• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Psychiatry Rep. Author manuscript; available in PMC Mar 31, 2008.
Published in final edited form as:
Curr Psychiatry Rep. Aug 2007; 9(4): 313–318.
PMCID: PMC2276697
NIHMSID: NIHMS40271

Individualizing Antipsychotic Drug Therapy in Schizophrenia: The Promise of Pharmacogenetics

Abstract

The first- and second-generation antipsychotic drugs have become mainstay drug treatment for schizophrenia. However, patients who receive antipsychotic drugs differ with respect to treatment response and drug-induced adverse events. The biological predictors of treatment response are being researched worldwide, with emphasis on molecular genetic predictors of treatment response. Because of the rapid and exciting developments in the field, we reviewed the recent studies of the molecular genetic basis of treatment response in schizophrenia. The accumulating data suggest that DNA information in the pathways for drug metabolism and drug target sites may be an important predictor of treatment response in schizophrenia. The data suggest that clinicians may soon be using a patient's genotype to decide initial choice of antipsychotic drug treatment in schizophrenia. The pharmacogenetics of schizophrenia can improve the prospects of individualized treatment and drug discovery. Pharmacogenetic investigations of schizophrenia susceptibility loci, and genes controlling drug target site receptors, drug-metabolizing enzymes, the blood–brain barrier systems, and epigenetic mechanisms could lead to a molecular classification of treatment response and adverse events of psychotropic drugs.

Introduction

Treatment response in schizophrenia is heterogeneous [1•]. Schizophrenia afflicts approximately 1% of the world's population. The disorder is characterized by disturbances of perception, thought, and volition, with significant impairment in social and occupational functioning. Comorbid conditions are common in schizophrenia, and approximately 10% of patients with schizophrenia commit suicide. The first-generation (FGA) and second-generation (SGA) antipsychotic drugs are US Food and Drug Administration (FDA)-approved first-line treatment for schizophrenia. Antipsychotic drugs have improved the long-term prognosis of schizophrenia, although serious adverse effects, including metabolic abnormalities [2], cardiovascular events [3], and movement disorders [4], remain important considerations for every treating clinician. A recent multicenter study found that more than 70% of patients with chronic schizophrenia discontinued their antipsychotic drugs, owing to poor effectiveness or tolerability [5••]. This suggests that sensitive prediction of treatment response and drug-induced adverse events remains an unmet need in the treatment of schizophrenia [6].

In current practice, clinicians initiating antipsychotic drug therapy in schizophrenia gauge treatment response a priori, using clinical variables. This practice is not always associated with optimal treatment and could result in significant morbidity and mortality [7]. In addition, patients who fail their initial drug treatment in schizophrenia are sometimes switched to another antipsychotic drug based on trial and error. Although a number of studies have suggested that clozapine may be more effective than other atypical antipsychotic drugs after a failed treatment with an atypical, safety monitoring remains an important issue with clozapine therapy [8]. These problems that clinicians frequently encounter when choosing antipsychotic drug treatment for schizophrenia suggest a need for an accurate method of predicting treatment response and drug-induced adverse events in order to maximize the benefits of therapy and minimize unnecessary drug exposure. Thus, the prospect of individualized treatment of schizophrenia based on DNA information has generated intense research interest, and there is much optimism regarding its future commercial application. In spite of the rapid pace of pharmacogenetics research, there are daunting obstacles with which the field must grapple in order for the research findings to translate from bench to bedside. For example, there is a need to continue developing new initiatives to refine phenotypes such as treatment response, diagnosis, and adverse effects. Also, there is a need to narrow down the search for markers of treatment response to informative genes or chromosomal loci using emerging quantitative approaches and technologies [9].

In the present paper, we review recent studies that have continued to further the exciting pioneering work in the field of pharmacogenetics and comment on future directions of the field.

Pharmacogenetics and Antipsychotic Drug Response

Most of the recent pharmacogenetic studies in schizophrenia have evaluated treatment response using the candidate gene approach [1•]. The candidate genes may be related to the following: drug target receptors and second messengers (pharmacodynamic pharmacogenetic studies), drug-metabolizing enzymes or blood–brain or blood–intestine barrier systems (pharmacokinetic pharmacogenetic studies), or putative schizophrenia susceptibility loci.

