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The Psychiatric Quarterly Mar 2015The overall impact of first and second generation antipsychotics on quality of life and symptoms of people with schizophrenia remains controversial. We applied health... (Comparative Study)
Comparative Study Randomized Controlled Trial
The overall impact of first and second generation antipsychotics on quality of life and symptoms of people with schizophrenia remains controversial. We applied health state modeling to data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia study, a randomized trial of antipsychotic medications, and evaluated the likelihood of patients moving to more favorable health states over time. We applied K-means clustering to the data to create discrete groupings of patients with symptom and side effect characteristics that were then validated using quality of life measures. We compared cluster distributions across medications at baseline and 6 months after randomization. 1,049 patients were included in the initial cluster analysis. Five health states were identified: (1) low symptoms and low side effects (LS + LSE) (2) low symptoms and obesity (LS + Ob) (3) high symptoms and low side effects (HS + LSE) (4) high symptoms with depression and akathisia (HS + Dp + Ak) and (5) moderate symptoms and high side effects (MS + HSE). Six-month outcomes among patients randomly assigned to perphenazine, olanzapine, risperidone and quetiapine were compared. At baseline, almost 20% of patients were in the worst health state (HS + Dp + Ak), with greater decreases at 6 months in this health state for perphenazine (9.2% decrease) and olanzapine (11.1%) groups compared to risperidone (4.7%) and quetiapine (6.7%). This study demonstrated that health state analysis can provide insight into the overall clinical state of patients beyond the mere comparison of average scores and largely confirmed original CATIE findings.
Topics: Adult; Antipsychotic Agents; Cluster Analysis; Female; Follow-Up Studies; Health Status; Humans; Male; Models, Theoretical; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Time Factors; United States
PubMed: 25294277
DOI: 10.1007/s11126-014-9326-2 -
Schizophrenia Research Feb 2018Despite advances in sequencing candidate genes and whole genomes, no method has accurately predicted who will or will not benefit from a specific antipsychotic... (Randomized Controlled Trial)
Randomized Controlled Trial
Despite advances in sequencing candidate genes and whole genomes, no method has accurately predicted who will or will not benefit from a specific antipsychotic medication among patients with schizophrenia. We propose a computational algorithm that utilizes a person-centered approach that directly identifies individual patients who will respond to a specific antipsychotic medication. The algorithm was applied to the data obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The predictors were either (1) 13 single-nucleotide polymorphisms (SNPs) and 53 baseline variables or (2) 25 SNPs and the same 53 baseline variables, depending on the existing findings and data availability. The outcome variables were either (1) improvement in the Positive and Negative Syndrome Scale (PANSS) (Yes/No) or (2) completion of phase 1/1A (Yes/No). Each of those four predictor-outcome combinations was tried for each of the five antipsychotic medications (Perphenazine, Olanzapine, Quetiapine, Risperidone, and Ziprasidone), leading to 20 prediction experiments. For 18 out of 20 experiments, all three performance measures were greater than 0.50 (sensitivity 0.51-0.79, specificity 0.52-0.79, accuracy 0.52-0.74). Notably, the model provided a promising prediction for Ziprasidone for the case involving completion of phase 1/1A (Yes/No) predicted by 13 SNPs and 53 baseline variables (sensitivity 0.75, specificity 0.74, accuracy 0.74). The proposed algorithm simultaneously used both genetic information and clinical profiles to predict individual patients' response to antipsychotic medications. As the method is not disease-specific but a general algorithm, it can be easily adopted in many other clinical practices for personalized medicine.
Topics: Algorithms; Antipsychotic Agents; Drug Therapy, Computer-Assisted; Humans; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precision Medicine; Schizophrenia; Sensitivity and Specificity
PubMed: 28495491
DOI: 10.1016/j.schres.2017.05.001 -
JAMA Internal Medicine Oct 2022An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on...
IMPORTANCE
An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes.
OBJECTIVE
To examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren.
DESIGN, SETTING, AND PARTICIPANTS
This register-based cohort study included 667 517 children born in Denmark from January 1, 1997, to December 31, 2009, and who were attending public primary and lower secondary school. All children had completed at least 1 language (Danish) or mathematics test as part of the Danish National School Test Program between 2010 and 2018. Data were analyzed from November 1, 2021, to March 31, 2022.
EXPOSURES
Antipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register.
MAIN OUTCOMES AND MEASURES
Differences in standardized test scores (range, 1-100; higher scores indicate better test results) in language and mathematics between children of mothers with and without antipsychotic prescription fills during pregnancy were estimated using linear regression models. Seven sensitivity analyses, including a sibling-controlled analysis, were performed.
