g-protein gene 825c\u003et polymorphism is associated with response to clozapine in brazilian...

$: G-protein gene 825C\u003eT polymorphism is associated with response to clozapine in Brazilian schizophrenics$
RESEARCH ARTICLEFor reprint orders, please contact:[email protected]

G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics
Fabiana B Kohlrausch1, Angélica Salatino-Oliveira1, Clarissa S Gama2, Maria Inês Lobato2, Paulo Belmonte-de-Abreu2 & Mara H Hutz1†
†Author for correspondence1Universidade Federal do Rio Grande do Sul, Departamento de Genética, Instituto de Biociências, Caixa Postal 15053, 91501-970, Porto Alegre, RS, BrazilTel.: +55 513 308 6720;Fax: +55 513 343 5850;E-mail: [email protected] Federal do Rio Grande do Sul, Departamento de Psiquiatria, Porto Alegre, Brazil

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Keywords: clozapine, GNB3 gene, pharmacogenetics, polymorphisms

10.2217/14622416.9.10.1429 ©

Aims: Clozapine treatment of schizophrenia is effective only in 30–60% of individuals. Since genetic factors are believed to play a significant role in the variation of response to antipsychotics, the aim of the present study was to verify the effect of a G-protein gene polymorphism on clozapine response and clozapine-induced generalized seizures in Brazilian patients with schizophrenia. Patients & methods: In total, 121 schizophrenic patients in treatment with clozapine were genotyped for the 825C>T polymorphism it the GNB3 gene using PCR. Results: Homozygosity for the T825 allele was more frequent among nonresponders (χ2 = 7.708; p = 0.021), and carriers of this allele had a higher risk to present a convulsion episode (χ2 = 7.279; p = 0.007). These results were confirmed after controlling for covariates by logistic regression. Conclusion: Our data suggest an influence of the 825C>T polymorphism on clozapine response in persons with schizophrenia and also on a specific neurological side effect (generalized seizures) under clozapine treatment.

Schizophrenia is a complex psychiatric disordercharacterized by clusters of specific clinical symp-toms (positive, negative and disorganized, in moststudies), with extensive variation between individ-uals [1]. It can greatly limit the patient’s ability tofunction normally, and thus impairs their qualityof life. Among the repertoire of drugs used to treatthe disorder, several meta-analyses have evidencedthat the antipsychotic clozapine displays greatereffectiveness compared with typical neurolepticdrugs, with effect size of 0.48 relative to typicalantipsychotics [2]. This medication has a uniquereceptor-binding profile, which includes severaltarget affinities, ranging from low to high, withdopamine D1–5, serotonin 5-HT1–3, 5-HT6and 5-HT7, α1–2- and β1–3-adrenergic, muscariniccholinergic M1–5, and histaminergic H1 and H3receptors [3]. It displays preferential affinities withserotonin receptors and, consequently, a lack ofextrapyramidal side effects compared with classi-cal neuroleptics. Therefore, the dopaminergic andserotonergic receptor systems have been suggestedto play major roles in schizophrenia and are themain targets of antipsychotic treatment [4].

Although it is associated with a superior clinicalefficacy to other antipsychotics [2], only 30–60%of individuals resistant to typical antipsychoticsrespond to clozapine [5,6]. At the same time, it dis-plays other undesirable adverse effects (ADRs),such as agranulocytosis, weight gain, hypotension,somnolence, constipation and several types ofconvulsive symptoms, including new-onset gener-alized seizures (NOGS). Despite the relatively low

frequency, it represents a great burden in schizo-phrenic patients’ care and a substantial impact onmedication adherence and response. This substan-tial unexplained interindividual variation in clini-cal response or ADR occurrence under clozapinedrug treatment remains a critical problem in themanagement of schizophrenia [7].

