Quetiapine Research Articles

In Vitro and In Vivo Evaluation of Quetiapine Fumarate Nanoemulsion for Brain Targeting Through Intranasal Route

In Vitro and In Vivo Evaluation of Quetiapine Fumarate Nanoemulsion for Brain Targeting Through Intranasal Route

Risk of long-term care admissions among Medicare beneficiaries treated with pimavanserin or quetiapine for Parkinson's disease psychosis in USA: a retrospective administrative claims database analysis.

Aim: Risk of long-term care (LTC) admission (LTCA) associated with atypical antipsychotic (AAP) use among patients with Parkinson's disease psychosis (PDP) is a major concern. However, no comparative studies have examined the differences in risk of LTC admissions between pimavanserin (PIM), the only FDA-approved AAP for PDP, and other off-label AAPs including quetiapine (QUE). Objective: To examine all-cause LTCA rates and risk among PDP patients treated with AAPs such as QUE or PIM. Methods: Analysis of Parts A, Band D claims (100% Medicare sample; 2013-2019) of Medicare beneficiaries with PDP that initiate ≥12-month continuous PIM or QUE monotherapy from 1 January 2014 to31 December 2018 (i.e., index date) without any AAP use in the 12-month pre-index period was conducted. Outcome assessments among 1:1 propensity score-matched (31 variables - age, sex, race, region and 27 Elixhauser comorbidities) beneficiaries on PIM versus QUE included risk of all-cause skilled nursing facility stays (SNF-stays), LTC-stays, and overall LTCA (i.e., SNF-stays or LTC-stays). All-cause LTCA rates and LTCA risk were compared using logistic regression and cox proportional hazards models, respectively, controlling for demographics, comorbidities and co-existing-dementia or insomnia. Results: Of the matched sample (n=842 for each group) from total sample (n=9652), overall all-cause LTCA and SNF-stay rates were 23.2 and 20.2% for PIM versus 33.8 and 31.4% for QUE, respectively (p<0.05, for each). Hazard ratio (95% CI) for risk of SNF-stay and overall LTCA was 0.78 (0.61, 0.98) and 0.80 (0.66, 0.97), respectively, for PIM versus QUE beneficiaries (p<0.05, for each). Conclusion: The 20% lower risk of LTCA (i.e., greater delay) with PIM versus QUE in this analysis may suggest that PIM should be started early for the treatment of PDP.

Preparation and characterization of quetiapine fumarate loaded transfersome as a novel drug delivery system

Modern medicine delivery techniques like transdermal patches are vital for treating numerous disorders. With the aid of TDDS, first pass metabolism is prevented, which aids in achieving effective bioavailability. Drug molecules are also released into the systemic circulation at a controlled and predetermined rate. The objective of this study was creating matrix-type Quetiapine fumarate loaded transdermal patches with water bath method using different polymers like HPMC 5 cps, HPMC 15 cps, and Ethyl cellulose in different ratios. Polyethylene glycol-400, Dimethyl sulfoxide (DMSO) as a plasticizer and permeation enhancer, Solvents including methanol and chloroform in 1:1 ratio employed. FT-IR study indicated that pure drug and excipients are compatible with each other. The formulated patches are evaluated for thickness, weight variation, folding endurance, percentage moisture content, percentage moisture uptake, drug content and In vitro diffusion studies. A transfersomal formulation containing 25 mg of the drug and 10 mg of span 80 was concluded as the optimized formulation (F1) as it showed maximum drug entrapment (84.8%) and cumulative percent drug release (98.51%)

A novel UHPLC-MS/MS method for trace level identification and quantification of genotoxic impurity 2-(2-chloroethoxy) ethanol in quetiapine fumarate