Antipsychotic drugs or their potent metabolites appear to exert therapeutic effects by binding proximal molecular targets in the central nervous system (CNS), especially dopamine and serotonin receptors. Indeed, the efficacy of FGAs for positive symptoms of schizophrenia (delusions and hallucinations) may be associated with blockade of dopamine receptors, and the efficacy of SGAs for positive and negative symptoms (alogia, avolition, and affective blunting) also may be associated with occupancy of the serotonin receptors. Thus, investigators have used the tools of pharmacogenetics to interrogate genes encoding these affinity-binding sites of antipsychotic drugs. Most of these studies have used the case-control association design to compare allele or genotype frequencies in treatment responders (cases) versus nonresponders (controls).

In addition, the cytochrome P450 systems have been candidate genes of focus in pharmacokinetic pharmacogenetic studies of schizophrenia because of their important role in drug metabolism. Emerging evidence also suggests that genetic markers for treatment response in the pathways for disease pathophysiology could exist; several centers are researching schizophrenia susceptibility loci for evidence of linkage to treatment response.

Pharmacodynamic Pharmacogenetic Studies in Schizophrenia

Individual variations in the genes coding for dopamine and serotonin receptors have suggested pharmacogenetic studies of these systems. Recent pharmacogenetic studies have continued to investigate the dopamine D2 receptor (DRD2) and serotonin 5-HT2A receptor genes. These genes were the prime targets of early studies of clozapine response.

Dopamine receptor studies

In prior studies, the DRD2 gene was found to influence short-term response to DRD2 antagonists haloperidol and risperidone [1013], but not clozapine [14]. Heterozygosity for the Taq1A allele of DRD2 was associated with favorable short-term response to haloperidol [13]. The other DRD2 studies suggested that the DRD2 Ser311Cys polymorphism also might play a role in risperidone efficacy for positive, negative, and cognitive symptoms and that the DRD2 Ins-A2/Del-A1 diplotype might influence better response to risperidone. Some of these early pharmacogenetic studies were criticized for small sample sizes and diagnostic and drug heterogeneity. In addition, the recent data on clozapine's preferential binding in extrastrial (cortical) sites may have implication for future pharmacogenetic studies [15].

Recently, Lencz et al. [16•] have focused on drug-naïve schizophrenia patients to help minimize heterogeneity associated with prior treatment. They studied the effect of DRD2 promoter region polymorphisms (A -241G and -141C Ins/Del) on treatment response among 61 patients experiencing first-episode schizophrenia. The patients were randomly assigned to 16 weeks of treatment with either risperidone or olanzapine. Time to sustained response among carrier of rare- versus wild-type alleles was evaluated using survival analysis. The study revealed that time to response was faster among the G carriers (AG or GG) than the wild-type homozygotes (AA genotype) and slower among the -141C Del carriers (-141C Ins/Del or -141C Del/Del) compared with the wild-type homozygotes (-141C Ins/Ins genotype). This finding suggests that the D2 gene may mediate clinical response to SGAs. Diplotype analysis revealed a similar response pattern, with the slowest response being among Del carriers with no G alleles. Thus, pharmacogenetic investigations should continue to focus on the promoter region of DRD2 to strengthen available evidence [16•].

The serotonin receptor studies

The serotonin receptor genes were also the focus of early pharmacogenetic investigations of clozapine response. The early studies examined the influence of 5-HT2A gene in clozapine response, with a meta-analysis suggesting a clear association between the T102C polymorphism and clozapine response [17].

In a recent naturalistic study of the pharmacogenetics of schizophrenia, Reynolds et al. [18] reported important findings in a cohort of 117 drug-naïve Han Chinese patients who received treatment primarily with risperidone and chlorpromazine for 10 weeks. The study investigated the -759 C/T polymorphism of the serotonin 5-HT2C and antipsychotic drug response and found significant effect on the negative, but not the positive, symptoms scores on the Positive and Negative Syndrome Scale [18].

More recently, Reynolds et al. [19•] also reported a naturalistic study of antipsychotic drug response and 5-HT1A gene among 63 patients with first-episode psychosis. The report indicated that the patients were drug naïve at the initiation of the study, although the initial drug assignment was not specified. However, at 3 months of treatment, patients were taking risperidone (30%), olanzapine (28.6%), quetiapine (15.9%), haloperidol (9.5%), ziprasodone (6.3%), amisulpride (1.5%), and no antipsychotic drugs (7.9%). The genetic analysis showed a significant association between the presence of G allele of the -1019 C/G polymorphism and poor negative symptom efficacy. The study also observed a statistically significant association between genotype and reduction in the reported severity of depression. The strengths of the study included the fact that the patients were drug naïve with no significant comorbid substance abuse histories. Also, the reported association between the functional -1019 C/G polymorphism and negative symptom improvement was independent of baseline scores. However, there is a need for a large sample replication using a prospective random treatment assignment strategy [19•].

Novel targets in the signal transduction pathway

Some recent pharmacogenetic studies in schizophrenia have investigated putative targets of antipsychotic drugs in the signal transduction system. In a pilot study, Bishop et al. [20] found no significant association between the C825T single-nucleotide polymorphism (SNP) of the G-protein beta 3 subunit coupled to the primary targets of antipsychotic medications and response to a fixed-dose treatment with olanzapine (7.5–20 mg) for 2 to 6 weeks [20].

A putative target of antipsychotic drugs is the dopamine receptor interacting protein (DRIP) gene. The DRIP gene is important in regulating dopamine receptor signal transduction. A recent pharmacogenetic study found polymorphisms in NEF3, in the DRIP gene family, to be associated with early response to antipsychotic drugs. Of 22 SNPs in five DRIP-encoding genes that the investigators screened, two in NEF3, (rs 1457266, P = 0.01; rs 1379357, P = 0.006) were associated with treatment response, with a five-SNP haplotype in NEF3 being over-represented in responders compared with nonresponders. The authors speculated that this finding, if replicated, could open up some interesting possibilities in pharmacogenetic research because NEF3 is primarily associated with dopamine D1 receptor [21].

Pharmacokinetic Pharmacogenetic Studies

Recent pharmacokinetic pharmacogenetic studies in schizophrenia have also examined the cytochrome P450 gene family and the genes encoding the blood–brain barrier protein systems.

Cytochrome P450 systems

Genotyping for cytochrome P450 systems could be a simple tool for predicting optimal dosing requirements for antipsychotic drugs. Indeed, the hope of pharmacogenetic-guided therapeutic drug monitoring was strengthened with the recent introduction of the AmpliChip CYP450 Test (Roche, Basel, Switzerland). The AmpliChip Test provides information about cytochrome P450 2D6 and 2C19 [22]. The recent data from Europe [23], Asia [24], and North America suggest that a systematic 2D6 gene test can distinguish the metabolic capacities of psychiatric patients. Because 2D6 metabolizes risperidone, proper identification of poor metabolizers could lower the risk of risperidone-induced adverse events. The FDA has defined cytochrome P450 2D6 as “a valid biomarker,” but the cost effectiveness of routine 2D6 genotyping remains to be fully evaluated [25,26].

Blood–brain and blood–intestine barrier systems

The biology of the genes coding for proteins that import nutrients and export toxic wastes across cell membranes has become a major focus of pharmacogenetic research because variability in the transporters they control can influence differences in drug bioavailability.

Two major families of membrane transporters have been described: the solute carrier (SLC) and the adenosine triphosphate-binding cassette (ABC) transporters.

The SLC transports neurotransmitters, nutrients, heavy metals, and other substrates into the cells. An example of this family of transporters is the serotonin transporter sodium-dependent solute carrier transporter (SLC6A4) encoded on chromosome 17q11 [27]. The short (or deletion) form of SLC6A4 has 44 base pairs of the variable number of tandem repeats polymorphism. The short form of SLC6A4 appears to predict antidepressant drug response, although no consistent association was found in pharmacogenetic studies of antipsychotic drugs [28,29]. Another member of the SLC transporters, the dopamine transporter, may play a role in psychotropic drug response, particularly methyl-phenidate and antidepressants [30].

The ABC transporters translocate a wide variety of substrates, including amino acids, peptides, ions, sugars, toxins, lipids, and drugs. The ABC transporters have been implicated in a number of serious human diseases, including cystic fibrosis and immune system disorders. This family of transporters includes the MsbA in multidrug resistance (MDR1), which pumps xenobiotics from the cells [31]. Tumor cell resistance resulting from an enhanced efflux of structurally unrelated drugs is termed MDR.

An important member of ABC transporters is the P-glycoprotein (ABCB1), which is found in body organs such as the small intestine, kidneys, and brain. The P-glycoprotein is encoded in the MDR1 gene on chromosome 7q21.1 and appears to influence antipsychotic drug concentrations in the CNS by pumping drugs that have entered the brain uphill across the blood–brain barrier and back into plasma [32]. Although prior genetic studies found no effects of ABCB1 on treatment response in schizophrenia, a recent study from China suggests that a favorable response to risperidone may be associated with the TT genotype of C1236T polymorphism, but not the rs13233308, G2677T/A, and C3435T polymorphisms [33]. Yasui-Furukori et al. [34] also conducted a study of acutely ill schizophrenia patients in Japan to examine the C3435T and G 2677T/A polymorphisms. In the study, 31 schizophrenia patients who were genotyped for these two variants received bromperidol for 3 weeks. Blood levels of the drug were monitored and then correlated with five subgrouped symptoms after the period of treatment. The study found an association between the C3435T polymorphism, with treatment response with the TT genotype predicting higher drug concentration in the brain. The G 2677T/A variation was found to be less useful as a predictor of response to bromperidol [34].