Most monoaminergic receptors (e.g., DRD1–5,5-HT2A and 5-HT2C) are intracellularly coupledto G proteins (i.e., G-protein-coupled receptors[GPCRs]). G proteins are composed of α, β and γsubunits and each subunit is coded by many dif-ferent gene products. The GNB3 gene codes theβ-subunit 3 of G proteins (Gβ3) and the 825C>Tpolymorphism located in exon 10 of this gene hasbeen shown to be associated with alternative splic-ing of exon 9. The Tallele results in an in-framedeletion of 41 amino acids and this shorterprotein leads to an increased intracellular signaltransduction by stimulation of several GPCRs [8].

Since genetic factors are believed to play a sig-nificant role in the variation of response to anti-psychotics [9], catecholamine receptors areGPCRs and antipsychotics exert their therapeu-tic effects by competitive antagonism of post-synaptic GPCRs [10], the role of the GNB3 genein clozapine therapeutic efficacy is promising. Ina previous study, Müller et al. observed that thehomozygous C825 genotype was significantlyassociated with relative clinical improvementafter 6 and 12 weeks (p < 0.01 and p = 0.03,respectively) in 145 schizophrenic patients [11].Anttila et al. described, in 94 schizophrenic

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RESEARCH ARTICLE – Kohlrausch, Salatino-Oliveira, Gama, Lobato, Belmonte-de-Abreu & Hutz

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patients, that there was a trend for the hetero-zygous genotype C825/T825 to be more com-mon in responders than in nonresponders [12].Wang et al. [13] and Bishop et al. [14] addressedthe influence of the 825C>T polymorphism onweight gain after clozapine and olanzapine treat-ment. In both studies, there was evidence thatthe T825 homozygous individuals experiencedmore weight gain after treatment.

In this study, we evaluate the effect of the825C>T polymorphism in the GNB3 gene onthe response to clozapine treatment in a Braziliansample of patients of European ancestry with aDiagnostic and Statistical Manual of MentalDisorders (DSM-IV) diagnosis of schizophrenia.

Patients & methodsSample characteristicsIn total, 121 patients with schizophrenia wererecruited for a pharmacogenetic study on clozap-ine response and side effects, using a naturalisticapproach. All patients included in the study wereof European ancestry to avoid false-positiveresults due to population stratification [15].

The patients had been treated with a stabledose of clozapine for at least 3 months, since2001. All patients were comprehensively assessedby Board-Certified Psychiatrists with at leastfour interviews in the presence of a relative andmet clinical criteria for schizophrenia accordingto the DSM-IV [16], with additional assessmentby standardized interviews using the OperationalCriteria Checklist for Psychotic Disorders(OPCRIT) [17]. Each patient signed a writteninformed consent to participate in the study,which was approved by the Ethics Committee ofthe Federal University of Rio Grande do Sul(Porto Alegre, Brazil).

All patients using clozapine fulfilled Kane’s cri-teria for treatment refractoriness or intolerance totypical antipsychotic therapy, defined as a lack ofsatisfactory clinical response to at least two ormore standard antipsychotics, administered atdoses equivalent to at least 1000 mg chlorpro-mazine, for a minimal period of 6 weeks, andpoor functioning level over the past 5 years [18].Clozapine response was evaluated by the treatingphysician using the Brief Psychiatric Rating Scale(BPRS) [19], and a 30% reduction of the scoreswas considered as the threshold for appropriateresponse. This criterion for clozapine responsewas approved by the Clinical Protocol and Thera-peutic Proceedings of the Brazilian Health Minis-try [20]. A total of 66 patients were classified asresponders and 55 as nonresponders to clozapine

treatment. Additional information about the sub-jects and comedication were recorded by clinicalinterviews and review of patient records. Theresponse assignment was made before associationwith other medication. According to Chong andRemington [21], one strategy to treat clozapinenonresponder patients is to augment clozapinewith other somatic treatments. There is evidenceto suggest a number of promising augmentationstrategies when patients respond poorly to clozap-ine alone, but they need a control of the potentialbenefit of particular combinations. Therefore,almost all nonresponders received comedications,because the Brazilian treatment protocol [20] sug-gests that individuals showing unsatisfactoryresponse to clozapine should try combinations ofother medications with clozapine before changingto other antipsychotics. These comedications pre-scribed for nonresponders usually included typicalantipsychotics (antipsychotic potentiating), lith-ium (when affective symptoms are prominent; itmay enhance the action of the antipsychotic)and/or antidepressants (which may improve posi-tive and negative symptoms in conjunction withclozapine) [21].

