Track topics on Twitter Track topics that are important to you
Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were incapable to obtain any particular biological response. In relation to ERK1/2 activation, we found that 5-HT2A serotonin receptor antagonists Ketanserin and M100907, both partially reduced Clozapine effect. In addition, we also observed an increase of potency of Clozapine effect in HeLa transfected cells with recombinant 5-HT2A receptor and in rat glioma C6 cells that express a higher amount of this receptor. This indicates that ERK1/2 stimulation induced by Clozapine could, to some extent, be mediated by 5-HT2A receptor, through a novel mechanism that is called "biased agonism", even though other cellular targets are involved. This evidence may be relevant to explain the superiority of Clozapine among the APDs.
This article was published in the following journal.
Name: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Clozapine is widely underused. No study has assessed views of patients suitable for, but not yet receiving, clozapine. We aimed to assess views of clozapine in patients eligible for clozapine but not ...
When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this prac...
The dysfunction of parvalbumin-positive (PV+) interneurons, the most abundant type of hippocampal GABAergic inhibitory interneuron, has been implicated in mood disorders. We recently reported that adu...
Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide data from Finnish health care re...
Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition....
The purpose of this study is to examine the short – term effects of clozapine on alcohol use in persons with schizophrenia and an alcohol use disorder. The hypothesis is that clozapine ...
A Study Comparing the Efficacy and Tolerability of Ziprasidone vs. Clozapine for the Treatment of Schizophrenia in Patients Who Continue to Have Symptoms on or Cannot Tolerate Other Antipsychotic Drugs
The purpose of this study is to compare the efficacy and safety of ziprasidone and clozapine in schizophrenic patients who are resistant and/or intolerant to antipsychotic treatment
The role of Therapeutic Drug Monitoring (TDM) in clozapine dose adjustment have been debated. Blood samples for s-clozapine monitoring should be drawn 12 hours post dose. The scope of thi...
Serotonin receptors, especially the 5HT2A receptor, are thought to be involved in the effects of various recreationally used psychedelic substances such as LSD. LSD potently stimulates the...
Schizophrenia is a mental health problem usually starting in the late teens/early twenties, and often lasting many years. The standard medication ('antipsychotics') for this problem is usu...
A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.
A serotonin receptor subtype found widely distributed in peripheral tissues where it mediates the contractile responses of variety of tissues that contain SMOOTH MUSCLE. Selective 5-HT2A receptor antagonists include KETANSERIN. The 5-HT2A subtype is also located in BASAL GANGLIA and CEREBRAL CORTEX of the BRAIN where it mediates the effects of HALLUCINOGENS such as LSD.
A subtype of dopamine D2 receptors that has high affinity for the antipsychotic CLOZAPINE.
An antipsychotic agent that is structurally related to piperazines and quinolones. It is a partial agonist of SEROTONIN RECEPTOR, 5-HT1A and DOPAMINE D2 RECEPTORS, where it also functions as a post-synaptic antagonist, and an antagonist of SEROTONIN RECEPTOR, 5-HT2A.
A cyclin subtype that is found as a component of a heterotrimeric complex containing cyclin-dependent kinase 7 and CDK-activating kinase assembly factor. The complex plays a role in cellular proliferation by phosphorylating several CYCLIN DEPENDENT KINASES at specific regulatory threonine sites.