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The Journal of Clinical Psychiatry Mar 2020To compare longitudinal metabolic effects of 7 antipsychotics, including body mass index (BMI), waist circumference (WC), blood pressure (BP), glucose, triglycerides... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare longitudinal metabolic effects of 7 antipsychotics, including body mass index (BMI), waist circumference (WC), blood pressure (BP), glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); to investigate risk factors for metabolic syndrome (MetS); and to make recommendations on frequency and timing of monitoring metabolic measurements.
METHODS
This randomized, open-label, pharmacologic trial was conducted among patients with schizophrenia (DSM-IV) in 32 hospitals across China. Patients were randomly assigned to 7 groups and assessed at baseline, 2, 4, and 6 weeks. Linear mixed-effect models were used to assess changes of metabolic measures over time. Multivariable logistic regression analysis was performed to investigate the risk factors for MetS.
RESULTS
In total, 2,550 (718 drug-naïve) of 2,774 patients finished the study between July 6, 2010, and November 30, 2011. We found significant (P < .05) changes for BMI, WC, TG, and LDL-C, with TG and LDL-C reaching a plateau. Interactions between baseline metabolic condition and changes over time were observed for BMI (χ² = 43.11, P < .001), WC (χ² = 36.34, P < .001), systolic BP (χ² = 11.92, P = .002), glucose (χ² = 6.09, P = .01), and TG (χ² = 6.01, P = .01). Antipsychotics generally had greater adverse effects on patients who were initially screened as metabolically normal. After controlling for other associated factors, we found that antipsychotics resulted in differing risk for incident MetS, with a similar pattern to findings in other populations: olanzapine (odds ratio [OR] = 3.36, P < .001) > quetiapine (OR = 3.29, P < .001) > perphenazine (OR = 2.73, P = .007) > risperidone (OR = 2.21, P = .02) > aripiprazole (OR = 1.74, P = .15) ≈ haloperidol (OR = 1.75, P = .22) ≈ ziprasidone (OR = 1, reference).
CONCLUSIONS
Metabolic traits should be monitored frequently in early stages of antipsychotic treatment due to rapid and substantial changes. Clinicians should not assume low risk for patients with normal metabolic parameters at baseline.
TRIAL REGISTRATION
Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000934.
Topics: Adult; Antipsychotic Agents; Aripiprazole; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Male; Metabolic Syndrome; Olanzapine; Piperazines; Quetiapine Fumarate; Risk Factors; Risperidone; Schizophrenia; Thiazoles; Triglycerides
PubMed: 32237292
DOI: 10.4088/JCP.19m12785 -
The Journal of Clinical Psychiatry Mar 2020Patients with schizophrenia and comorbid alcohol use disorder remain understudied. This post hoc analysis evaluated data from Phase 1 of the Clinical Antipsychotic... (Comparative Study)
Comparative Study
Course of Psychosis in Schizophrenia With Alcohol Use Disorder: A Post Hoc Analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia Phase 1 Study.
OBJECTIVE
Patients with schizophrenia and comorbid alcohol use disorder remain understudied. This post hoc analysis evaluated data from Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study (January 2001-December 2004).
METHODS
Patients without substance abuse (except marijuana use) in the month before study entry were categorized into those with a history of alcohol use disorder (SZ + AUD) within 5 years before study entry and those without alcohol use disorder (SZ-only) per DSM-IV criteria. Time to first and recurrent exacerbations and hospitalizations were compared between disease states and between olanzapine and perphenazine, quetiapine, risperidone, and ziprasidone.
RESULTS
A total of 1,338 patients (SZ + AUD = 22.6%; SZ-only = 77.4%) were included. Time to first exacerbation of SZ was significantly shorter in the SZ + AUD versus SZ-only population (median = 5.4 vs 6.4 months; hazard ratio [HR] = 1.20 [95% CI, 1.01-1.42]; P = .039). Similar findings were observed for first hospitalization (HR = 1.63 [95% CI, 1.20-2.22]; P = .002) and recurrent hospitalizations (HR = 1.60 [95% CI, 1.18-2.15]; P = .002). The most common reasons leading to exacerbation in both groups were an increase in symptom severity and lack of efficacy. In patients with SZ + AUD related or unrelated to marijuana, perphenazine, quetiapine, risperidone, and ziprasidone were associated with significantly shorter time to first exacerbation versus olanzapine.
CONCLUSIONS
This post hoc analysis confirmed that patients with SZ + AUD had a worse illness course than patients with SZ-only and suggests that olanzapine may be associated with a longer time to first and recurrent exacerbations versus other antipsychotics in this difficult-to-treat population. Further research is needed to identify effective treatments for this important yet understudied patient population.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT00014001.
Topics: Adult; Alcoholism; Antipsychotic Agents; Comorbidity; Female; Hospitalization; Humans; Male; Olanzapine; Outcome Assessment, Health Care; Perphenazine; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Severity of Illness Index; Symptom Flare Up; Thiazoles; Time Factors
PubMed: 32220153
DOI: 10.4088/JCP.19m12731 -
The Annals of Pharmacotherapy Oct 2020Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could...
BACKGROUND
Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could perhaps cause osteoporosis by increasing serum prolactin levels. However, the association between antipsychotics and the risk for developing osteoporosis has been controversial.
OBJECTIVE
The present study aimed to assess the association between antipsychotic use and onset of osteoporosis in real-world settings.
METHODS
A multimethod data-mining approach using different algorithms and databases was used. First, disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2017) with reporting odds ratio (ROR) and information component (IC) being used to indicate a signal. Furthermore, a sequence symmetry analysis using data from a large Japanese administrative claims database (2005-2017; JMDC Inc, Japan) was conducted. Short-term intervals (ie, 12, 24, and 36 months) were set to investigate the association between antipsychotic use and onset of osteoporosis using the adjusted sequence ratio (SR) to indicate a signal.
RESULTS
No potential association between osteoporosis and all antipsychotics was observed in the FAERS database, except for perphenazine, which exhibited significant signals using both ROR and IC. Moreover, no potential association between osteoporosis and antipsychotics was observed in the JMDC claims database, except for sulpiride and aripiprazole. None of the antipsychotics indicated significant signals using all analyzed items (ROR, IC, and adjusted SR).
CONCLUSION AND RELEVANCE
Real-world data show no association between antipsychotic use and the onset of osteoporosis. Further pharmacoepidemiological studies are needed for causality assessment.
Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Antipsychotic Agents; Data Mining; Databases, Factual; Humans; Odds Ratio; Osteoporosis; Pharmacovigilance; Prolactin; United States; United States Food and Drug Administration
PubMed: 32186394
DOI: 10.1177/1060028020913974 -
Journal of Chromatography. A Jun 2020This work focused on the development and validation of a method based on hollow fiber-based solid-phase microextraction coupled to ultra-performance liquid...
Development of a method of hollow fiber-based solid-phase microextraction followed by ultra performance liquid chromatography-tandem mass spectrometry for determination of five antipsychotics in human whole blood and urine.