The occurrence of clozapine-induced general-ized (new-onset) seizures was assessed by clinicalinterviews with patients and relatives, reportingclear descriptions of tonic–clonic generalized sei-zures (from 2001 to 2005) collected by clinicalpsychiatrists who were not aware of genotypes.For all subjects, NOGS during clozapinetreatment had not required drug discontinuation. The characteristics of the individuals investi-gated are shown in Table 1. The mean daily doseof clozapine was 540.91 mg/day, but varied from100 to 900 mg/day. A generalized convulsiveepisode had been observed in 27 out of 121 sub-jects (22.3%), after prolonged exposure to cloza-pine. As NOGS are completely known as anadverse reaction to clozapine, the seizure diagno-sis was not assessed using EEG. As stated byWong and Delva [22], it is of limited practicalvalue to investigate plasma levels and/or to per-form an EEG to diagnose a seizure episode dueto clozapine treatment. Therefore, according tostandard procedures, those patients sufferingconvulsions remained using clozapine, andsodium valproate was included after the episode.

Laboratory proceduresGenomic DNA was isolated from peripheralblood leukocytes by standard procedures [23]. A267-bp fragment of the GNB3 gene, includingthe 825C>T polymorphism, was amplified by

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G-protein gene polymorphism & clozapine response in schizophrenics – RESEARCH ARTICLE

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Table 1. Characteris

Characteristics

Number of patients

Gender

Male

Female

Age (years), mean ± SE*

Age at illness onset (years), mean ± SE‡

Illness duration (years), mean ± SE§

Age at clozapine startin(years), mean ± SE¶

Clozapine dose#

Comedication**

Clozapine response: *Stude¶Mann–Whitney test: z = -0

New-onset generalized sei

p = 0.268; ¶Mann–Whitney**Presence of comedicationSE: Standard error.

PCR using oligonucleotide primers and restric-tion mapping with BsaJI as described byRosskopf et al. [24].

Statistical analysisAllele frequencies were estimated by gene count-ing. The agreement of genotype frequencies withHardy–Weinberg equilibrium was assessed by χ2

tests. Significance of allelic and genotype fre-quency differences between responders and non-responders and between presence and absence ofa convulsion episode were assessed by Pearson’sχ2 test or, if any cell count was less than 5, byFisher’s exact test. Residual analysis and oddsratio (OR) calculations were performed usingPEPI Software, Version 4.0 [25].

Logistic regression was performed to estimatethe effect of the 825C>T polymorphism onresponse status and NOGS occurrence, afteradjusting for possible confounders. The responseregression model was adjusted for two indepen-dent risk variables: illness duration (≥16 years) andclozapine treatment duration (≥3 years). Comedi-cation was not included in the model because it ishighly correlated with nonresponse to clozapine(Pearson correlation = 0.901; p < 0.0001). TheNOGS regression model was adjusted for theeffect of clozapine dose (≥650 mg/day), presenceof comedication (sodium valproate was not con-sidered a comedication for statistic analyses

purposes, except when another medication wasalso present), and clozapine treatment duration(≥3 years). The covariates were dichotomizedbefore analysis because the assumption of a linearrelation between nonresponse and the log odds ofthese variables was not met. Statistical analyseswere performed using the SPSS software packageversion 10.0. The significance level was set at ap-value of less than 0.05. The PEPI Software, Ver-sion 4.0 POWR program [25] was used to calculatesample statistical power.