RESULTS
Of the 667 517 children included (51.2% males), 1442 (0.2%) children were born to mothers filling an antipsychotic prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antipsychotics was not associated with performance in language (crude mean test score: 50.0 [95% CI, 49.1-50.9] for the exposed children vs 55.4 [95% CI, 55.4-55.5] for the unexposed children; adjusted difference, 0.5 [95% CI, -0.8 to 1.7]) or in mathematics (crude mean test score: 48.1 [95% CI, 47.0-49.3] for the exposed children vs 56.1 [95% CI, 56.1-56.2] for the unexposed children; adjusted difference, 0.4 [95% CI, -1.0 to 1.8]). There was no evidence that results were modified by the timing of filling prescriptions, classes (first-generation and second-generation) of antipsychotics, or the most commonly prescribed antipsychotic monotherapies, including chlorprotixene, flupentixol, olanzapine, zuclopenthixol, quetiapine, perphenazine, and methotrimeprazine. The results remained robust across sensitivity analyses, including sibling-controlled analyses, negative control exposures analyses, and probabilistic bias analyses.
CONCLUSIONS AND RELEVANCE
In this register-based cohort study, maternal prescription fill for antipsychotics during pregnancy did not appear to be associated with standardized test scores in the offspring. The findings provide further reassuring data on offspring neurodevelopmental outcomes associated with antipsychotic treatment during pregnancy.
Topics: Antipsychotic Agents; Child; Clopenthixol; Cohort Studies; Denmark; Female; Flupenthixol; Humans; Male; Methotrimeprazine; Olanzapine; Perphenazine; Pregnancy; Prescriptions; Quetiapine Fumarate
PubMed: 35969410
DOI: 10.1001/jamainternmed.2022.3388 -
The Journal of Veterinary Medical... Sep 2016Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a...
Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. Perphenazine (PPZ) is one of the phenothiazines and widely used as an antipsychotic drug. Recently, it is reported that PPZ directly binds with scaffolding subunit of PP2A complex and exerts anti-tumor effects on human T cell acute lymphoblastic leukemia. However, the effect of PPZ on canine lymphoma has not been studied. Here, we investigated the potential therapeutic role of PPZ and its molecular mechanism in canine T-cell lymphoma. In canine T-cell lymphoma cell lines, UL-1 and Ema, PPZ decreased cell survival in a dose-dependent manner. Increased caspase 3 activity and Annexin V positive cells suggested that PPZ induced apoptosis. PPZ dephosphorylated Akt, MEK1/2 and ERK1/2. Akt inhibitor, but not MEK1/2 inhibitor and ERK1/2 inhibitor, induced cell death, indicating the importance of Akt dephosphorylation for the anti-tumor effect of PPZ. Finally, we observed enhanced PP2A activity by PPZ treatment. The present results for the first time revealed that PPZ induced canine lymphoma cells apoptosis through Akt dephosphorylation via PP2A activation. Our study suggests the possible therapeutic application of phenothiazines for canine T-cell lymphoma.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Flow Cytometry; Immunoblotting; Lymphoma; Lymphoma, T-Cell; MAP Kinase Signaling System; Oncogene Protein v-akt; Perphenazine; Phosphorylation; Protein Phosphatase 2
PubMed: 27150024
DOI: 10.1292/jvms.15-0707 -
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 -
Journal of Controlled Release :... Feb 2021Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of...
Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection.
Topics: Bile; Colloids; Polymers; Solubility; Water
PubMed: 33333120
DOI: 10.1016/j.jconrel.2020.12.016 -
Postgraduate Medicine 2015Tardive dyskinesia (TD) is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking... (Review)
Review
Tardive dyskinesia (TD) is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking dopamine receptor-blocking agents. The pathophysiology of TD is complex, multifactorial and still not fully understood. Although there is no identified effective and standard treatment for TD, several agents have been tried for the management of this motor disturbance. The aim of this case series is to review the literature in regard to the identification, diagnosis and the treatment of TD with anticholinergics, anticholinergic medication withdrawal, cholinergic agents, botulinum toxin intramuscular injections, tetrabenazine, levetiracetam, propranolol and zolpidem, and to describe one case of TD that responded favorably to clonazepam and two cases of TD that responded favorably to Ginkgo biloba.
