Antischizophrenic Drugs Research Articles

Fluspirilene exerts an anti-glioblastoma effect through suppression of the FOXM1-KIF20A axis.

Given the infiltrative nature of human glioblastoma (GBM), cocktail drug therapy will remain a vital tool for the treatment of the disease. We investigated fluspirilene, perphenazine, and sulpiride, three classic anti-schizophrenic drugs, as possible anti-GBM agents. The CCK-8 assay demonstrated that fluspirilene possesses the most outstanding anti-GBM effect. We performed molecular mechanisms studies in vitro and an orthotopic xenograft model in mice. Fluspirilene inhibited proliferation and migration in vitro in U87MG and U251 GBM cell lines. Flow cytometry demonstrated that treatment increased apoptosis and cells accumulated in the G2/M phase. Our analysis of publicly available expression data for several cell lines treated with the drug led to the identification of several genes, including KIF20A, that are downregulated by fluspirilene and lead to growth inhibition/apoptosis. We also demonstrated that siRNA knockdown of KIF20A, a member of the kinesin family, attenuated cell proliferation in GBM cells and an orthotopic xenograft model in mice. A regulator of KIF20A, the oncogenic transcription factor FOXM1, was identified using the String database, which harbors protein interaction networks. In fluspirilene-treated cells, FOXM1 protein was decreased, indicating that KIF20A was downregulated in the presence of the drug due to decreased FOXM1 protein. These results demonstrate that fluspirilene is an effective anti-GBM agent that works by suppressing the FOXM1-KIF20A oncogenic axis.

Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux

Targeted therapies and immunotherapy have brought substantial benefits to patients with melanoma. However, brain metastases remain the biggest threat to the survival and quality of life of melanoma patients. One of the major challenges to an effective therapy is the inability of drugs to penetrate the blood-brain barrier (BBB). Anti-schizophrenic drugs can cross the BBB, and many of them have demonstrated anti-cancer effects. Repurposing existing drugs for new clinical indications is an alluring strategy for anticancer drug discovery. Herein, we applied this strategy and screened a small collection of existing anti-schizophrenic drugs to use as anti-melanoma agents. Among them, trifluoperazine dihydrochloride (TFP) exhibited promising potencies for suppressing the growth and metastasis of melanoma, both in vitro and in vivo. TFP obviously suppressed the viability of melanoma cells within the micromolar range and inhibited the growth of melanoma in the subcutaneous mice models. Notably, intraperitoneal (i.p.) administration of TFP (40 mg/kg/day) obviously inhibited the growth of intra-carotid-injection established melanoma brain metastasis and extended the survival of brain metastasis-bearing mice. Moreover, TFP significantly suppressed lung metastasis and bone metastasis of melanoma in preclinical metastasis models. Mechanistically, TFP caused G0/G1 cell cycle arrest and mitochondrial-dependent intrinsic apoptosis of melanoma cells. In addition, TFP treatment increased the expression of microtubule associated protein 1 light chain 3 beta-II (LC3B-II) and p62 in vitro, suggesting an inhibition of autophagic flux. TFP decreased LysoTracker Red uptake after treatment, indicating impaired acidification of lysosomes. Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.

A Comparative Study on Relative Safety and Efficacy of Chlorpromazine and Risperidone in Schizophrenia patients

Patient safety is the foremost concern in the healthcare system. However, only a few studies have been conducted regarding the safety and efficacy of antischizophrenic drugs in the south Indian population. The main objective is to study relative safety profile and efficacy between Chlorpromazine and Risperidone among Schizophrenia patients teaching hospital. Prospective, observational, comparative study conducted for six months among Schizophrenia patients. The data was collected from 62 enrolled subjects with the help of questionnaires and scales, and data was analyzed by using a t-test and other relevant descriptive analysis by using the statistical software SPSS version 20.0. Out of a total of 70 patients, males were 39, andfemales were 31. Out of 70 patients, only 62 patients completed the study according to the inclusion criteria. The occurrence of schizophrenia was higher in the age of late adolescence and early adulthood. Risperidone was more effective in treating negative and general symptoms compare to chlorpromazine, but equally efficacious in treating positive symptoms. Poor medication adherence was found in patients receiving both drugs. Chlorpromazine is more effective in a patient with predominantly positive symptoms. Risperidone is more effective and should be preferred in patients with positive, negative, and general symptoms.