ResultsTable 1 shows demographic and clinical charac-teristics of the patient’s sample. Patients wereaged between 16 and 64 years (34.02 ±8.79 years) and 83.5% were men. Amongpatients with good response, only one individual(1.5%) received comedication (paroxetine), andall others were in monotherapy with clozapine.Comparison of seizure frequency betweenresponders and nonresponders showed that non-responders (who have taken higher doses thanresponders; z = -2.853; p = 0.004) presented ahigher frequency of NOGS (36.4%) thanresponders (10.6%; χ2 = 11.482; p = 0.001).

The 825C>T polymorphism genotype fre-quencies were in Hardy–Weinberg equilibrium.An association between this polymorphism andclinical response to clozapine was observed

tics of the 121 investigated patients with schizophrenia under clozapine.

Total Clozapine response New-onset generalized seizures

Responders Nonresponders Positive Negative

121 66 55 27 94

101/121 (83.5%) 56 (84.8%) 45 (81.8%) 19 (70.4%) 82 (87.2%)

20 (16.5%) 10 (15.2%) 10 (18.2%) 8 (29.6%) 12 (12.8%)

34.02 ± 8.79 33.92 ± 7.92 34.13 ± 9.84 34.37 ± 9.41 33.91 ± 8.66

18.83 ± 5.06 19.76 ± 6.02 17.71 ± 3.31 17.78 ± 3.52 19.13 ± 5.40

15.21 ± 8.53 14.26 ± 7.59 16.37 ± 9.50 16.81 ± 8.84 14.74 ± 8.44

g 30.18 ± 9.20 30.24 ± 8.44 30.12 ± 10.15 29.04 ± 9.03 30.52 ± 9.27

540.91 ± 186.7 497.12 ± 177.95 593.45 ± 184.90 638.52 ± 146.57 512.87 ± 188.18

51 (42.1%) 1 (1.5%) 50 (90.9%) 15 (55.6%) 36 (38.3%)

nt’s t-test: t = 0.127, p = 0.899; ‡Mann–Whitney test: z = -1.715; 86, p = 0.09; §Mann–Whitney test: z = -1.387, p = 0.165;

.665, p = 0.506; #Mann–Whitney test: z = -2.853, p = 0.004.

zures: *Student’s t-test: t = -0.236, p = 0.813; ‡Mann–Whitney test: z = -1.140, p = 0.254; §Student’s t-test: t = -1.112,

test: z = -0.804, p = 0.421; #Mann–Whitney test: z = -3.085, p = 0.002.

(medication used to treat convulsion not included).

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Table 2. Genotype aclozapine treatmen

Phenotype

Responders

Nonresponders

p-value

NOGS positive

NOGS negative

p-value

NOGS: New-onset generali

(Table 2). Homozygosis for the T825 allele wasmore frequent among nonresponders (27.3%)than in responders (10.6%) and, conversely,homozygosis for the C825 allele was observed inhigher frequency among responders (47.0 vs27.3% in nonresponders) (χ2 = 7.708;p = 0.021). When we pooled homozygous andheterozygous individuals for the T825 allele,considering all T825 carriers, we also observedsignificant differences between responders andnonresponders (χ2 = 4.939; p = 0.026; OR: 2.36[95% CI: 1.03–5.50]). Analyses of allele fre-quencies also showed a significant associationbetween the T825 allele and unsatisfactoryresponse to clozapine (χ2 = 8.259; p = 0.004;OR: 2.14 [95% CI: 1.23–3.74]).

Carriers of the T825 allele showed anincreased risk for a convulsive episode (χ2 =5.607; p = 0.018). Taking both response statusand NOGS occurrence together, we observedthat carriers of the T825 allele have a higher riskof being a nonresponder and presenting a con-vulsion episode (χ2 = 7.169; p = 0.007; OR: 4.43[95% CI: 1.29–17.38]).

After controlling for confounders in logisticregression analyses, the 825C>T polymorphismwas confirmed to be significantly associated withclozapine response (Table 3). Since clozapine dosewas significantly different between NOGS-posi-tive and -negative patients (Table 1), the possibilitythat clozapine dose was responsible for NOGSoccurrence was tested by logistic regression analy-ses including dose as a confounder. In the NOGSregression model, clozapine treatment durationwas significantly associated with NOGS occur-rence, but high clozapine doses and co-medica-tion were not significantly associated with NOGSwhen genotypes were considered (Table 3).