In addition, the observed interaction between ABCB1 and cytochrome P450 3A in the energy-dependent export of drugs should be an interesting area for future pharmacogenetics studies [35,36••].

Pharmacogenetics of Antipsychotic Drug-induced Adverse Events

Antipsychotic drug-induced weight gain

It is now well established that genetic and nongenetic mechanisms underlie antipsychotic drug-induced weight gain and metabolic abnormalities. The risk of these serious adverse events appears to be particularly high among patients receiving multiple antipsychotic drugs [37]. The early pharmacogenetic studies in Han Chinese patients treated over a 10-week period suggested that single-nucleotide substitutions in the promoter region of serotonin receptor, type 2C (5-HT2C) could be associated with antipsychotic drug-induced weight gain and metabolic abnormalities [18]. Templeman et al. [38] recently completed a study in Europe that suggested that this finding also might be true for first-episode, drug-naïve Caucasian patients with psychosis who received 9 months of treatment with antipsychotic drugs. The study found that participants with the -795T variation gained less weight than participants without this allele. The same cohort of patients also demonstrated a significant association of the 2548 A/G variation of the leptin gene and weight gain at 9 months, but not at 3 months of the study. The authors suggested that the result of the study implicates leptin in 5-HT2C receptor-related weight gain.

In a pilot study in North America, Bishop et al. [20] found no association between G-protein beta 3 gene and weight gain in patients receiving fixed treatment with olanzapine for a period of 6 weeks. Indeed, a lot of research work still needs to be done to fully elucidate the pharmacogenetics of weight gain in schizophrenia [39].

Antipsychotic drug-induced tardive dyskinesia

Abnormal involuntary movement is associated with treated and untreated schizophrenia, and patients receiving antipsychotic medication should be monitored for extrapyramidal symptoms [4]. Recently, de Leon et al. [36••] studied 516 severely ill patients, 31% of whom were diagnosed with tardive dyskinesia. The study design allowed the investigators to assess the impact of a number of genes on tardive dyskinesia after controlling for clinical variables associated with tardive dyskinesia. The study suggested that the use of information regarding dopamine D2 receptor, MDR1, and glutathione-S-transferase GSTT1 genotypes did not significantly improve model prediction as compared with the use of clinical variables alone. However, information about the ser9Gly variation of dopamine D3 and the glutathione GSTM1 appeared to improve prediction of tardive dyskinesia after controlling for clinical variables [36••].

In a recent study of 282 patients treated with typical antipsychotic medications, Liou et al. [40] investigated genetic variants of endothelial nitric oxide synthase (NOS3), namely the -786T > C in the promoter region, the 27-base pair variable number of tandem repeats in intron 4, and the Glu298Asp in exon 7. The study found no association between the NOS3 gene alleles and genotypes with tardive dyskinesia. However, the haplotype analysis showed a positive signal with tardive dyskinesia that should be re-evaluated with a large sample of patients receiving SGAs consistent with current prescribing patterns [40]. These studies suggest that pharmacogenetics could provide clinicians with an important tool for predicting adverse effects of antipsychotic drugs.

Conclusions

Recent pharmacogenetic studies have investigated the role of polymorphic genes in treatment response and drug-induced adverse events in patients diagnosed with schizophrenia. Studied gene variations in the past year included those influencing pharmacokinetic and pharmacodynamic factors. The progress in the past year supports the promise of individualized drug therapy in schizophrenia using the molecular genetic approach. Also, the studies could help to improve our understanding of the mechanism of action of antipsychotic drugs and ultimately lead to drug discovery. Nonsynonymous SNPs remain the main focus of pharmacogenetic research in schizophrenia. These variations cause amino acid substitutions in polypeptides with potential for functional consequences (functional polymorphisms). The more abundant synonymous SNPs, which do not affect protein sequence, also should be researched with equal vigor because haplotypic variants of these “silent” polymorphisms could have functional roles [41,42].