A selective and sensitive new reversed-phase method was developed and validated by using Waters Acquity UHPLC system coupled with Waters Micromass Quattro PremierXE (MS/MS) to identify and quantify the genotoxic impurity 2-(2-chloroethoxy) ethanol at trace level (∼2.0 ppm) in quetiapine fumarate. The method used positive ion electrospray ionization with a multiple reaction monitoring detection mode using ACE3 C18(100 mm × 4.6 mm × 3.0 µm) column. For analysis, an isocratic program was developed using 0.01 M ammonium acetate in Milli-Q water (mobile phase A) and methanol (mobile phase B) in 20:80v/v ratio. Elution of 2-(2-chloroethoxy) ethanol was monitored using triple quadrupole mass spectrometer with an injection volume of 10 μl, a column oven temperature of 40 °C, an auto-sampler temperature of 15 °C, and flow rate of 0.5 mL/min. The retention time of 2-(2-chloroethoxy) ethanol was observed at 2.38 min. The LOQ and LOD were determined at concentrations of 0.235 ppm and 0.070 ppm respectively. The correlation coefficient R 2 was 0.9983 and the percent recoveries of method range from 98.1% to 114.0%. The method was successfully validated according to International Council for Harmonization requirements (ICH Q2(R1) and ICH M7(R1)) for genotoxic impurities. The method was sensitive, selective, accurate and precise and therefore can be used for identification and quantification of genotoxic impurity 2-(2-chloroethoxy) ethanol in quetiapine fumarate.

Roles of Fatty Acid Chain Length and Enzyme-Oriented Drug Controlled Release from pH-Triggering Self-Assembled Fatty Acid Conjugated Quetiapine Nanosuspensions.

Quetiapine (QTP) is a first-line antipsychotic drug, but its therapeutic druggability and patient adherence were limited due to high oral dose strength, low bioavailability and physicochemical/biopharmaceutical issues. To investigate the roles of fatty acid chain length and enzyme-oriented QTP controlled release from pH-triggering self-assembled fatty acid conjugated QTP nanosuspensions (NSPs). QTP was conjugated with different chain length fatty acids (C10-decanoic acid, C14-myristic acid, C18-stearic acid) to obtain QTP-fatty acid conjugates (QFCs: QD, QM, QS) by exploiting 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/4-dimethylaminopyridine (EDC/DMAP) conjugation chemistry. Then, the solubility, partitioning coefficient (log P), cell viability and cleavage kinetics of QFCs were evaluated. The pH-triggering self-assembled behaviors of QFCs to form QTP-fatty acid NSPs (QDN, QMN, QSN) by varying pH, QFC concentration and proton-to-QTP ratios were characterized. The morphological images, critical micelle concentration (CMC), physicochemical properties and enzyme-oriented QTP controlled release of NSPs were examined. Three QFCs were synthesized with different chain length fatty acids from QTP after desalting fumarate from QTP fumarate. The pH, QFC concentration and proton-to-quetiapine molar ratio could influence physicochemical properties and nanonization behaviors of QFCs. All three QFCs showed no effect on the viability of myoblast cells. The pH-triggering self-assembly of amphiphilic QFCs to form nanoparticles (NPs) occurred as the amine moiety of QTP was readily ionized in a strongly acidic environment (pH 1.2). Interestingly, the longer the fatty acid chain length, the lower water solubility, the higher log P (lipophilicity) and the smaller NP particle size were observed. The conversion rate of QFCs to liberate QTP by esterase in human plasma and liver S9 fractions was also inversely proportional to the fatty acid carbon chain length. Interestingly, the freeze-dried QMN showed the esterase-oriented controlled release of QTP over one month, unlike the initial burst release of QDN or the slowly delayed release pattern of QSN. A new pH-triggering self-assembled nanonization platform was developed using different chain length fatty acid conjugated QTP in low pH environment. By varying fatty acid chain length, the enzyme-oriented QTP controlled release dosage form was challenged to enhance the therapeutic effectiveness of QTP.

Combined in vivo metabolic effects of quetiapine and methadone in brain and blood of rats

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC–MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225–296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.

