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Schizophrenia Research Dec 2014Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release,...
Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.
Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers, Pharmacological; Dibenzothiazepines; Female; Genotyping Techniques; Glucagon-Like Peptide-1 Receptor; Haplotypes; Humans; Male; Models, Genetic; Olanzapine; Perphenazine; Piperazines; Polymorphism, Single Nucleotide; Quetiapine Fumarate; Receptors, Glucagon; Regression Analysis; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Weight Gain; White People
PubMed: 25449714
DOI: 10.1016/j.schres.2014.09.038 -
Role of D₁/D₂ dopamin receptors antagonist perphenazine in morphine analgesia and tolerance in rats.Bosnian Journal of Basic Medical... May 2013While opioid receptors have been implicated in the development of tolerance, the subsequent mechanisms involved in these phenomena have not been completely understood....
While opioid receptors have been implicated in the development of tolerance, the subsequent mechanisms involved in these phenomena have not been completely understood. The purpose of this study was to investigate effects of D1/D2 dopamine receptors antagonist perphenazine on morphine analgesia and tolerance in rats. Male Wistar albino rats weighing 190-205 g were used in these experiments. To constitute of morphine tolerance, animals received morphine (50 mg/kg) once daily for 3 days. After last dose of morphine was injected on day 4, morphine tolerance was evaluated by the analgesia tests. The analgesic effects of perphenazine (1, 5, and 10 mg/kg ), D1-dopamine receptor antagonist SCH 23390 (1 mg/kg), D2-dopamine receptor antagonist eticlopride (1 mg/kg), and morphine were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Obtained data suggested that D1/D2 dopamine receptors antagonist perphenazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting D2-dopamine receptor. Because the data indicated that D2-dopamine receptor antagonist eticloride, but not D1-dopamine receptor antagonist SCH 23390, significantly decreased morphine tolerance in analgesia tests. In addition, administration of perphenazine with morphine increased morphine analgesia. Results from the present study suggested that dopamine receptors play a significant role in the morphine analgesic tolerance. In particular, D2-dopamine receptor has an important role rather than D1-dopamine receptor in development tolerance to morphine.
Topics: Analgesia; Animals; Benzazepines; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Tolerance; Male; Morphine; Pain; Perphenazine; Rats; Rats, Wistar; Receptors, Dopamine D1; Salicylamides; Time Factors
PubMed: 23725509
DOI: 10.17305/bjbms.2013.2394 -
International Journal of Molecular... Feb 2021Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as...
Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.
Topics: Animals; Anions; Barbiturates; Cations; Central Nervous System; Chickens; Electricity; Isoelectric Point; Liposomes; Membranes, Artificial; Models, Biological; Perphenazine; Phosphatidylcholines; Scattering, Radiation; Solutions; Static Electricity
PubMed: 33668791
DOI: 10.3390/ijms22052270 -
Molecular Psychiatry Jan 2011Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel... (Comparative Study)
Comparative Study Randomized Controlled Trial
Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.
Topics: Antipsychotic Agents; Benzodiazepines; Chromosomes, Human, Pair 4; Dibenzothiazepines; Double-Blind Method; Follow-Up Studies; Genome-Wide Association Study; Humans; Olanzapine; Perphenazine; Pharmacogenetics; Piperazines; Polymorphism, Single Nucleotide; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome
PubMed: 19721433
DOI: 10.1038/mp.2009.89 -
The Mental Health Clinician Jul 2019In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United...
INTRODUCTION
In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States.
METHODS
The Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine-4 antipsychotics commonly used in the United States with a "strong recommendation" for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges.
RESULTS
Olanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges.
DISCUSSION
Several limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.
PubMed: 31293849
DOI: 10.9740/mhc.2019.07.287 -
Biological Psychiatry Mar 2013Tauopathies, including Alzheimer's disease and frontotemporal dementia, are diseases characterized by the formation of pathological tau protein aggregates in the brain...
BACKGROUND
Tauopathies, including Alzheimer's disease and frontotemporal dementia, are diseases characterized by the formation of pathological tau protein aggregates in the brain and progressive neurodegeneration. Presently no effective disease-modifying treatments exist for tauopathies.
METHODS
To identify drugs targeting tau neurotoxicity, we have used a Caenorhabditis elegans model of tauopathy to screen a drug library containing 1120 compounds approved for human use for the ability to suppress tau-induced behavioral effects.
RESULTS
One compound, the typical antipsychotic azaperone, improved the motility of tau transgenic worms, reduced levels of insoluble tau, and was protective against neurodegeneration. We found that azaperone reduces insoluble tau in a human cell culture model of tau aggregation and that other antipsychotic drugs (flupenthixol, perphenazine, and zotepine) also ameliorate the effects of tau expression in both models.
CONCLUSIONS
Reduction of dopamine signaling through the dopamine D2 receptor with the use of gene knockouts in Caenorhabditis elegans or RNA interference knockdown in human cell culture has similar protective effects against tau toxicity. These results suggest dopamine D2 receptor antagonism holds promise as a potential neuroprotective strategy for targeting tau aggregation and neurotoxicity.
Topics: Animals; Animals, Genetically Modified; Behavior, Animal; Caenorhabditis elegans; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Nerve Degeneration; Neurotoxicity Syndromes; Tauopathies; tau Proteins
PubMed: 23140663
DOI: 10.1016/j.biopsych.2012.08.027 -
The Journal of Clinical Investigation Feb 2014T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we...