Current commercial applications of the candidate gene approach have focused on the prediction of adverse effects of psychotropic drugs. For example, a newly developed tool known as PGxPredict:Clozapine (Clinical Data, Inc., New Haven, CT) will allow clinicians to prospectively identify patients at risk for clozapine-induced agranulcytosis. This test is based on a genetic marker, HLA-DQB1, that is overrepresented in patients who developed a white blood cell count (WBC) of less than 500 during clozapine treatment as compared with control patients who were treated with clozapine for at least 1 year without a significant reduction in WBC or absolute neutrophil count (ANC). Clinicians using the PGxPredict:Clozapine test still must monitor the patient's WBC and ANC in line with prescribing guidelines.

Moreover, the development of whole genome association approaches to complex traits may be important in pharmacogenetic studies. Recently, our group [43] and others have utilized microarray platforms that genotype hundreds of thousands of SNPs to detect novel genes for psychiatric illnesses. These approaches may soon be applied to pharmacogenetic phenotypes, although significant issues will remain surrounding the ascertainment of sufficiently large DNA datasets from patients administered the same treatments to enable these comprehensive genomic approaches. Nevertheless, it seems inevitable that these datasets will be collected and will augur in a new generation of genome-wide association studies.

Acknowledgments

Dr. Nnadi has received grant support from Abbott Laboratories. Dr. Malhotra has served as a consultant and speaker for and received grant support from Bristol-Myers Squibb, Pfizer, Inc., Clinical Data, Inc., and AstraZeneca International.

This work was supported by grants from the NIMH, MH 01760 (to Dr. Malhotra), the NCRR/AECOM RR 17672 (to Dr. Nnadi), and the NARSAD (to Dr. Malhotra). The authors wish to thank Patricia Raikos for her logistic support.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as:

