximum EEG Peak, As Linked to Cortical Neurodegeneration, Ovarian Estrogen Receptor Alpha, and Melatonin Receptor 2.

RATIONALE: Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances. OBJECTIVES: The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated. METHODS: Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17ß-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed. RESULTS: CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2. CONCLUSIONS: CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects.

Disparities by Socioeconomic Status and Diagnosis of Dementia in the Prescribing of Antipsychotics in a Real-World Data Population Over 60 Years of Age.

Background: Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia. Objective: To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer's disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex. Methods: A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statisticalanalysis. Results: Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52-1.68), age over 80 years (OR: 1.56; CI: 1.47-1.65), institutionalization (OR: 12.61; CI: 11.64-13.65), diagnosis of dementia (OR: 10.18; CI: 9.55-10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58-4.01) and psychosis (OR: 4.96; CI: 4.64-5.30). Conclusions: The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity.