Classics in Chemical Neuroscience: Clozapine

Wenthur, Cody J.; Lindsley, Craig W.

doi:10.1021/cn400121z

Cited by 124 publications

(125 citation statements)

References 52 publications

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“…Apart from blocking the receptors traditionally explaining the antipsychotic action of atypical APDs, CLO possesses an affinity for the full range of receptors: serotonin, dopamine, adrenergic, cholinergic and histaminic [4] , as well as ion channels, transporters and other molecules [4,5] . CLO also differentially changes the expression of numerous genes [6,7] .…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway

Karbownik¹,

Szemraj²,

Wieteska³

et al. 2016

Pharmacology

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Background/Aims: The PIK3CD gene encodes the delta catalytic subunit of phosphoinositide 3-kinase (PI3K), an element of the neuregulin 1-downstream ErbB4-PI3K signaling pathway, which was recently identified as a molecular target for the treatment of schizophrenia. The aim of the study was to examine the effect of haloperidol (HALO), clozapine (CLO), olanzapine (OLA), quetiapine (QUE) and amisulpride (AMI) on the mRNA and protein expression of genes encoding the elements of ErbB4-PI3K pathway, in a human central nervous system cell line. Methods: The U-87MG human glioblastoma cell line was used as an experimental model. Quantitative polymerase chain reaction was used to examine the expression of mRNA and enzyme-linked immunosorbent assay for protein expression. Results: At concentrations reached in clinical settings in the brain, CLO, as well as OLA and QUE to a lesser extent, but not AMI and probably not HALO, decreased the mRNA expression of PIK3CD. Protein expression of the gene did not confirm the mRNA expression profile. Conclusions: The tested antipsychotic drugs (APDs) in the U-87MG glioblastoma cell line differentially regulates the mRNA expression of PIK3CD; however, the protein expression does not confirm these findings. The results of the study may help deepen the understanding of the mechanism of action of APDs.

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Section: Introductionmentioning

confidence: 99%

“…Complex pharmacology of CLO probably contributes to its unprecedented antipsychotic efficacy [8] . Up to now, however, despite intense studies, the reason why CLO is more effective than other APDs is not well understood [4] . In order to solve the mystery presented by CLO, further studies elucidating its mechanism of action are required.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway

Karbownik¹,

Szemraj²,

Wieteska³

et al. 2016

Pharmacology

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“…This indicates that orexin A controls various functions [11,12] including regulation of sleep/wake cycle [13]. Neuroleptic drugs, as haloperidol, clozapine, olanzapine, risperidone and quetiapine, can modify body temperature, as showed by various experimental models [14][15][16][17][18][19]. In the present mini-review, we summarize our published data in an unique report so to emphasize the influences of these neuroleptic drugs on the control of body temperature, exerted by orexinergic system.…”

Section: Introductionmentioning

confidence: 92%

Neuroleptic Drugs Affect Sympathetic and Thermogenic Reactions to Orexin A

S¹

2014

J Psychiatry

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This review of our literature describes the effects of many neuroleptic drugs on the sympathetic and hyperthermic reactions due to orexin A, a neuropeptide affecting body temperature and food intake by an increase in sympathetic activity. Haloperidol reduces, while clozapine and olanzapine block the hyperthermia induced by orexin A. Risperidone enhances the elevation of body temperature due to orexin A. Quetiapine delays these hyperthermic effects. The implications on human therapeutic strategies are discussed, including the involvement of orexinergic pathway in the induction of obesity, induced by these neuroleptic substances. We summarize our published data in a unique report so to emphasize the influences of these neuroleptic drugs on the control of body temperature, exerted by orexinergic system. This large vision could be also useful to address therapeutic choices.Patients with serious mental illness are at higher risk of developing metabolic abnormalities (e.g., weight gain, increased blood pressure, and glucose or lipid levels) in comparison to general population. Since the risk increases following initiation of narcoleptic therapy, it must assess carefully risks and benefits when choosing a particular antipsychotic drug.

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“…It has been argued that dopamine D 2 antagonism is central to AP effects, 27 but we have at least 2 other forms of psychosis, clozapine responsive and clozapine resistant; in both cases, D 2 antagonism alone is insufficient for establishing response (Figure 1). 28 In focusing on positive symptoms, we believe there is value in employing the CGI-SCH scale. 29,30 The CGI itself has been shown to be as sensitive as the BPRS in detecting efficacy differences between APs.…”

Section: Focus On Positive Symptomsmentioning

confidence: 99%

Subtyping Schizophrenia by Treatment Response: Antipsychotic Development and the Central Role of Positive Symptoms

Lee

Takeuchi

Fervaha

et al. 2016

FOC

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We have recently proposed a model for subtyping schizophrenia based on antipsychotic (AP) treatment response. Evidence suggests that APs, both old and new, are comparable in terms of efficacy; however, one AP, clozapine, is uniquely effective in one subgroup of patients (that is, those with treatment-resistant schizophrenia [TRS]). This permits us to subdivide schizophrenia into 3 specific groups: AP responsive, clozapine responsive, and clozapine resistant. Here, we integrate this model with current criteria related to TRS and ultraresistant schizophrenia, the latter referred to in our model as clozapine resistant. We suggest several modifications to existing criteria, in line with current evidence and practice patterns, particularly emphasizing the need to focus on positive symptoms. While APs can favourably impact numerous dimensions related to schizophrenia, it is their effect on positive symptoms that distinguishes them from other psychotropics. Further, it is positive symptoms that are central to AP and clozapine resistance, and it is these people that place the greatest demands on acute and long-term inpatient resources. In moving AP development forward, we advocate specifically focusing on positive symptoms and capitalizing on the evidence we have of 3 subtypes of psychosis (that is, positive symptoms) based on treatment response, implicating 3 distinguishable forms of underlying pathophysiology. Conversely, pooling these groups risks obfuscating potentially identifiable differences. Such a position does not challenge the importance of dopamine D 2 receptor blockade, but rather highlights the need to better isolate those other subgroups that require something more or entirely different. W W W Sous-typage de la schizophrénie par la réponse au traitement : développement des antipsychotiques et rôle central des symptômes positifsNous avons récemment proposé un modèle de sous-typage de la schizophrénie basé sur la réponse au traitement antipsychotique (AP). Les données probantes suggèrent que les AP, anciens comme nouveaux, sont d'efficacité comparable; cependant, un AP, la clozapine, a une efficacité unique dans un sous-groupe de patients (c'est-à-dire, ceux qui souffrent de schizophrénie résistante au traitement [SRT]). Ceci nous permet de subdiviser la schizophrénie en 3 groupes spécifiques : réceptive aux AP, réceptive à la clozapine, et résistante à la clozapine. Ici, nous intégrons ce modèle à des critères actuels liés à la SRT et à la schizophrénie ultrarésistante, cette dernière étant identifiée dans notre modèle comme étant résistante à la clozapine. Nous suggérons plusieurs modifications open access

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Classics in Chemical Neuroscience: Clozapine

Cited by 124 publications

References 52 publications

Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway

Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway

Neuroleptic Drugs Affect Sympathetic and Thermogenic Reactions to Orexin A

Subtyping Schizophrenia by Treatment Response: Antipsychotic Development and the Central Role of Positive Symptoms

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