Genetic variation of the 5-HT2A receptor and response to clozapine

Nöthen, Markus M.; Rietschel, Marcella; Erdmann, Jeanette; Oberländer, Heinrich; Möller, H.-J.; Naber, Dieter; Propping, Peter; Burnet, Philip W.J.; P, Harrison

doi:10.1016/s0140-6736(95)92756-5

Cited by 97 publications

(51 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A more consistent picture comes from studies showing an influence of the functional His452Tyr polymorphism of the 5-HT 2A receptor on the clozapine response (Arranz et al, 1996;Masellis et al, 1998). Although several other studies failed to detect an association of this SNP and treatment response (Masellis et al, 1995;Nothen et al, 1995;Jonsson et al, 1996;Malhotra et al, 1996;Lin et al, 1999), a recent metaanalysis showed a relatively strong association of the Tyr variant with poor response to clozapine (Arranz et al, 1998b). Mutations in the promoter (VNTR, T-759C, and G-995A), and coding region (Cys23Ser) of the 5-HT 2C receptor have also been associated with clozapine response and improvement in negative symptoms Arranz et al, 2000b;Reynolds et al, 2005).…”

Section: Tph1 = Tryptophan Hydroxylasementioning

confidence: 93%

“…A number of studies reported significant associations between the linked 5-HT 2A A-1438G and T102C receptor SNPs and response to atypical antipsychotics (mostly clozapine), but there are some discrepant results with respect to the risk-alleles for non-responding Arranz et al, 1998a;Arranz et al, 1998b;Joober et al, 1999;Yu et al, 2001;Lane et al, 2002;Hamdani et al, 2005; see also Arranz and de Leon, 2007). In addition, there are several studies reporting that there is no association between the T102C substitution and the therapeutic response to clozapine and other antipsychotics (Masellis et al, 1995;Nothen et al, 1995;Jonsson et al, 1996;Malhotra et al, 1996;Lin et al, 1999). A more consistent picture comes from studies showing an influence of the functional His452Tyr polymorphism of the 5-HT 2A receptor on the clozapine response (Arranz et al, 1996;Masellis et al, 1998).…”

Section: Tph1 = Tryptophan Hydroxylasementioning

confidence: 99%

See 1 more Smart Citation

Serotonin and Schizophrenia

Quednow

Geyer

Halberstadt

2010

Handbook of Behavioral Neuroscience

View full text Add to dashboard Cite

Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades. Therefore, the present work will give an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we will discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, post-mortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a major role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin. Serotonin and Schizophrenia AbstractAlthough the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades.Therefore, the present work will give an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we will discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, post-mortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a major role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin.3

show abstract

Section: Tph1 = Tryptophan Hydroxylasementioning

confidence: 93%

Section: Tph1 = Tryptophan Hydroxylasementioning

confidence: 99%

Serotonin and Schizophrenia

Quednow

Geyer

Halberstadt

2010

Handbook of Behavioral Neuroscience

View full text Add to dashboard Cite

show abstract

“…An amino-acid substitution in the same gene, His452Tyr, was also found to be associated with clozapine response. 128,129 Although several other reports failed to find these polymorphisms significantly associated, [117][118][119][120]122 a meta-analyses showed a clear association of the Tyr variant with poor response to clozapine (OR = 5.55). 121 The Tyr variant of this polymorphism is reportedly associated with reduced calcium release and reduced ability to activate phospholipases C and D, 173,174 which may lead to a reduced signal and indirectly to a lower efficacy of the targeting antipsychotics.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

View full text Add to dashboard Cite

The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

show abstract

“…Only one association study 37 addressed -and failed to detect -a link between the T25N SNP and clozapine response. We found no effect of the T25N polymorphism on clozapine affinity or efficacy.…”

Section: Differential Pharmacology Of 5-ht 2a Snpsmentioning

confidence: 99%

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

et al. 2005

View full text Add to dashboard Cite

The 5-HT 2A -serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT 2A -serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT 2A -serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT 2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

show abstract

Genetic variation of the 5-HT2A receptor and response to clozapine

Cited by 97 publications

References 6 publications

Serotonin and Schizophrenia

Serotonin and Schizophrenia

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

Contact Info

Product

Resources

About