DiscussionIn this study, we examined the possible influ-ence of a polymorphism in the GNB3 gene and

efficacy of clozapine treatment. Our findingspoint to an association between the GNB3825C>T polymorphism and clozapine responseand NOGS occurrence in Brazilian patientswith schizophrenia.

Antipsychotics exert their therapeutic effectsby competitive antagonism of postsynapticreceptors (thus reducing subsequent GPCRactivity) [10]. Since both dopamine and serotoninreceptor subtypes activate intracellular pathwaysthrough GPCRs, the effect of the variability inthe GNB3 gene might affect medicationresponse and CNS toxicity of clozapine.

Anttila et al. found a trend-like positive associ-ation with the 825C>T polymorphism amongmale patients with good response to typicalneuroleptics compared with nonresponders [12].Müller et al. hypothesized that the 825C>Tpolymorphism could be associated with responseto antipsychotics in a population of chronicschizophrenic patients, and found that theC825/C825 genotype was significantly associ-ated with clinical improvement to clozapine,suggesting that genetic susceptibility fordecreased signal transduction may enhanceantipsychotic efficacy [11]. Findings of thepresent study also showed an associationbetween the 825C>T polymorphism of theGNB3 gene and clozapine efficacy. We found asignificant effect of the T825 allele with anincreasing chance of unfavorable clozapineresponse of approximately two-times, and a pos-itive effect on response of the C825/C825 geno-type. This association of the C825/C825genotype (or a lower signal transduction) withfavorable response replicates the previous studyby Müller et al. [11] and may be new evidencethat genetic susceptibility for decreased signaltransduction caused by the T825 variant mightenhance antipsychotic efficacy. The T825 allelethat was associated with worse response andNOGS in the present investigation was also

nd allele frequencies of the 825C>T polymorphism in schizophrenics receiving t.

C/C T/C T/T C T

31 (47.0%) 28 (42.4%) 7 (10.6%) 0.68 0.32

15 (27.3%) 25 (45.4%) 15 (27.3%) 0.50 0.50

0.021 0.004

5 (18%) 14 (52%) 8 (30%) 0.45 0.55

41 (44%) 39 (41%) 14 (15%) 0.64 0.36

0.033 0.007

zed seizures.




Table 3. Logistic reg

Variables

Response model

Illness duration (≥16 yea

Treatment duration (≥3

GNB3 825C>T*

NOGS model

Clozapine dose (≥650 m

Comedication

Treatment duration (≥3

GNB3 825C>T*

*T/T and T/C genotypes; χ2 β: Estimated coefficient; CIWald: Test the statistical si

associated with more weight gain after antipsy-chotic treatment in two previous studies [13,14].These results taken together point to an influ-ence of this polymorphism in the efficacy andsafety of clozapine treatment, in which carriers ofa T allele seem to have a worse prognosis.

In a previous study from our group [26], theT825 variant frequency was 0.33, which was onthe same range as those described in other Cau-casian populations (21–38%) [27]. By contrast,the observed frequency in the present study andin the schizophrenic patients described in a pre-vious investigation [11] varied from 40–51%.These differences could be a reflection of abnor-malities in the function and/or expression ofG proteins, which have been implicated in avariety of pathophysiologic states. The under-standing of the mechanisms by which G proteinsmodulate neuronal activity may be one of thekeys to understanding the functioning and com-plexities of the nervous system. Two studiesattempted to verify the possible involvement ofthe 825C>T polymorphism in mood disorderand schizophrenia pathogenesis [28,29], but with-out significant results. More studies are neededto clarify this possible relationship.