In vitro alcohol induced dose dumping studies for Quetiapine fumarate floating drug delivery systems

Alcohol dose dumping can occur due to the solubility of the pharmaceutical excipients, the solubility of the drug, and the formulation’s drug release mechanism. Cellulosics are the most commonly used polymers in pharmaceutical controlled release technologies. The ethanol vulnerability of tablets made with HPMC K250, HPMC K750 and HPMC K1500 were investigated with the low soluble drug quetiapine fumarate. Quetiapine fumarate is an antipsychotic drug and it is suitable drug candidate for FDDS due to its solubility in low pH. HPMC K250, HPMC K750 and HPMC K1500 were used as a polymer matrix to control the release of quetiapine fumarate up to 24 hr. The quetiapine floating tablets were prepared by direct compression method. All the tablets were evaluated for the Pre-compression and post Compression Parameter. In-vitro dissolution study was done in Normal Dissolution Media, 0.1N Hcl and also in 10%, 20%, 30% and 40% v/v hydro alcoholic media for up to 24 hrs. All HPMC K250, HPMC K750 and HPMC K1500 preparation did not fail in alcoholic media. From these studies it was concluded that the concern around alcohol dose dumping seems negligible for these polymers.

Comparative efficacy and safety of 4 atypical antipsychotics augmentation treatment for major depressive disorder in adults: A systematic review and network meta-analysis.

Atypical antipsychotic (AAP) augmentation is an alternative strategy for patients with major depressive disorder (MDD) who had an inadequate response to antidepressant therapy (ADT). We aimed to compare and rank the efficacy and safety of 4 AAPs in the adjuvant treatment of MDD. We searched randomized controlled trials (RCTs) published and unpublished from the date of databases and clinical trial websites inception to April 30, 2023. The evidence risk of bias (RoB) and certainty are assessed using the Cochrane bias risk tool and grading of recommendations assessment, development, and evaluation (GRADE) framework, respectively. Using network meta-analysis, we estimated summary risk ratios (RRs) or standardized mean difference (SMD) based on the random effects model. 56 eligible studies comprising 11448 participants were included. In terms of primary efficacy outcome, compared with placebo (PBO), all AAPs had significant efficacy (SMD = -0.40; 95% CI, -0.68 to -0.12 for quetiapine (QTP); -0.35, -0.59 to -0.11 for olanzapine (OLA); -0.28, -0.47 to -0.09 for aripiprazole (ARI) and -0.25, -0.42 to -0.07 for brexpiprazole (BRE), respectively). In terms of acceptability, no significant difference was found, either agents versus agents or agents versus PBO. In terms of tolerability, compared with the PBO, QTP (RR = 0.24; 95% CI,0.11-0.53), OLA (0.30,0.10-0.55), ARI (0.39,0.22-0.69), and BRE (0.37,0.18-0.75) were significantly less well tolerated. 8 (14.2%) of 56 trials were assessed as low RoB, 38 (67.9%) trials had moderate RoB, and 10 (17.9%) had high RoB; By the GRADE, the certainty of most evidence was low or very low. Adjuvant AAPs had significant efficacy compared with PBO, but treatment decisions must be made to balance the risks and benefits.

Consensus on the pharmacological treatment of acute stress disorder in Chinese pilots: a Delphi study

BackgroundAppropriate medication is very important for pilots with acute stress disorder. Improper medication can not only affect the physical and mental health of the pilots but can also endanger flight safety. Hence, we aimed to quickly and effectively relieve symptoms and restore cognitive function by forming a consensus of Chinese experts on the pharmacological treatment of acute stress disorder in pilots using the Delphi method.MethodsRelevant literature was searched to enumerate the current status of pharmacological treatment of acute stress disorder in pilots, followed by two rounds of expert consultation and discussion according to the listed status of the survey using the Delphi method. A descriptive statistical method was used to analyze the basic information, authority coefficients, concentration of opinions, and survey items of the experts to develop a consensus on the pharmacological treatment of acute stress disorder in pilots.ResultsA total of 16 experts in psychiatry, pharmacology, and aerospace medicine from different provinces and cities across China were invited for consultation. The recovery rate of the two rounds of consultation was 100%, and the expert authority coefficients were 0.897 and 0.906, respectively. Kendall’s coefficient of concordance of indicators at all levels was 0.564–0.594 (p < 0.01). Based on the number of votes received, alprazolam tablets (16), eszopiclone tablets (15), and lorazepam tablets (14) were recommended for the treatment of excitatory psychomotor symptoms of acute stress disorder; paroxetine tablets (15) and sertraline tablets (15) were available for psychomotor depressive symptoms; olanzapine tablets (15), olanzapine orally disintegrating tablets (14), and quetiapine fumarate tablets (14) were selected for psychotic symptoms.ConclusionsThis study formed a consensus on rapid and effective pharmacological treatment for different symptoms of acute stress disorder pilots, which provides a reference for clinical treatment.