Ultra-high performance liquid chromatography tandem mass spectrometry method for detection of anti-schizophrenic drugs and the evaluation of their therapeutic reference ranges

Objective A highly feasible and reliable ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)method was presented for therapeutic drug monitoring of five anti-schizophrenic drugs (aripiprazole, amisulpride, olanzapine, paliperidone and ziprasidone) simultaneously and the reference range of plasma concentration was investigated. Methods establishment and evaluation. The selectivity, accuracy, precision, stability and linear range of established UPLC-MS/MS method were evaluated according to FDA and CLSI. After a ten-month clinical application, a retrospective analysis of 253 positive samples was carried out to investigate conformance of the AGNP therapeutic reference range for Chinese patients. Results The five anti-schizophrenic drugs could be simultaneously measured by the established UPLC-MS/MS within 6 minutes. The LOQs were 0.1 to 9.0 ng/ml. The correlation coefficients were all higher than 0.997 7. The intra-day and inter-day precisions were less than 11.1%, and the recoveries ranged from 86.2% to 104.8%. The clinical results suggested the good consistency in reference range with AGNP for olanzapine, aripiprazole, paliperidone and ziprasidone. While for amisulpride, the plasma concentration level (445.2±231.5) ng/ml was significantly higher than the AGNP-recommended range (100-320) ng/ml. Conclusion The established UPLC-MS/MS method was very suitable for monitoring anti-schizophrenic drugs.(Chin J Lab Med, 2017, 40: 787-792) Key words: Antipsychotic agents; Plasmaconcentration; Drug monitoring; Chromatography, high pressure liquid; Tandem mass spectrometry; Reference values

Development of a UPLC-MS/MS method for routine therapeutic drug monitoring of aripiprazole, amisulpride, olanzapine, paliperidone and ziprasidone with a discussion of their therapeutic reference ranges for Chinese patients.

A highly feasible and reliable ultra-high performance liquid chromatography tandem mass spectrometry method was presented for therapeutic drug monitoring of five anti-schizophrenic drugs (amisulpride, olanzapine, aripiprazole, paliperidone and ziprasidone) simultaneously. To meet the requirements of practical clinical usage (easy handling, high throughput and cost effectiveness), the pretreatment process was simplified (only including protein precipitation and mobile phase dilution steps) and the UPLC separation cycle was set within 6 min. The whole methodology was carefully validated according to the latest international guidelines showing the excellent selectivity, accuracy, precision, applicability and stability. After a 10 month clinical application, a retrospective analysis of 253 positive samples was carried out to investigate conformance with the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie therapeutic reference range for Chinese patients. The results suggested good consistency for olanzapine, aripiprazole, paliperidone and ziprasidone, while for amisulpride, the plasma concentration level (445.2 ± 231.5 ng/mL) was relatively higher than the recommended range (100-320 ng/mL). We supposed that such phenomenon indicated the necessity of reconstructing a Chinese-specific therapeutic reference range for amisulpride treatment, which would be helpful to improve medication efficiency and safety for Chinese patients.

Experimental treatment of antipsychotic-induced movement disorders.

Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects. Antipsychotic-drug-induced tardive dyskinesia prompted researchers to explore novel drugs with fewer undesirable extrapyramidal side effects. Preclinical studies suggest a role of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission and motivating a search for better therapeutic strategies for schizophrenia and related disorders. In addition, adjunctive treatment with antioxidants such as vitamin E, red rice bran oil, and curcumin in the early phases of illness may prevent additional oxidative injury, and thus improve and prevent further possible worsening of related neurological and behavioral deficits in schizophrenia. This review explains the role of serotonergic receptors and oxidative stress, with the aim of providing principles for prospect development of compounds to improve therapeutic effects of antischizophrenic drugs.

Light and electron microscopic study on the effect of antischizophrenic drugs on the structure of seminiferous tubules of adult male albino rats.

