Serotonin Subtype 2 Receptor Genes and Clinical Response to Clozapine in Schizophrenia Patients

Masellis, Mario; Basile, Vincenzo S.; Meltzer, Herbert Y.; Lieberman, Jeffrey A.; Sevy, Serge; Macciardi, Fabìo; Cola, Philip A.; Howard, Alfreda; Badri, Farideh; Nöthen, Markus M.; Kalow, W.; Kennedy, James L.

doi:10.1016/s0893-133x(98)00007-4

Cited by 227 publications

(141 citation statements)

References 53 publications

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“…35 The H452Y variant is the most widely studied 5-HT 2A receptor SNP. Two studies 26,36 reported a statistically significant association between the frequency of the Try452 allele and poor response to clozapine; a third study 27 reported a higher frequency of the Try452 allele among clozapine non-responders than in responders, although the difference between groups was not statistically significant. Notably, the Malhorta et al study examined a smaller sample size than the Arranz et al and Masellis et al studies.…”

Section: Differential Pharmacology Of 5-ht 2a Snpsmentioning

confidence: 96%

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

et al. 2005

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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.

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Section: Differential Pharmacology Of 5-ht 2a Snpsmentioning

confidence: 96%

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

et al. 2005

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“…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%

“…Individual association studies had identified several variants in clozapinetargeted receptor with influence on clinical outcome. 114,121,126,129,199 We combined information of genetic variants associated with response and developed an algorithm for the prediction of clozapine outcome. A combination of variants in the genes coding for 5-HT 2A , 5-HT 2C , H 2 receptors and for the serotonin transporter 5-HTT resulted in the correct prediction of response in 76% of cases.…”

Section: Prediction Of General Responsementioning

confidence: 99%

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

2007

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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.

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“…The potent D 4 /5-HT 2a receptor antagonist fananserin has been found ineffective in acutely psychotic patients with schizophrenia (Truffinet et al in press), perhaps because D 4 receptor antagonism has a propsychotic effect, not the reverse. Additional evidence supporting the role of 5-HT 2a receptor blockade in the action of clozapine and possibly other drugs with potent 5-HT 2a affinities is available from the several reports that the His452Tyr allele of the 5-HT 2a receptor, which is present in 10-12% of the population, is associated with a higher frequency of poor response to clozapine (Masellis et al 1998). Thus, taken together, the evidence from clinical trial data suggests that 5-HT 2a receptor blockade may contribute to antipsychotic drug action.…”

Section: Novel Antipsychotics and The 5-ht 2a Receptor Antipsychotic mentioning

confidence: 99%

The Role of Serotonin in Antipsychotic Drug Action

Meltzer

1999

Neuropsychopharmacology

624

266

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Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact thatRecent interest in the role of serotonin (5-HT) in the mechanism of action of antipsychotic drugs is in large part the result of the discovery of the efficacy of clozapine in treating the delusions, hallucinations, and disorganization of schizophrenic patients who failed to respond to classical neuroleptic drugs (Kane et al. 1988;Meltzer 1992). It has also been demonstrated that clozapine can improve the negative symptoms of schizophrenia, i.e., affective flattening, anergia, anhedonia, and avolition . Clozapine was, earlier, shown to cause fewer extrapyramidal side effects (EPS) than typical antipsychotic drugs; there have been no reported cases of tardive dyskinesia with clozapine, and it is tolerable to patients with Parkinson's disease and even able to improve some types of motor dysfunction in patients who develop dopamine (DA) agonistinduced psychosis (see Meltzer and Nash 1991; Meltzer et al. 1995 for refs). Clozapine has also been found not to cause elevations of serum prolactin levels (Meltzer 1979). Recently, clozapine has been shown to have other clinical advantages over typical neuroleptic drugs, most notably the ability to improve some aspects of the cognitive dysfunction of schizophrenia, such as attention, verbal fluency (semantic memory), recall memory, and some measures of executive function, e.g., maze and performance, thought it does not improve working memory (Meltzer and McGurk in press). There is extensive evidence that clozapine is able to decrease the risk of suicide in schizophrenia (Meltzer and Okayli 1995). It has also been found effective as an antimanic agent and Serotonin and Antipsychotic Drugs 107S a mood stabilizer in treatment-resistant mood disorders (Calabrese et al. 1996). Suicide, mania, depression, and mood stabilization have been related to abnormalities in serotonergic availability and receptor responsivity . Determining the biological basis for these advantages of clozapine, many of which may involve effects on 5-HT, is of great theoretical and clinical importance.Because clozapine produces agranulocytosis, developing other antipsychotic drugs with similar benefits but without this side effect has been a major research goal since 1988. This effort has produced risperidone, olanzapine, quetiapine, ziprasidone, and sertindole which have been approved for use in the treatment of schizophrenia in various countries as well as other putative antipsychotic agents in development, e.g., M100907. However, there appear to be differences between these agents in efficacy and in at least some side effects. This review considers what is known about the role of 5-HT in the efficacy for positive and negative symptoms, neuroleptic refractory positive symptoms, and extrapyramidal side effects of the novel antipsychotic agents, and looks at possible strategies for developing other antipsychotic agents which depend upon serotonergic function in ways that differ from clozapine. Beca...

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Serotonin Subtype 2 Receptor Genes and Clinical Response to Clozapine in Schizophrenia Patients

Cited by 227 publications

References 53 publications

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

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

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

The Role of Serotonin in Antipsychotic Drug Action

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