Synthesis Folate-linked Chitosan-coated Quetiapine/BSA Nano-Carriers as the Efficient Targeted Anti-Cancer Drug Delivery System.

Quetiapine (QTP) has been known to suppress cancer progression in patients suffering from mental disorders. This study aimed to produce the folate-linked chitosan-coated quetiapine/BSA nano-carriers (FCQB-NCs) and evaluate their antioxidant, apoptotic, and anti-metastatic potentials on prostate, pancreas, colon, and breast cancer cell lines. The FCQB-NCs were designed, produced, and characterized using DLS, FESEM, FTIR, and Zeta potential techniques. The nano-carriers antioxidant activity was studied by applying ABTS, DPPH, and FRAP assays. The FCQB-NCs' cytotoxicity and apoptotic/metastatic properties were evaluated utilizing MTT assay and qPCR-based analysis for measuring the apoptotic (Nf-KB)/metastatic (MMP2, MMP9, and MMP13) gene expression, respectively. The AO/PI fluorescent cell staining, DAPI staining, and scratch assay methods were conducted to verify the apoptotic and anti-metastatic activities of FCQB-NCs. The 51-nm FCQB-NCs (PDI = 0.26) exhibited antioxidant activity and selectively decreased the MDA-MB-231 cancer cells' viability by inducing Nf-KB overexpression, which caused the apoptosis pathway activation. Moreover, the FCQB-NCs suppressed the MDA-MB-231 cells' metastatic activity by down-regulating the MMP2, MMP9, and MMP13 gene expression, verified by detecting the decreased migration rate. The FCQB-NCs selectively induced apoptosis and suppressed metastasis in the human breast cancer cell line, which can be attributed to the stepwise release of QTP in two primary (extra-cellular release) and secondary (intra-cellular release) phases. The efficient selective cytotoxic impact of FCQB-NCs can be due to the novel stepwise release mechanism of the FCQB-NCs based on the two-phase entrapment of QTP by BSA and chitosan molecules. Therefore, FCQB-NCs have the potential to be used as an efficient selective anti-breast cancer.

Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients.

To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. The average age of the included population (n= 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P< .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P< .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P< .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P< .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P= .012) and poor (+17%, P= .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.

Quetiapine Moderates Doxorubicin-Induced Cognitive Deficits: Influence of Oxidative Stress, Neuroinflammation, and Cellular Apoptosis.

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress.

Participation of quetiapine in oxidative stress and inflammation status in the treatment of drug overdose

Quetiapine (QT) belongs to the second generation of antipsychotics. It is mostly used to treat depression, bipolar disorder, and schizophrenia. During biotransformation via myeloperoxidase (MPO) QT is oxidized to quinoneimine and a reactive radical, which may contribute to the development of oxidative stress during intoxication. The coexisting inflammation may also significantly contribute to the disturbances in the course of QT poisoning. In this study, twenty-one patients poisoned with quetiapine were examined. The study aimed to assess the correlation between blood QT concentration and selected oxidative stress as well as inflammation biomarkers, such as MPO and C-reactive protein (CRP) levels in the serum of poisoned patients. The obtained results were related to the values of the control group consisting of 21 healthy people, untreated and not poisoned with the drug. In patients with a toxic QT concentration in the blood (3.15 ± 2.11 μg/mL), the activity of MPO and CRP serum level were significantly higher in comparison to the control group. The mean level of CRP in the study group was 76.74 mg/L, while in the control group only 1.86 mg/L. The increase in MPO activity and CRP blood level in patients after QT overdose may confirm the hypothesis of oxidative disorders arising during its biotransformation and concomitant inflammation. Statistically significant relationships between selected biomarkers and blood QT concentration, the patient's clinical condition and the type of therapy were demonstrated.

Quetiapine Albumin Nanoparticles as an Efficacious Platform for Brain Deposition and Potentially Improved Antipsychotic Activity.

Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Therefore, this study aimed to develop an intravenous QP albumin nanoparticles (NPs) system for improving QP antipsychotic activity and brain targeting. QP-loaded albumin NPs were prepared by the desolvation method. The fabricated NPs were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. In vivo pharmacokinetics and biodistribution in rats were studied. In addition, the antipsychotic activity of the optimized platform was also investigated. Human serum albumin (HSA) concentration, pH, and stirring time were modulated to optimize QP albumin NPs with a particle size of 103.54 ± 2.36 nm and a QP EE% of 96.32 ± 3.98%. In addition, the intravenous administration of QP albumin NPs facilitated QP brain targeting with a 4.9-fold increase in targeting efficiency compared to the oral QP solution. The QP albumin NPs improved the QP antipsychotic activity, indicated by suppressing rats' hypermobility and reducing the QP's extrapyramidal side effects. The obtained results proposed that intravenous QP- NPs could improve QP brain targeting and its antipsychotic efficiency.

Patients treated with pimavanserin or quetiapine for Parkinson’s disease psychosis: analysis of health resource utilization patterns among Medicare beneficiaries

BackgroundPimavanserin (PIM) is the only FDA approved atypical antipsychotic (AAP) for the treatment of Parkinson’s Disease Psychosis (PDP) while other off-label AAPs like quetiapine (QUE) are also used. Real-world comparative effects of PIM and QUE on health resource utilization (HCRU) may provide insights about their relative benefits.ObjectivesTo examine annual HCRU among newly initiated PIM or QUE monotherapy among patients with PDP.MethodsRetrospective analysis of 100% Medicare (Parts A, B, and D) claims of patients with PDP during 1 January 2013 to 31 December 2019 was conducted. Treatment-naive patients with first prescription for PIM or QUE from 1 January 2014 to 31 December 2018 were selected if they had ≥12-months continuous monotherapy and had no prior AAP use for ≥12-month pre-index. Post-index 12-month HCRU was compared between 1:1 propensity score matched (PSM) PIM or QUE cohorts. HCRU outcomes included: rates of all-cause and psychiatric-related inpatient hospitalizations by stay-type [i.e., long-term stays (LT-stays), short-term stays (ST-stays), skilled nursing facility stays (SNF-stays)], outpatient hospitalizations, emergency room (ER) visits, and office visits. Relative risk and 95% confidence intervals are reported [RR (95% CI)].ResultsA total of 842 and 7,116 were treated with PIM and QUE, respectively. Mean age and gender distribution were similar among both groups. After PSM, those on PIM (n=842) had significantly lower RR for all-cause: inpatient hospitalizations [RR=0.78 (0.70–0.87)], ST-stays [RR=0.75 (0.66–0.84)], SNF-stays [RR=0.64 (0.54–0.76)], and ER visits [RR=0.91 (0.84–0.97)] vs. QUE (n=842). PIM patients had slightly higher RR for all-cause office visits [RR=1.03 (1.01–1.05)] vs. QUE. Psychiatric-related inpatient hospitalizations were also lower for PIM vs. QUE: [RR=0.63 (0.48–0.82)] ST-stays [RR=0.61 (0.43–0.86)], SNF-stay [RR=0.69 (0.47–1.02)], and ER visits [RR=0.53 (0.37–0.76)].ConclusionsIn this analysis of PDP patients, PIM monotherapy resulted in nearly 22% and 37% lower all-cause hospitalizations and psychiatric-related inpatient hospitalizations compared to QUE.