Sexual dysfunction and infertility are symptoms which have been rarely studied in patients treated with antischizophrenic drugs, aripiprazole and olanzapine, for long period. This work aimed to investigate the effects of aripiprazole and olanzapine on the structure of seminiferous tubules of rats at both light microscopic and ultrastructural levels. Sixty adult male rats were divided into 3 groups (n = 20): control group (Group I) and two experimental ones (II and III). Rats in Group II received 2 mg/kg/day aripiprazole while rats in Group III received 0.5 mg/kg/day olanzapine for 14 weeks. Thereafter, testis were removed and processed for both light and electron microscopic study. Qualitative morphological analyses and histomorphometric measurements of seminiferous tubules were performed. Rats in Group II showed reduction of testicular weight, seminiferous tubules' diameter, epithelial height, spermatogenic count, spermatogenic index and spermatogenic score whereas Sertoli cells count was increased. Olanzapine-treated rats also showed epithelial desquamation, separation and apoptotic changes of germ cells. Sertoli cells showed vacuolization, dilatation of smooth endoplasmic reticulum and accumulation of lipid droplets. Abnormality in the shape and structure of late spermatids and presence of giant cells were also demonstrated. Aripiprazole induced less adverse histological changes in rat testis than olanzapine. Olanzapine followed by aripiprazole had adverse histological effects on the structure of the seminiferous tubules, which may affect spermatogenesis.

Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs.

The complex mechanism of glutamate dehydrogenase in insulin secretion.

Leucine is the only physiologic amino acid that can stimulate insulin release by itself, and a great deal of evidence suggests that leucine does this by allosterically activating glutamate dehydrogenase (GDH). GDH catalyzes the oxidative deamination of endogenous glutamate, which is present at a high concentration in the pancreatic β-cell. Studies that support this role of leucine include the fact that leucine and 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), a nonmetabolizable leucine analog, are activators of GDH and promote insulin release from pancreatic islets (1–4). Although the addition to pancreatic islets of glutamine alone—which by its conversion to glutamate enormously increases the intracellular concentration of glutamate—does not stimulate insulin release, adding glutamine in the presence of leucine or BCH causes a robust stimulation of insulin release. Patients with mutations in the region of the GDH gene that encodes the part of the GDH protein where the allosteric inhibitor guanosine triphosphate (GTP) binds to the enzyme suffer from hyperinsulinism and hypoglycemia (5), and this indicates that GDH is involved in insulin secretion in humans. In addition, recent studies showed that short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency causes hyperinsulinism secondary to a loss of inhibition of GDH by SCHAD (6). Antischizophrenic drugs can produce hyperglycemia in patients (7,8) perhaps due to their ability to inhibit GDH. Both insulin release and GDH activity are decreased by SIRT4 (9), a mitochondrial ADP-ribosyl transferase, and deletion of GDH in β-cells partially abolishes the insulin secretory response (10). GDH catalyzes the reaction NAD(P) + Glutamate ⇆ NAD(P)H + α-ketoglutarate + NH4+ (Fig. 1). The catalytically active form of the enzyme is six identical 5.7 × 104 molecular weight monomers configured as a hexamer (11–13). When the concentration of the hexamer is high, it polymerizes (12,13). In addition to …

Comparative potencies of calcium channel antagonists and antischizophrenic drugs on central and peripheral calcium channel binding sites

Dihydropyridines are potent agents on [3H]nitrendipine binding sites in heart and brain membranes. Like the phenylalkylamines, they are slightly more active on heart than on brain [3H]nitrendipine binding sites. On the other hand, the diphenylalkylamines, the diphenylpiperazines and the antischizophrenic drugs of the diphenylbutylpiperdine type are more potent on brain [3H]nitrendipine binding sites. The findings suggest tissue heterogeneity of [3H]nitrendipine binding sites and the possible development of diphenylbutylpiperidine-diphenylbutylpiperazine analogues that could selectively act on brain calcium channel antagonist binding sites.

