Association of Risperidone Treatment Response With a Polymorphism in the 5-HT 2A Receptor Gene

Department of Psychiatry, Tzu Chi University, Hua-lien, Taiwan, Taiwan
American Journal of Psychiatry (Impact Factor: 12.3). 10/2002; 159(9):1593-5. DOI: 10.1176/appi.ajp.159.9.1593
Source: PubMed


This study investigated the effect of the 102-T/C polymorphism in the 5-HT(2A) receptor gene on risperidone efficacy.
One hundred Han Chinese patients with acutely exacerbated schizophrenia were given risperidone for up to 42 days. The patients were genotyped for 5-HT(2A) polymorphisms. Psychopathology was measured biweekly with the Positive and Negative Syndrome Scale while the patients were taking risperidone. Generalized estimating equation methods were used to analyze the effects of treatment duration, T/C genotypes, and other prognostic factors on Positive and Negative Syndrome Scale performance.
Patients with the C/C genotype had lower total scores, negative subscale scores, and general psychopathology scores but not positive subscale scores on the Positive and Negative Syndrome Scale than patients with the 102-T/C genotype. Patients with the T/C and T/T genotypes had comparable total and subscale scores. The number of previous hospitalizations and the dose of risperidone also affected Positive and Negative Syndrome Scale total scores.
These results suggest that variations in the 5-HT(2A) receptor gene may influence individual responses to risperidone.

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    • "Several authors found an association between re - sponse to risperidone and polymorphisms in serotonin receptor genes ( Lane et al . , 2002 ; Kim et al . , 2008 ; Wang et al . , 2008 ; Angelucci et al . , 2009 ; Mössner et al . , 2009 ) and dopamine receptor genes ( Lencz et al . , 2006 ; Xing et al . , 2007 ; Furukori , 2010 ) ."
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    ABSTRACT: Objective To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone.Methods Genotyping was performed in 70 healthy volunteers receiving a single 1 mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry. Prolactin concentration was quantified by direct chemiluminescence.ResultsPoor CYP2D6 metabolizers showed higher risperidone Cmax, area under the curve (AUC), and t1/2, as well as lower clearance. They also showed lower Cmax and AUC and higher t1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iCmax), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19.Conclusions Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT, and VKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1, and NAT2. Copyright © 2014 John Wiley & Sons, Ltd.
    Full-text · Article · Sep 2014 · Human Psychopharmacology Clinical and Experimental
    • "Some examples of these associations provide an indication of the difficulties associated with drawing definitive conclusions regarding the value of these pharmacogenetic studies. Lane et al. (2002) indicated that the 5-HT 2A receptor 102C/ C genotype is related to better clinical response to risperidone in Chinese patients. However, Arranz et al. (1998) showed that the 102C/C genotype is more frequent among clozapine non-responders than responders in Europeans. "
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    ABSTRACT: There is substantial evidence for the importance of serotonin system dysfunction in the biology of mood, anxiety disorders and psychotic illness, as well as in the behavioral disturbances associated with neurodegenerative disorders. Interactions with serotonin receptors are likely to contribute to the mechanisms of action of many psychiatric drugs. There is substantial individual difference in response to drug treatment – not all patients show benefit, the treatment is often inadequate, and adverse effects of drugs may reduce their tolerability. Genetic factors are likely to contribute substantially to this individual variability; variability in serotonin receptor genes can influence both response to drug treatment and the emergence of adverse effects. This chapter concentrates on the functional pharmacogenetics of the main serotonin receptors involved in psychiatric drug action. The 5-HT1A, 5-HT2A and 5-HT2C receptors are the main focus; however, 5-HT1B, 5-HT4, 5-HT6 and 5-HT7 receptors are also discussed. The genes for these receptors exhibit polymorphisms that in some cases have functional effects on the expression or structure of the gene product. The potential involvement of these functional polymorphisms of serotonin receptor genes in the pharmacological mechanism of psychiatric drug action, notably treatment response and development of side effects, is discussed.
    No preview · Article · Dec 2010 · Handbook of Behavioral Neuroscience
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    • "Secondly, as recalled above, the majority of pharmacogenetic studies were performed on second generation antipsychotics, and mainly on clozapine, in accordance with the need to identify patients that can benefit of such effective but potentially life-threatening treatment. This implies that mostly severe and resistant patients have been included in these studies, in contrast with our sample and that of the Lane et al. [19] study which comprised both good responders and poor responders to antipsychotics. Similarities in the recruitment of the latter two samples probably explain why the data of Lane et al. [19] and ours are convergent. "
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    ABSTRACT: The -1438A/G polymorphism of the 5-HT2A gene has been found to be associated with clinical response to clozapine and other second generation antipsychotics. Testing the impact of this marker on response to first generation antipsychotics (which have a lower affinity for the 5-HT2A receptor) provides the opportunity to help disentangling the two different roles that this polymorphism might have. A psychopharmacogenetic role should be detected only for antipsychotics with high affinity to the 5-HT2A receptor (therefore to second generation antipsychotics). An alternative role would imply tagging a subgroup of patients responsive to any antipsychotic, whatever their affinity, meaning that the association is more depending on non pharmacological charaterictics, such as clinical specificities. A family-based sample of 100 Algerian patients with schizophrenia (according to DSM-IV criteria) and their 200 biological parents was recruited, in order to avoid stratification biases. Patients were all treated, or have been treated, by conventional antipsychotics (mainly haloperidol) for at least four weeks, at appropriate dosage. May and Dencker scale was used to distinguish responders and non responders. No allele of the -1438A/G polymorphism of the 5-HT2A gene was transmitted in excess (50 transmitted for 38 untransmitted) in the whole sample of patients with schizophrenia (p = .90). In contrast, a significant excess of transmission of the G allele was observed (p = .02) in the subgroup of patients with good treatment response (17 transmitted for 6 untransmitted). Using a TDT approach, we showed that the G allele of the -1438A/G polymorphism of the gene coding for the 5-HT2A receptor was associated to schizophrenia with good response to conventional antipsychotics, although this conclusion is based on 88 informative patients only. Because previous data showed the same result with atypical antipsychotics, it can be concluded that the G allele tags a subgroup of schizophrenic patients with greater chance of improvement with antipsychotics of either type.
    Full-text · Article · Feb 2008 · BMC Psychiatry
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