Lumateperone 42 mg in an Open-Label Switch Study in Patients with Stable Schizophrenia: Results by Previous Antipsychotic

AbstractIntroductionLumateperone (LUMA) is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. An open-label study (Study 303) evaluated the safety and tolerability of LUMA in outpatients with stable schizophrenia who switched from previous antipsychotic (AP) treatment. This post hoc analysis of Study 303 investigated the safety and tolerability of LUMA stratified by previous AP in patients who switched to LUMA treatment for 6 weeks.MethodsAdult outpatients (≥18 years) with stable schizophrenia were switched from previous AP to LUMA 42 mg once daily for 6 weeks followed by switching to another approved AP for 2 weeks follow-up. Post hoc analyses were stratified by most common previous AP: risperidone or paliperidone (RIS/PAL); quetiapine (QET); aripiprazole or brexpiprazole (ARI/BRE); olanzapine (OLA). Safety analyses included adverse events (AE), vital signs, and laboratory tests. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions-Severity (CGI-S) scale.ResultsThe safety population comprised 301 patients, of which 235 (78.1%) were previously treated with RIS/PAL (n=95), QET (n=60), ARI/BRE (n=43), or OLA (n=37). Rates of treatment-emergent AEs (TEAEs) while on LUMA were similar between previous AP groups (44.2%-55.8%). TEAEs with incidences of ≥5% in any AP group were dry mouth, somnolence, sedation, headache, diarrhea, cough, and insomnia. Most TEAEs were mild or moderate in severity for all groups. Rates of serious TEAEs were low and similar between groups (0%–7.0%).Statistically significant (P&lt;.05) decreases from baseline were observed in the OLA group that switched to LUMA in total cholesterol and low-density lipoprotein cholesterol with significant decreases thereafter on LUMA. Statistically significant decreases in prolactin levels were observed in both the RIS/PAL (P&lt;.0001) and OLA (P&lt;.05) groups. Patients switched from RIS/PAL to LUMA showed significant (P&lt;.05) decreases for body mass index, waist circumference, and weight. At follow-up, 2 weeks after patients switched back from LUMA to another AP, none of the decreases in laboratory parameters or body morphology observed while on LUMA maintained significance.Those switching from QET had significant improvements from baseline at Day 42 in PANSS Total score (mean change from baseline −3.47; 95% confidence interval [CI] −5.27, −1.68; P&lt;.001) and CGI-S Total score (mean change from baseline −0.24; 95% CI, −0.38, −0.10; P&lt;.01).ConclusionIn outpatients with stable schizophrenia, LUMA 42 mg treatment was well tolerated in patients switching from a variety of previous APs. Patients switching from RIS/PAL or OLA to LUMA had significant improvements in cardiometabolic and prolactin parameters. These data further support the favorable safety, tolerability, and efficacy of LUMA in patients with schizophrenia.FundingIntra-Cellular Therapies, Inc.

Efficacy of Quetiapine Monotherapy and Combination Therapy for Patients with Bipolar Depression with Mixed Features: A Randomized Controlled Pilot Study.

Effective pharmacotherapy of bipolar depression with mixed features defined by DSM-5 remains unclear in clinical treatment guidelines. Quetiapine (QTP) and valproate have potential treatment utility but are often inadequate as monotherapy. Meanwhile, the efficacy of combination therapies of QTP plus valproate or lithium have yet to be verified. Hence, we conducted a randomized controlled pilot study to evaluate the efficacy of QTP monotherapy in patients with bipolar depression with mixed features defined by DSM-5 and compared the combination therapy of QTP plus valproate (QTP + V) versus QTP plus lithium (QTP + L) for those patients who responded insufficiently to QTP monotherapy. Data was analyzed according to the intent-to-treat population. Generalized linear mixed model was performed by using "nlme" package in R software. A total 56 patients were enrolled, among which, 35 patients responded to QTP alone, and 11 and 10 patients were randomly assigned to QTP + V and QTP + L group, respectively. Nearly 60% enrolled patients responded to QTP monotherapy at the first two weeks treatment. No statistically significant difference in efficacy between QTP + V and QTP + L was observed. In conclusion, QTP monotherapy appeared to be efficacious in patients with bipolar depression with mixed features, and for those who responded insufficiently to QTP, combining with either valproate or lithium appeared to have positive effects.