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.
Topics: Animals; Animals, Genetically Modified; Apoptosis; Cell Line, Tumor; Cell Survival; Chromatography, Affinity; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mass Spectrometry; Mice; Perphenazine; Phenothiazines; Phosphorylation; Pigmentation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Phosphatase 2; Proteomics; Receptors, Notch; Time Factors; Zebrafish
PubMed: 24401270
DOI: 10.1172/JCI65093 -
Clinical Psychopharmacology and... Dec 2011To investigate the patterns of antipsychotic use in China and to analyze the factors that influence antipsychotic prescriptions.
OBJECTIVE
To investigate the patterns of antipsychotic use in China and to analyze the factors that influence antipsychotic prescriptions.
METHODS
A standardized survey was conducted from May 20 to 24 2002 in five different regions of China with varying economic levels. The patterns of antipsychotic medication use were analyzed in a sample of 4,779 patients with schizophrenia. The survey gathered information on demographic characteristics, clinical profiles, and antipsychotic medications prescribed. Multiple logistic regression was used to analyze factors related to patterns of antipsychotic medication use.
RESULTS
A plurality of patients with schizophrenia was treated with clozapine (39%); this was followed by risperidone, sulpride, chlorpromazine, perphenazine, and haloperidol. More than 56.3% of patients were treated with only one atypical antipsychotic. The mean daily dose of chlorpromazine was 365±253 mg (mean±standard deviation), and 6.5% of patients were treated with depot injections of typical antipsychotic medications. A total of 73.7% (n=3,523) of patients with schizophrenia received monotherapy, 24.8% (n=1,183) received two antipsychotics, 1.1% (n=52) received three antipsychotics, and one received four different antipsychotics. Patients often simultaneously received other classes of medications including anticholinergic agents, benzodiazepines, β-blockers, antidepressants, and mood stabilizers. Economic status and clinical symptoms were the main factors that contributed to the patterns of antipsychotic prescription.
CONCLUSION
The present study suggests that atypical antipsychotic medications, especially clozapine, are the primary psychiatric treatments of choice in the management of schizophrenia in China. Moreover, the economic status and clinical profile of the patient are the major factors affecting the prescription of antipsychotic medication.
PubMed: 23429971
DOI: 10.9758/cpn.2011.9.3.122 -
The Journal of Clinical Psychiatry Jan 2011According to the American Psychiatric Association Clinical Practice Guidelines for schizophrenia, second-generation antipsychotics may be specifically indicated for the... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
According to the American Psychiatric Association Clinical Practice Guidelines for schizophrenia, second-generation antipsychotics may be specifically indicated for the treatment of depression in schizophrenia. We examined the impact of these medications on symptoms of depression using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), conducted between January 2001 and December 2004.
METHOD
Patients with DSM-IV-defined schizophrenia (N = 1,460) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of 4 second-generation drugs (olanzapine, quetiapine, risperidone, or ziprasidone) and followed for up to 18 months (phase 1). Patients with tardive dyskinesia were excluded from the randomization that included perphenazine. Depression was assessed with the Calgary Depression Scale for Schizophrenia (CDSS). Mixed models were used to evaluate group differences during treatment with the initially assigned drug. An interaction analysis evaluated differences in drug response by whether patients had a baseline score on the CDSS of ≥ 6, indicative of a current major depressive episode (MDE).
RESULTS
There were no significant differences between treatment groups on phase 1 analysis, although there was a significant improvement in depression across all treatments. A significant interaction was found between treatment and experiencing an MDE at baseline (P = .05), and further paired comparisons suggested that quetiapine was superior to risperidone among patients who were in an MDE at baseline (P = .0056).
CONCLUSIONS
We found no differences between any second-generation antipsychotic and the first-generation antipsychotic perphenazine and no support for the clinical practice recommendation, but we did detect a signal indicating a small potential difference favoring quetiapine over risperidone only in patients with an MDE at baseline.
Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Chronic Disease; Comorbidity; Depression; Depressive Disorder, Major; Double-Blind Method; Drug Costs; Drug Therapy, Combination; Female; Humans; Longitudinal Studies; Male; Middle Aged; Perphenazine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome
PubMed: 20868641
DOI: 10.4088/JCP.09m05258gre -
Translational Psychiatry Feb 2022QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac... (Randomized Controlled Trial)
Randomized Controlled Trial
QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P < 0.001, area under the curve [AUC] was 0.797), especially for the first episode patients (P < 0.001, AUC was 0.872). We identified two loci located within genes related to mitochondrial function and cell growth and differentiation, which were both associated with schizophrenia and heart function. The combination of PRS and clinical data could predict whether patients with schizophrenia have the side effect of QTc interval prolongation, which could fundamentally guide the choice of antipsychotic in patients with schizophrenia, especially for the first-episode patients.
Topics: ATPases Associated with Diverse Cellular Activities; Antipsychotic Agents; Electrocardiography; Genome-Wide Association Study; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mitochondrial Proteins; Proto-Oncogene Proteins; Risperidone; Schizophrenia
PubMed: 35136033
DOI: 10.1038/s41398-022-01825-0