This work focused on the development and validation of a method based on hollow fiber-based solid-phase microextraction coupled to ultra-performance liquid chromatography tandem mass spectrometry (HF-based-SPME-UPLC-MS/MS) for the determination of five antipsychotics at a pg mL level in human whole blood and urine. Four types of hollow fiber membrane materials, including polyether sulfone, polypropylene, polyvinyl chloride and polyvinylidene fluoride were investigated. Finally, polyether sulfone hollow fiber without any modification was selected as the adsorption medium for solid-phase microextraction (SPME) with the following extraction procedure: the analytes were adsorbed onto the hollow fiber in the sample bottle with application of ultrasonication. Subsequently, the hollow fiber was transferred into a slim glass tube containing an appropriate solvent, and the analytes were desorbed by ultrasound treatment before detection by UPLC-MS/MS. In order to obtain satisfactory extraction efficiency, extraction parameters such as hollow fiber membrane material, pH, hollow fiber length, extraction time, desorption solvent and desorption time were investigated. Under the optimum experimental conditions, this method allowed for determination of five antipsychotics in human whole blood with excellent limits of quantification (LOQs) (25.0, 12.5, 25.0, 25.0 and 12.5 pg mL for perphenazine, chlorpromazine, chlorprothixene, promethazine and trifluoperazine, respectively). The corresponding LOQs in human urine were 25.0, 12.5, 12.5, 12.5 and 12.5 pg mL for the respective antipsychotics. The precision (RSD) was no more than 13.3%. The extraction recoveries for human whole blood and urine were in the range of 46.4-96.6% and 65.2-101.9%, respectively. The proposed method was compared with other methods from the literature and the results demonstrate that it is a simple, sensitive, efficient and green technique. It is suitable for analyzing trace target analytes in complex matrices such as biological samples and can provide a reliable tool for drug monitoring especially in forensic analysis and case of drug abuse.
Topics: Adsorption; Adult; Antipsychotic Agents; Chromatography, Liquid; Female; Humans; Liquid Phase Microextraction; Polymers; Reproducibility of Results; Solid Phase Microextraction; Solvents; Sulfones; Tandem Mass Spectrometry
PubMed: 32173026
DOI: 10.1016/j.chroma.2020.461000 -
Translational Psychiatry Mar 2020Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the...
Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR = 0.95, P < 3.47 × 10) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR = 0.84, P = 2.18 × 10) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR = 1.39, P = 0.03), rs480409 (OR = 0.73, P = 0.04), rs78137319 (OR = 3.09, P = 0.04), rs1154370 (OR = 1.51, P = 0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.
Topics: Antipsychotic Agents; Benzodiazepines; Genome-Wide Association Study; Humans; Quetiapine Fumarate; Receptors, Metabotropic Glutamate; Risk Factors; Risperidone; Schizophrenia
PubMed: 32127521
DOI: 10.1038/s41398-020-0763-4 -
Pharmacological Reports : PR Apr 2020High level of comorbidity between bipolar disorder or schizophrenia and cardiovascular diseases (CVD) in clinical practice may contribute to drug-drug interactions...
BACKGROUND
High level of comorbidity between bipolar disorder or schizophrenia and cardiovascular diseases (CVD) in clinical practice may contribute to drug-drug interactions between medications used in these conditions. The aim of this study was to evaluate harmful interactions between antipsychotics and medications used in treatment of CVD.
METHODS
The analysis of 52 cases of adverse reactions with a clinical picture indicates that they were the result of the combination of antipsychotic with cardiovascular medications.
RESULTS
The highest number of interactions with antipsychotics was recorded among beta-blockers (n = 13, 25% of all cases), including cardiac arrhythmias [atrial fibrillation (n = 1): risperidone plus atenolol; bradycardia (n = 1): perphenazine with metoprolol; ventricular arrhythmias: sertindole with metoprolol (n = 1) and ziprasidone with sotalol (n = 3)] and hypotension [chlorprotixene with nebivolol or metoprolol (n = 2)]. 12 cases concerned statins-myalgia, myopathy, or creatine kinase elevation appeared after combination of atorvastatin with haloperidol (n = 1), quetiapine (n = 3) or risperidone (n = 1), and simvastatin with quetiapine (n = 5) or risperidone (n = 2). There were also cases of interactions observed for the use of antipsychotics with anti-arrhythmic drugs (amiodarone, flecainide, propafenone) (n = 11), calcium channel blockers (n = 6), and other cardiac medications: clonidine, dabigatran, doxazosin, ivabradine, and losartan (n = 10).