• Of importance

•• Of major importance

l.•. Malhotra AK, Murphy GM, Jr, Kennedy JL. Pharmacogenetics of psychotropic drug response. Am J Psychiatry. 2004;161:780–796. [PubMed]This paper provides an overview of current concepts in psychiatric pharmacogenetics.
2. Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2006;15:177–206. [PubMed]
3. Meltzer HY, Davidson M, Glassman AH, Vieweg WV. Assessing cardiovascular risks versus clinical benefits of atypical antipsychotic drug treatment. J Clin Psychiatry. 2002;63 9:25–29. [PubMed]
4. Kane JM. Tardive dyskinesia circa 2006. Am J Psychiatry. 2006;163:1316–1318. [PubMed]
5••. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. [PubMed]The results of Clinical Antipsychotic Trials of Intervention Effectiveness have renewed the debate about the gains and limitations of antipsychotic drug treatment.
6. Kane JM, Freeman HL. Towards more effective antipsychotic treatment. Br J Psychiatry Suppl. 1994;25:22–31. [PubMed]
7. Nnadi CU, Goldberg JF, Malhotra AK. Genetics and psychopharmacology: prospects for individualized treatment. Essent Psychopharmacol. 2005;6:193–208. [PMC free article] [PubMed]
8. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600–610. [PubMed]
9. Athanasiou MC, Malhotra AK, Xu C, Stephens JC. Discovery and utilization of haplotypes for pharmacogenetic studies of psychotropic drug response. Psychiatr Genet. 2002;12:89–96. [PubMed]
10. Lane HY, Lee CC, Liu YC, Chang WH. Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics. Pharmacogenomics. 2005;6:139–149. [PubMed]
11. Yamanouchi Y, Iwata N, Suzuki T, et al. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 2003;3:356–361. [PubMed]
12. Lane HY, Lee CC, Chang YC, et al. Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function. Int J Neuropsychopharmacol. 2004;7:461–470. [PubMed]
13. Schafer M, Rujescu D, Giegling I, et al. Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychiatry. 2001;158:802–804. [PubMed]
14. Arranz MJ, Li T, Munro J, et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics. 1998;8:481–484. [PubMed]
15. Grunder G, Landvogt C, Vernaleken I, et al. The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology. 2006;31:1027–1035. [PubMed]
16•. Lencz T, Robinson DG, Xu K, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163:529–531. [PubMed]This study suggests that pharmacogenetic investigations of drug-naïve schizophrenia patients can help to minimize heterogeneity associated with prior treatment.
17. Arranz MJ, Munro J, Sham P, et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res. 1998;32:93–99. [PubMed]
18. Reynolds GP, Templeman LA, Zhang ZJ. The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1021–1028. [PubMed]
19•. Reynolds GP, Arranz B, Templeman LA, et al. Effect of 5-HT1A receptor gene polymorphism on negative and depressive symptom response to antipsychotic treatment of drug-naive psychotic patients. Am J Psychiatry. 2006;163:1826–1829. [PubMed]Earlier reports have linked treatment response to genetic variation in pharmacodynamic factors related to serotonin system, and this study strengthened this evidence further.
20. Bishop JR, Ellingrod VL, Moline J, Miller D. Pilot study of the G-protein beta3 subunit gene (C825T) polymorphism and clinical response to olanzapine or olanzapine-related weight gain in persons with schizophrenia. Med Sci Monit. 2006;12:BR47–BR50. [PubMed]
21. Strous RD, Greenbaum L, Kanyas K, et al. Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication. Int J Neuropsychopharmacol. 2007;10:321–333. [PubMed]
22. de Leon J, Susce MT, Murray-Carmichael E. The AmpliChip CYP450 genotyping test: integrating a new clinical tool. Mol Diagn Ther. 2006;10:135–151. [PubMed]
23. Rasmussen JO, Christensen M, Svendsen JM, et al. CYP2D6 gene test in psychiatric patients and healthy volunteers. Scand J Clin Lab Invest. 2006;66:129–136. [PubMed]
24. Cho HY, Lee YB. Pharmacokinetics and bioequivalence evaluation of risperidone in healthy male subjects with different CYP2D6 genotypes. Arch Pharm Res. 2006;29:525–533. [PubMed]
25. Nnadi CU, Goldberg JF, Malhotra AK. Pharmacogenetics in mood disorder. Curr Opin Psychiatry. 2005;18:33–39. [PMC free article] [PubMed]
26. van der Weide J, Hinrichs JW. The influence of cytochrome p450 pharmacogenetics on disposition of common antidepressant and antipsychotic medications. Clin Biochem Rev. 2006;27:17–25. [PMC free article] [PubMed]
27. Leabman MK, Huang CC, DeYoung J, et al. Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci U S A. 2003;100:5896–5901. [PMC free article] [PubMed]
28. Tsai SJ, Hong CJ, Yu YW, et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res. 2000;44:177–181. [PubMed]
29. Kaiser R, Tremblay PB, Schmider J, et al. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry. 2001;6:179–185. [PubMed]
30. Kirchheiner J, Nickchen K, Sasse J, et al. A 40-basepair VNTR polymorphism in the dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment. Pharmacogenomics J. 2007;7:48–55. [PubMed]
31. Reyes CL, Ward A, Yu J, Chang G. The structures of MsbA: insight into ABC transporter-mediated multidrug efflux. FEBS Lett. 2006;580:1042–1048. [PubMed]
32. Boulton DW, DeVane CL, Liston HL, Markowitz JS. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 2002;71:163–169. [PubMed]
33. Xing Q, Gao R, Li H, et al. Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. Pharmacogenomics. 2006;7:987–993. [PubMed]
34. Yasui-Furukori N, Saito M, Nakagami T, et al. Association between multidrug resistance 1 (MDR1) gene polymorphisms and therapeutic response to bromperidol in schizophrenic patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:286–291. [PubMed]
35. Christians U, Schmitz V, Haschke M. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol. 2005;1:641–654. [PubMed]
36••. de Leon J, Susce MT, Pan RM, et al. Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness. J Clin Psychopharmacol. 2005;25:448–456. [PubMed]Prediction models containing the conjoint effects of genes and clinical variables could be important features of future pharmacogenetic studies. This approach was well illustrated in this study.
37. Correll CU, Frederickson AM, Kane JM, Manu P. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res. 2007;89:91–100. [PMC free article] [PubMed]
38. Templeman LA, Reynolds GP, Arranz B, San L. Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics. 2005;15:195–200. [PubMed]
39. Correll CU, Malhotra AK. Pharmacogenetics of antipsychotic-induced weight gain. Psychopharmacology (Berl) 2004;174:477–489. [PubMed]
40. Liou YJ, Lai IC, Lin MW, et al. Haplotype analysis of endothelial nitric oxide synthase (NOS3) genetic variants and tardive dyskinesia in patients with schizophrenia. Pharmacogenet Genomics. 2006;16:151–157. [PubMed]
41. Nackley AG, Shabalina SA, Tchivileva IE, et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006;314:1930–1933. [PubMed]
42. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:466–467. [PubMed]
43. Lencz T, Morgan TV, Athanasiou M, et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry. 2007;12:572–580. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...