Article

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: 13.56). 10/2002; 159(9):1593-5. DOI: 10.1176/appi.ajp.159.9.1593
Source: PubMed

ABSTRACT 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.
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    • "Thus, several studies have reported a lower density of 5-HT 2A receptors in schizophrenic patients (Dean et al., 1999; see Dean, 2003). Further, atypical antipsychotics share the common feature of being high-affinity antagonists at the 5-HT 2A receptor (Meltzer et al., 2003; Roth et al., 2004), and allelic variations in the 5-HT 2A receptor gene influences the clinical response to these compounds (Ellingrod et al., 2002; Lane et al., 2002). Similarly, affinity at 5-HT 2 receptors for a series of phenethylamines correlates both with the potency of these compounds as hallucinogens (Titeler et al 1988; Sadzot et al 1989) as well as with their potency to substitute for DOM as a discriminative stimuli (Glennon et al., 1984). "
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    ABSTRACT: Activation of 5-HT2A receptors has been shown to be an essential component of the discriminative stimulus effects of indoleamine and phenethylamine hallucinogens. The objective of the present study was to determine the neuroanatomical location of the 5HT2A receptors which may be responsible for the stimulus effects of the phenethylamine hallucinogen [-]2,5-dimethoxy-4-methylamphetamine (DOM). It was hypothesized that brain areas containing altered 5-HT2A receptor expression in the context of a similar alteration in DOM-induced stimulus control might be important in mediating the stimulus effects of DOM. Fisher 344 rats were treated with either clozapine (25 mg/kg/day) or DOM (2 mg/kg/day) for 7 days, and the consequences of these drug treatment regimens on DOM-induced stimulus control and on 5-HT2A receptor expression in several brain areas were determined. Chronic administration of clozapine was associated with a wide-spread decrease in levels of 5-HT2A/2C receptors. Conversely, treatment with DOM had varied effects including a neuroanatomically selective decrease in 5-HT2A/2C receptor levels that was restricted to the olfactory nucleus. Both chronic treatment with DOM and clozapine decreased the stimulus effects of DOM. The present findings suggest a role for the olfactory nucleus in producing the stimulus effects of DOM.
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    • "Treatment response was evaluated with the positive and negative symptoms scales (PANSS). Compared to patients with no 102C allele, patients with the 102C allele were significantly more improved in the total PANSS and negative symptoms subscales, but not in the positive symptoms subscale (Lane et al. 2002). Important pharmacogenetic considerations in antipsychotic treatment response have come from metaanalysis of serotonin 5-HT 2A receptor gene studies. "
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    ABSTRACT: Antipsychotic medications have revolutionized the treatment of schizophrenia and other psychotic spectrum dis-orders. Despite their clear benefit, concerns persist about response variability and treatment-emergent side effects of antipsychotic drugs. We conducted a medline search of studies on pharmacogenetics of antipsychotic drugs response. Current advances in pharmacogenetics suggest unique approaches that might tailor patients’ treatment to the likelihood of beneficial response to antipsychotic drugs. Ultimately, some of the promising candidate genes might help clinicians make more informed decisions about antipsychotic treatment response before prescribing the medications.
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