The relative dependence of calcium antagonists and neuroleptics binding to brain and heart receptors on drug lipophilicity

QSAR analysis of the binding of calcium antagonists to brain and heart tissue shows that relative binding to brain tissue increases with increasing octanol/water partition coefficients. A number of antischizophrenic drugs follow the same pattern.

Use of biomarkers in the discovery of novel anti-schizophrenia drugs

Schizophrenia is characterized by a diverse symptomatology that often includes positive, cognitive and negative symptoms. Current anti-schizophrenic drugs act at multiple receptors, but little is known about how each of these receptors contributes to their mechanisms of action. Screening of novel anti-schizophrenic drug candidates targeting single receptors will be based on biomarker assays that measure signalling pathways, transcriptional factors, epigenetic mechanisms and synaptic function and translate these effects to behavioural effects in animals and humans. This review discusses current states of the validity of biomarkers in the identification of novel anti-schizophrenic drug candidates.

Observance médicamenteuse et rechutes dans la schizophrénie : des neuroleptiques classiques aux APAP

In recent years, the goals of treatment in schizophrenia have evolved from objective improvements in psychotic symptoms to encompass patient-related factors such as subjective response and quality of life. Patient satisfaction with antipsychotic therapy is influenced by multiple factors. The most frequently reported reasons for dissatisfaction include drug side effects, lack of involvement in treatment planning or decision-making and lack of involvement of family members in the care plan. Conventional clinical trials have been largely focused on establishing efficacy of drugs, leaving the study of compliance to a loosely organized postmarketing surveillance system. There has been renewed interest in studying compliance behaviour in recent years propelled by two forces: an exponential growth in the development and testing of new therapeutic agents, and the growing burden of chronic diseases that require reliance on life-long medical treatments. Both the pharmaceutical industry and clinicians have come to appreciate the old adage “much falls between the cup and the lip” that aptly conveys the barriers between the development of new drugs in a laboratory and improving the quality of life of people in the community. Novel antipsychotic drugs are perhaps unduly criticized for not improving patients’ compliance, while the reasons for noncompliance in schizophrenia may lie elsewhere, warranting a reexamination of the prevailing concepts, constructs and measures of compliance. Noncompliance and treatment dropouts are inherent aspects of the natural history of schizophrenia, irrespective of the type of treatment and the quality of care. This does not preclude, however, the continued search for newer and better anti-schizophrenic drugs, and more reliable alternative treatment strategies. The majority of studies have demonstrated that the APAP (long-Acting atyPical AntiPsychotic) are associated with significant improvements in quality of life, functional status and patient satisfaction compared with conventional agents. The therapeutic alliance is the key to achieving optimal outcomes, by providing information and education to meet patients’ needs, while facilitating compliance with drug therapy to ensure better clinical outcomes. A long-acting atypical antipsychotic that can ensure medication delivery will provide a platform for psychosocial interventions, and thus may further increase patient satisfaction and, ultimately, improve long-term outcomes in schizophrenia. Attitudes towards APAP play an important part in the treatment for schizophrenia and related disorders. The effectiveness of APAP is evident in acute and maintenance treatment of these disorders, and most mental health professionals recognize APAP as a cornerstone in treating affected people.

Atypical anti-schizophrenic drugs prevent changes in cortical N-methyl- d-aspartate receptors and behavior following sub-chronic phencyclidine administration in developing rat pups

We sought to determine the relationship between phencyclidine (PCP)-induced alterations in behavior and NMDAR expression in the cortex by examining the effect of anti-schizophrenic drug treatment on both. Sprague–Dawley rat pups were pretreated with risperidone or olanzapine prior to treatment with PCP on postnatal day 7 (PN7) or sub-chronically on PN7, 9, and 11. Pre-pulse inhibition (PPI) of acoustic startle was measured on PN24–26 and following a challenge dose of 4 mg/kg PCP, locomotor activity was measured on PN28–35. PCP treatment on PN7 did not cause a deficit in PPI, but did cause locomotor sensitization. This was prevented by both antipsychotics. PCP treatment on PN7 caused an up-regulation of NR1 and NR2B, which was not affected by either anti-schizophrenic drug. PCP treatment on PN7, 9, and 11 caused a deficit in PPI and a sensitized locomotor response to PCP challenge as well as an up-regulation of NR1 and NR2A, all of which were prevented by both atypical anti-schizophrenic drugs. These data support the hypothesis that sub-chronic, but not single injection PCP treatment in developing rats results in behavioral alterations that are sensitive to antipsychotic drugs and these behavioral changes observed could be related to up-regulation of cortical NR1/NR2A receptors.