Additional GNB3 nucleotide polymorphisms(-1429C>T, -350A>G, 657A>T and 814G>A)in linkage disequilibrium with 825C>T may berelated to the effect of this variant, but the func-tional significance of these polymorphismsremains unclear [24]. Several genes encodingreceptors have been considered relevant tounderstanding the progression of disease andtherapeutic outcome, and polymorphisms atthese genes may also potentially be involved inclinical response to atypical antipsychotics.Among them, serotonin receptor (HTR2A and

HTR2C) and dopamine receptor (DRD2 andDRD4) genes, targets for antipsychotic therapyand also GPCRs, are the main focus onpharmacogenetics studies of antipsychoticresponse [9]. Unfortunately, replications of stud-ies focusing on polymorphisms in these geneswere not always possible, making any conclusionabout the role of these genes in antipsychoticefficacy difficult.

Defects in ion channels, which are directlyinvolved in regulation of neuronal excitability,increase susceptibility to seizure [30]. G-protein-activated inwardly rectifying K+ (GIRK) chan-nels play an important role in the inhibitory reg-ulation of neural excitability in most brainregions through activation of variousGPCRs [31]. It has been shown that GIRK chan-nels are involved in seizure susceptibility [32],and dose-related inhibition of this function byantipsychotics can increase seizure susceptibility.Since clozapine strongly inhibits GIRKchannels [33], this effect can explain the relation-ship between GNB3 polymorphisms and sei-zures in patients exposed to this drug.Individuals homozygous for the C825 allele aresupposed to have a lower signal transductionand a potentially reduced inhibition of GIRKchannels under clozapine exposure; this couldreduce the risk of clozapine-induced seizures.Additional effects over seizures can be assignedto the metabolism of GABA, which is the majorinhibitory neurotransmitter.

The rate of seizure in our sample (22%) ishigh when compared with that shown in theliterature [34]. This point may be explained bythe fact that this is a 4-year study (a cumulativerisk of tonic–clonic seizures is estimated after4 years of treatment) [35] and that our sample

ression analyses predicting clozapine response and new-onset generalized seizures.

β SE Wald df p-value OR (95% CI)

rs) 0.539 0.388 1.922 1 0.166 1.71 (0.80–3.67)

years) 0.412 0.384 1.153 1 0.283 1.51 (0.71–3.20)

0.889 0.398 4.984 1 0.026 2.43 (1.11–5.31)

g) 0.382 0.518 0.543 1 0.461 1.47 (0.53–4.05)

0.327 0.505 0.419 1 0.517 1.39 (0.51–3.73)

years) 1.102 0.508 4.694 1 0.030 3.01 (1.11–8.15)

1.273 0.568 5.014 1 0.025 3.57 (1.17–10.88)

response model = 8.289, p = 0.040; χ2 NOGS model = 13.913, p = 0.008.: Confidence interval; df: Degree of freedom; NOGS: New-onset generalized seizures; OR: Odds ratio; SE: Standard error; gnificance of each coefficient (β) in the model (Z statistic).



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included mildly to severely affected patients whoreceived 540 mg/day clozapine on average (sei-zure episodes are more likely to occur at doseshigher than 450 mg/day). The significant asso-ciation with treatment duration in the regressionanalysis of NOGS may be a reflection of thepoint cited above. As most patients who pre-sented seizures were included among those witha worse response to clozapine, and thereforeamong those with higher medication doses, theassociation found might reflect the associationwith clozapine response. However, we suggestthat high doses may not be the only major riskfactor for clozapine-induced generalized sei-zures, but also specific genotypes. It is currentlydifficult to estimate the impact of genetic vari-ability on side effects because this would requirecomplex data on many factors that are stillunknown, as side effects may be a function ofvariant alleles at independently segregating loci,environmental exposures [36] and comedications.Despite this, our result should be considered aspositive preliminary evidence, since there are norecords of other studies addressing the relation-ship between SNPs and clozapine-associatedgeneralized seizures.