Topics: Adult; Aged; Anti-Dyskinesia Agents; Clonazepam; Diagnosis, Differential; Dopamine Antagonists; Dyskinesia, Drug-Induced; Female; Ginkgo biloba; Heartburn; Humans; Middle Aged; Movement Disorders; Perphenazine; Plant Extracts; Positron-Emission Tomography; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon; Treatment Outcome
PubMed: 26216578
DOI: 10.1080/00325481.2015.1074031 -
International Clinical... Jan 2018Arrhythmias are a frequent and potentially fatal side effect of antipsychotic treatment. Strict ECG monitoring and clinical interviews are the standards used to prevent... (Randomized Controlled Trial)
Randomized Controlled Trial
Arrhythmias are a frequent and potentially fatal side effect of antipsychotic treatment. Strict ECG monitoring and clinical interviews are the standards used to prevent arrhythmias. A biologic predictive tool is missing. The identification of a genetic makeup at risk of antipsychotic-induced arrhythmias is the aim of the present investigation. The aim of this study was to identify a molecular pathway enriched in single nucleotide polymorphisms associated with antipsychotic-induced QTc modifications. In total, 661 schizophrenic individuals from the CATIE study, M=486 (73.52%), mean age=40.92±11.02, were included. QTc variation was measured as a phase-specific change-created variable. A nested mixed regression for a repeated-measures model served in R for the analysis of the clinical and treatment-related covariates and molecular pathway analysis. Plink was used for the genetic genome-wide analysis. Quality checking was the standard (genotype call rate>0.95; minor allele frequency>0.01; Hardy-Weinberg equilibrium<0.0001) and the inflation factor was controlled by λ values. Quetiapine and perphenazine were associated with QTc variation during phase 1. No other significant association was detected. No significant inflation was detected. A number of molecular pathways were associated with QT variation at a conservative (adjusted) P value less than 0.05, including pathways related to neuronal wiring and collagen biosynthesis, along with pathways related to K+ currents and cardiac contraction. Pathways related to neuronal wiring, collagen biosynthesis, and ion currents were identified as possibly involved in QTc modifications during antispsychotic treatment in SKZ patients.
Topics: Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Risk Factors; Treatment Outcome
PubMed: 29064910
DOI: 10.1097/YIC.0000000000000198 -
Scientific Reports Oct 2022Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include...
Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.
Topics: Animals; Benactyzine; Antidotes; Prodrugs; Organophosphates; Acetylcholinesterase; Chemical Warfare Agents; Cholinergic Antagonists; Esters; gamma-Aminobutyric Acid; Organophosphate Poisoning; Cholinesterase Inhibitors
PubMed: 36302937
DOI: 10.1038/s41598-022-23141-9 -
Frontiers in Psychiatry 2023Depression is widespread global problem that not only severely impacts individuals' physical and mental health but also imposes a heavy disease burden on nations and...
BACKGROUND
Depression is widespread global problem that not only severely impacts individuals' physical and mental health but also imposes a heavy disease burden on nations and societies. The role of inflammation in the pathogenesis and pathophysiology of depression has received much attention, but the precise relationship between the two remains unclear. This study aims to investigate the correlation between depression and inflammation using a network medicine approach.
METHODS
We utilized a degree-preserving approach to identify the large connected component (LCC) of all depression-related proteins in the human interactome. The LCC was deemed as the disease module for depression. To measure the association between depression and other diseases, we calculated the overlap between these disease protein modules using the Sab algorithm. A smaller Sab value indicates a stronger association between diseases. Building on the results of this analysis, we further explored the correlation between inflammation and depression by conducting enrichment and pathway analyses of critical targets. Finally, we used a network proximity approach to calculate drug-disease proximity to predict the efficacy of drugs for the treatment of depression. We calculated and ranked the distances between depression disease modules and 6,100 drugs. The top-ranked drugs were selected to explore their potential for treating depression based on the hypothesis that their antidepressant effects are related to reducing inflammation.
RESULTS
In the human interactome, all depression-related proteins are clustered into a large connected component (LCC) consisting of 202 proteins and multiple small subgraphs. This indicates that depression-related proteins tend to form clusters within the same network. We used the 202 LCC proteins as the key disease module for depression. Next, we investigated the potential relationships between depression and 299 other diseases. Our analysis identified over 18 diseases that exhibited significant overlap with the depression module. Where S = -0.075 for the vascular disease and depressive disorders module, S = -0.070 for the gastrointestinal disease and depressive disorders module, and S = -0.062 for the endocrine system disease and depressive disorders module. The distance between them S < 0 implies that the pathogenesis of depression is likely to be related to the pathogenesis of its co-morbidities of depression and that potential therapeutic approaches may be derived from the disease treatment libraries of these co-morbidities. Further, considering that the inflammation is ubiquitous in some disease, we calculate the overlap between the collected inflammation module (236 proteins) and the depression module (202 proteins), finding that they are closely related (S = -0.358) in the human protein interaction network. After enrichment and pathway analysis of key genes, we identified the HIF-1 signaling pathway, PI3K-Akt signaling pathway, Th17 cell differentiation, hepatitis B, and inflammatory bowel disease as key to the inflammatory response in depression. Finally, we calculated the -score to determine the proximity of 6,100 drugs to the depression disease module. Among the top three drugs identified by drug-disease proximity analysis were Perphenazine, Clomipramine, and Amitriptyline, all of which had a greater number of targets in the network associated with the depression disease module. Notably, these drugs have been shown to exert both anti-inflammatory and antidepressant effects, suggesting that they may modulate depression through an anti-inflammatory mechanism. These findings demonstrate a correlation between depression and inflammation at the network medicine level, which has important implications for future elucidation of the etiology of depression and improved treatment outcomes.
CONCLUSION
Neuroimmune signaling pathways play an important role in the pathogenesis of depression, and many classes of antidepressants exhibiting anti-inflammatory properties. The pathogenesis of depression is closely related to inflammation.
PubMed: 37492068
DOI: 10.3389/fpsyt.2023.1184188