M 4 agonists/5HT 7 antagonists with potential as antischizophrenic drugs: Serominic compounds

Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT 7 antagonists and M 4 agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.

Schizophrenia: Neural Mechanisms for Novel Therapies

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated "negative" symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the alpha7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.

A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms

The objective was to test effects of ethyl eicosapentaenoate (E-E) on persistent ongoing symptoms in patients receiving different types of anti-schizophrenic drugs, typical antipsychotics, new atypical antipsychotics, and clozapine. 115 patients with DSM-IV-defined schizophrenia were studied, 31 on clozapine, 48 on new atypical drugs and 36 on typical antipsychotics. Placebo or 1, 2 or 4 g/day of E-E was given for 12 weeks in addition to the background medication. The main assessment was change from baseline to 12 weeks on the PANSS and its sub-scales. There were no treatment-related side effects or adverse biochemical or haematological effects. Patients on 2 and 4 g/day E-E showed significant reductions in triglyceride levels which had been elevated by clozapine. In patients given 2 g/day E-E there were improvements on the PANSS and its sub-scales, but there was also a large placebo effect in patients on typical and new atypical antipsychotics and no difference between active treatment and placebo. In patients on clozapine, in contrast, there was little placebo response, but a clinically important and statistically significant effect of E-E on all rating scales. This effect was greatest at 2 g/day. There was a positive relationship between improvement on rating scales and rise in red blood cell arachidonic acid concentration.

Genetic variations in human G protein-coupled receptors: implications for drug therapy.

Numerous genes encode G protein-coupled receptors (GPCRs)-a main molecular target for drug therapy. Estimates indicate that the human genome contains approximately 600 GPCR genes. This article addresses therapeutic implications of sequence variations in GPCR genes. A number of inactivating and activating receptor mutations have been shown to cause a variety of (mostly rare) genetic disorders. However, pharmacogenetic and pharmacogenomic studies on GPCRs are scarce, and therapeutic relevance of variant receptor alleles often remains unclear. Confounding factors in assessing the therapeutic relevance of variant GPCR alleles include 1) interaction of a single drug with multiple closely related receptors, 2) poorly defined binding pockets that can accommodate drug ligands in different orientations or at alternative receptor domains, 3) possibility of multiple receptor conformations with distinct functions, and 4) multiple signaling pathways engaged by a single receptor. For example, antischizophrenic drugs bind to numerous receptors, several of which might be relevant to therapeutic outcome. Without knowing accurately what role a given receptor subtype plays in clinical outcome and how a sequence variation affects drug-induced signal transduction, we cannot predict the therapeutic relevance of a receptor variant. Genome-wide association studies with single nucleotide polymorphisms could identify critical target receptors for disease susceptibility and drug efficacy or toxicity.

Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.

Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. These binding methods provide a simple in vitro means for evaluating new drugs as potential antischizophrenic agents.

α 2-Adrenoreceptor antagonism may contribute to the atypical properties of risperidone: experimental support for the Nutt case

The therapeutic efficacy and reduction in side effects claimed for new antischizophrenic drugs such as clozapine and risperidone have been ascribed to their heightened affinity for serotonin 5-HT(2) receptors rather than D-2 receptors. A case for α(2)-adrenoreceptor antagonism has recently been argued. We have confirmed that at least one atypical property of risperidone (a rapid decrement in its ability to depress self-stimulation) can be partly prevented by an α(2)-adrenoreceptor agonist (clonidine) but not by a 5-HT( 2) receptor agonist (DOI). This result supports the suggested role of α( 2)-adrenoreceptor antagonism in counteracting extrapyramidal effects during treatment with risperidone.