There were some limitations to our study. Thestudy design is observational–naturalistic, whichis valuable to better appreciate the role of geneticfactors in routine clinical practice beyond therealm of controlled clinical trials. However, thenaturalistic design is also a limitation of thestudy, since it is difficult to control for all con-founders in an observational study. However, itis unlikely that the result has been attributed toother events because we performed an extensiveassessment of potential confounders betweengroups. The sample size is not large; thus, thesedata require additional confirmation in a largersample. Despite that, our investigation has statis-tical power to detect an influence of differentialclozapine response and NOGS occurrence as afunction of GNB3 polymorphism (62 and 70%,respectively), emphasizing the relevance of thisSNP. Another important limitation is theabsence of clozapine plasma level information inour patients, which is a possible factor contribut-ing to the final phenotypes.

ConclusionIn conclusion, the data presented here provideadditional evidence of a role for a genetic factorinfluencing interindividual variation in drugresponse in persons with schizophrenia treated

with clozapine. Whether the NOGS resultingfrom clozapine treatment are related to theT allele of the 825C>T polymorphism should befurther investigated. Although the logistic regres-sion points to an independent effect of genotypefrom dose, significantly higher clozapine doseswere used by NOGS-positive patients. Thisstudy provides empirical evidence that the use ofpharmacogenomic approaches represents aunique opportunity for the prediction ofresponse of antipsychotic drugs.

Future perspectiveThere is strong evidence to suggest that geneticvariation plays an important role in inter-individual differences in clozapine response andtoxicity. The assessment of genetic variation ingenes encoding subunits of G proteins are apromissory example of the role of pharmaco-genetics in modern clinical psychiatry. Theinformation of this study might facilitate moreeffective treatment with clozapine in schizo-phrenia patients with European ancestry. Whengenetic variation attributable to limited or goodtreatment efficacy will be well established,pharmacogenetics may maximize efficacy andminimize the risk of adverse events, getting theright medicine in the right dose to the rightpatient. Clearly, more studies in this field, withother genes and more SNP genotyping, areneeded to disclose the genetic role in clozapineresponse and toxicity.

Financial & competing interests disclosure Financial support was provided by Institutos do Milênio,Conselho Nacional de Desenvolvimento Científico e Tec-nológico (CNPq, Brazil), Programa de Apoio a Núcleos deExcelência (PRONEX, Brazil) and Fundação de Amparo àPesquisa do Estado do Rio Grande do Sul (FAPERGS, Bra-zil). The authors have no other relevant affiliations or finan-cial involvement with any organization or entity with afinancial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart fromthose disclosed.

No writing assistance was utilized in the production ofthis manuscript.

Ethical conduct of research The authors state that they have obtained appropriate insti-tutional review board approval or have followed the princi-ples outlined in the Declaration of Helsinki for all human oranimal experimental investigations. In addition, for investi-gations involving human subjects, informed consent has beenobtained from the participants involved.




Executive summary

• Clozapine is effective • Since catecholamine r

response of clozapine

Materials & methods

• A total of 121 Braziliapolymorphism at the

Results

• The 825C>T polymoroccurrence (χ2 = 7.27

• C825/C825 individua• Logistic regression an

Conclusion

• Our data suggest an iinfluence of the polymdifficult to discriminatpatient genotype was

in treatment-resistant cases of schizophrenia, but only 30–60% of individuals respond to this medication.eceptors are G-protein-coupled (GPCRs), genetic variation in the GNB3 gene may be involved in the treatment.

n patients of European ancestry with schizophrenia treated with clozapine were genotyped for the 825C>T GNB3 gene using PCR and restriction mapping.

phism was associated with clozapine response (χ2 = 7.708; p = 0.021) and, in addition, with seizure 9; p = 0.007).ls have a lower risk of being a nonresponder and suffering a convulsion episode. alyses confirmed the previous associations.

nfluence of the 825C>T polymorphism on clozapine response in individuals with schizophrenia. The orphism on specific neurological side effects (generalized seizures) was also observed. However, it is more

e this effect from the higher clozapine doses observed in these patients, although the influence of the still significant after controlling for dose by logistic regression.

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1436 Pharmacogenomics (2008) 9(10) future science groupfuture science group

g-protein gene 825c\u003et polymorphism is associated with response to clozapine in brazilian...

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