CONCLUSIONS
Due to a high risk of interactions and related adverse effects, particular attention should be paid while using cardiovascular medications with antipsychotics. Clinical decisions should be preceded by a detailed analysis of safety, risk-benefit ratio to search for, as safe as possible, drug combinations.
Topics: Adrenergic beta-Antagonists; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Schizophrenia; Substrate Specificity
PubMed: 32124390
DOI: 10.1007/s43440-020-00058-6 -
World Psychiatry : Official Journal of... Feb 2020Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors...
Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial.
Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: -0.09±0.03, p=0.002) and SWITCH (week 24: -0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.
PubMed: 31922663
DOI: 10.1002/wps.20714 -
Drug Testing and Analysis Apr 2020Hair analysis is useful for documenting long-term exposure to drugs. The potential of hair analysis for therapeutic drug monitoring within the forensic field has been...
Hair analysis is useful for documenting long-term exposure to drugs. The potential of hair analysis for therapeutic drug monitoring within the forensic field has been studied, but reference values for some antidepressants and antipsychotics in the hair of individuals undergoing chronic therapy are still lacking. In the present study, a method was developed and validated for the determination of 23 analytes, including antidepressants, antipsychotics, and related metabolites, in human hair by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Hair samples (10 mg) were extracted with a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3) utilizing cryogenic grinding. The present method demonstrated sufficient selectivity, robustness, and accuracy. Sixteen analytes in hair were reported in 46 psychiatric patients receiving fixed drug dosages. To the best of our knowledge, the hair concentrations of perphenazine and norolanzapine, as well as the concentrations of amisulpride, aripiprazole and its metabolite dehydroaripiprazole, olanzapine, and sulpiride, in hair from individuals receiving fixed dosages is reported for the first time. A significant relationship between the administered dose and the concentration in the proximal hair segment was found only for clozapine, norclozapine, and chlorpromazine. The results confirmed that the idea of using hair concentrations to monitor a daily dose is inapplicable.
Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Chromatography, Liquid; Drug Monitoring; Hair; Humans; Limit of Detection; Male; Middle Aged; Schizophrenia; Tandem Mass Spectrometry
PubMed: 31875650
DOI: 10.1002/dta.2754 -
Journal of Computer-aided Molecular... Sep 2019Leishmaniasis is a neglected tropical disease caused by Leishmania parasites and is associated to more than 1.3 million cases annually. Some of the pharmacological...
Leishmaniasis is a neglected tropical disease caused by Leishmania parasites and is associated to more than 1.3 million cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonials, pentamidine, miltefosine, and amphotericin B. However, all are associated with a wide range of adverse effects and contraindications, as well as resistance from the parasite. In the present study, we looked for pharmacological alternatives to treat leishmaniasis, with a focus on drug repurposing. This was done by detecting potential homologs between proteins targeted by approved drugs and proteins of the parasite. The proteins were analyzed using an interaction network, and the drugs were subjected to in vitro evaluations and pharmacokinetics simulations to compare probable plasma concentrations with the effective concentrations detected experimentally. This strategy yielded a list of 33 drugs with potential anti-Leishmania activity, and more than 80 possible protein targets in the parasite. From the drugs tested, two reported high in vitro activity (perphenazine EC = 1.2 µg/mL and rifabutin EC = 8.5 µg/mL). These results allowed us to propose these drugs as candidates for further in vivo studies and evaluations of the effectiveness on their topical forms.
Topics: Antiprotozoal Agents; Computational Biology; Drug Repositioning; Humans; Leishmania; Leishmaniasis; Protozoan Proteins
PubMed: 31612362
DOI: 10.1007/s10822-019-00230-y -
Bioorganic & Medicinal Chemistry Letters Sep 2019Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of...
Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.
Topics: Animals; Antineoplastic Agents; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Mice; Molecular Structure; Oxazines; Phenothiazines; Protein Phosphatase 2; Sphingolipids; Structure-Activity Relationship
PubMed: 31383588
DOI: 10.1016/j.bmcl.2019.07.023