Construction of Pd-Ag/g-C3N4/CPE electrochemical nanosensor for simultaneous determination of clozapine and quetiapine antipsychotic drugs

A sensitive electrochemical procedure assisted by multivariate optimization approaches is applied for the simultaneous determination of antipsychotic drugs including clozapine (CLZ) and quetiapine (QTP) in the pharmaceutical and human plasma. The novel electrochemical nanosensor was fabricated carbon paste electrode by palladium-silver/graphitic carbon nitride nanostructure (Pd-Ag/g-C3N4/CPE). Firstly, we synthesized and characterized graphitic carbon nitride (g-C3N4) as well as Pd-Ag/g-C3N4 which was used for fabrication of modified CPE. Results of response surface methodology were specified that pH of 7.0, 20% of Pd-Ag/g-C3N4 nanostructure in the constructed CPE, sweep rate (0.06 V s−1) and pulse height (0.045 V) give maximum oxidation currents for both drugs. The electro-oxidation peaks current of CLZ and QTP at the Pd-Ag/g-C3N4/CPE surface were amplified dramatically versus CPE and their overpotentials were decreased. Under optimized experimental circumstances, linear answer in the ranges of 1.69–107.14 and 5.26–107.14 μM were obtained for CLZ and QTP, respectively. The LODs were obtained to be 0.5 and 1.5 μM for CLZ and QTP, respectively. The experimental presentation of the Pd-Ag/g-C3N4/CPE was validated by determining the concentration of CLZ and QTP in tablet samples and human plasma. The suggested system is easy, quick and can be applied as an effective analytical device in quality control of pharmaceutical industry.

Trace-level determination of potential genotoxic impurities in quetiapine fumarate using LC-MS.

A novel LC-MS method was developed and validated to determine three potential genotoxic impurities, namely 2-(2-aminophenylthio)benzoic acid hydrochloride, 2-aminothiophenol, and 2-(2-aminophenylthio)benzonitrile, at trace level (~1.6ppm) in quetiapine fumarate drug substance, an antipsychotic drug. These impurities are potentially genotoxic and therefore should be controlled at or below specific acceptance limits. An InertSustain AQ-C18 column (250 × 4.6 mm, 5 μm) in reversed-phase mode with the column temperature at 45°C was used. The mobile phase was 0.1% trifluoroacetic acid in water and acetonitrile with gradient elution mode, and the run time was 45 min. The flow rate was 0.8 ml/min. A mass spectrometer was used to quantify the amount of impurities using electrospray ionization mode at specific m/z 245.9, 126.0, and 226.9 for 2-(2-aminophenylthio)benzoic acid hydrochloride, 2-aminothiophenol, and 2-(2-aminophenylthio) benzonitrile, respectively. The method was found to be sensitive and possessed excellent linearity in the concentration ranges from the limit of quantification to 150% of the permitted level (0.47-2.36 μg/ml) with correlation coefficients above 0.999. The results showed that the method was specific, precise, linear, and accurate for the estimation of these three impurities in quetiapine fumarate.

Construction of a hydrophobic-hydrophilic open-droplet microfluidic chemosensor towards colorimetric/spectrophotometric recognition of quetiapine fumarate: a cost-benefit method for biomedical analysis using a smartphone.

Quetiapine fumarate (QF) is used to treat a number of mental/emotional diseases, including schizophrenia, bipolar disorder, and abrupt bouts of mania or depression linked to bipolar disorder. This antipsychotic medicine can be deadly if an overdose is given to a person. Therefore, the sensitive identification of QF in bodily fluids is very important. In this study, an innovative low-cost colorimetric chemosensor based on silver nanoprism transfiguration in a phosphate-buffered saline (PBS)/Cl- matrix was developed and successfully tested for the recognition of QF in human-exhaled breath condensate. Using this non-invasive colorimetric chemosensor, a broad linearity range of 0.001-1000 μM and a low limit of quantification of 0.001 μM for QF were attained. Notably, the proposed optical chemosensor is capable of detecting QF from a minimum amount of sample [500 μM in PBS and 0.001 μM in exhaled breath condensate] in the first few seconds of reaction by the naked eye. So, a rapid colorimetric assay for the on-site analysis of QF was developed and validated. Moreover, for the first time, a semi-analytical method was introduced that can provide a rough estimation of the QF concentration. This colorimetric system was, for the first time, integrated in an optimized microfluidic paper-based colorimetric device (μPCD), promising the development of an engineered colorimetric opto-sensor toward real-time and therapeutic drug monitoring (TDM) assay of drugs in real-world samples.