Eva J. Brandl

Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample.

BACKGROUND Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy. AIM We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP). PATIENTS & METHODS We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests. RESULTS We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs. CONCLUSION The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism.

Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain

BACKGROUND Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individuals risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG. METHODS A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate. RESULTS ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p=.068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G-rs10954173G-rs3828942G (p=.035) and AIWG. The rs7799039 G-allele (p=.042) and G-allele of rs3828942 (p=.032) were associated with higher weight gain. CONCLUSION Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin-melanocortin pathway.

Pharmacogenetics of Antipsychotics

Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods: We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion: First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings.

Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: Update and report from a pharmacogenetic service clinic

Abstract Genetic testing may help to improve treatment outcomes in order to avoid non-response or severe side effects to psychotropic medication. Most robust data have been obtained for gene variants in CYP2D6 and CYP2C19 enzymes for antipsychotics and antidepressant treatment. We reviewed original articles indexed in PubMed from 2008–2013 on CYP2D6 and CYP2C19 gene variants and treatment outcome to antidepressant or antipsychotic medication. We have started providing CYP2D6 and CYP2C19 genotype information to physicians and conducted a survey where preliminary results are reported. Studies provided mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Plasma levels were mostly found associated with CYP metabolizer status. Higher occurrence/severity of side effects were reported in non-extensive CYP2D6 or CYP2C19 metabolizers. Results showed that providing genotypic information is feasible and generally well accepted by both patients and physicians. Although currently available studies are limited by small sample sizes and infrequent plasma drug level assessment, research to date indicates that CYP2D6 and CYP2C19 testing may be beneficial particularly for non-extensive metabolizing patients. In summary, clinical assessment of CYP2D6 and CYP2C19 metabolizer status is feasible, well accepted and optimizes drug treatment in psychiatry.

Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients.

Abstract Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG. We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates. In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (Pcorrected = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (Pcorrected = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (Pcorrected = 0.011). Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.

Pharmacogenetics of obsessive–compulsive disorders

Genetic factors have been shown to influence occurrence and severity of several psychiatric disorders and also to modulate outcome to drug treatment. Obsessive-compulsive disorder (OCD) is a severe psychiatric condition with clear genetic roots; there is also some evidence to suggest that genetic factors may impact on response to drug treatment. Typically between 40 and 60% of patients are deemed nonresponders to antidepressant medication and clinical factors have only been modestly correlated with treatment response. Thus, identification of biological factors which may relate to treatment response could be extremely valuable in improving clinical outcome. In this article, we briefly review previous work regarding clinical and demographical factors associated with drug response in OCD, then focus on recent findings regarding candidate genes which may influence drug response, including those in the serotonin system, brain-derived neurotrophic factor and the glutamate transporter gene. The cytochrome system may also be highly relevant to drug response. Thus far, relatively few studies regarding the pharmacogenetics of OCD have been published, and therefore further investigation with functional analyses and consideration of environmental factors are warranted to facilitate clinical use of pharmacogenetic findings in the future.

Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder

Numerous studies have reported on pharmacogenetics of antidepressant response in depression. In contrast, little is known of response predictors in obsessive-compulsive disorder (OCD), a disorder with among the lowest proportion of responders to medication (40–60%). Our study is the largest investigation to date (N=184) of treatment response and side effects to antidepressants in OCD based on metabolizer status for CYP2D6 and CYP2C19. We observed significantly more failed medication trials in CYP2D6 non-extensive compared with extensive metabolizers (P=0.007). CYP2D6 metabolizer status was associated with side effects to venlafaxine (P=0.022). There were nonsignificant trends for association of CYP2D6 metabolizer status with response to fluoxetine (P=0.056) and of CYP2C19 metabolizer status with response to sertraline (P=0.064). Our study is the first to indicate that CYP genes may have a role in antidepressant response in OCD. More research is required for a future clinical application of genetic testing, which could lead to improved treatment outcomes.

A Hypothesis-Driven Association Study of 28 Nuclear-Encoded Mitochondrial Genes with Antipsychotic-Induced Weight Gain in Schizophrenia

Mitochondria are the main source of energy for neurons and have a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mitochondrial genes, particularly those involved in oxidative phosphorylation or involved in oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis, would be associated with antipsychotic-induced weight gain (AIWG). In total, we selected 28 genes and analyzed 60 SNPs (50 are functional), in 283 schizophrenia subjects, treated with atypical medications for up to 14 weeks. Association between AIWG (as measured by the % of weight gain from baseline) and SNP genotypes were tested using linear regression with treatment duration, baseline body weight, and medication type as covariates. We observed a significant association between rs6435326 in the NDUFS1 gene and AIWG in the subset of European patients (N=150, Pcorrected=0.02). The haplotype carrying the risk alleles of rs6435326 and two other SNPs (rs1053517 and rs1801318) in NDUFS1 was also nominally associated with percentage of weight gain (T-C-G vs A-T-A, P=0.005). In addition, stepwise linear regression was performed to select important variables predictive of the outcome, and a gene–gene interaction analysis was carried out. We observed a significant interaction between the TT risk genotype of rs6435326 in NDUFS1 and AG genotype of rs3762883 in COX18 (Pcorrected=0.001). A permutation-based test of all 60 SNPs jointly showed significant association with weight gain (P=0.02). Finally, our replication study of rs6435326, rs1053517 and rs1801318 in NDUFS1 using samples from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that rs1801318 was significantly associated with AIWG (N=200, Pcorrected=0.04), and the three SNPs were collectively associated with AIWG (P=0.04). In conclusion, our findings suggest an association between NDUFS1 and AIWG in schizophrenia subjects. To the best of our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG.

The AmpliChip® CYP450 Test and Response to Treatment in Schizophrenia and Obsessive Compulsive Disorder: A Pilot Study and Focus on Cases with Abnormal CYP2D6 Drug Metabolism

AIM Genetic factors can result in variance in drug metabolism enzyme function, which is one major mechanism impacting on interindividual variability in response and side effects. We therefore performed a pilot study to investigate genetic variants in the drug metabolizing enzymes CYP2D6 and CYP2C19. METHODS We evaluated 35 schizophrenic and 39 obsessive compulsive disorder (OCD) patients treated with various antipsychotics and antidepressants. Patients were assessed for treatment response and side effects. Genotyping for CYP2D6 and CYP2C19 was performed using the AmpliChip(®). Statistical analysis was performed using analysis of variance and Fishers exact test. Cases of poor metabolizers (PMs) or ultrarapid metabolizers (UMs) were examined in further detail to assess medication outcomes. RESULTS Statistical analysis identified no overall significant association of CYP2D6 metabolizer status with treatment response or occurrence of side effects. Nonetheless, case reports of PM and UM individuals indicated lack of response and/or occurrence of side effects in most of these patients. A secondary analysis comparing OCD subjects with impaired 2D6 function to extensive metabolizers was significant (p=0.021). CONCLUSION Although not conclusive, there was some association between CYP2D6 impaired metabolic status and medication response. Our case reports suggest a potential clinical benefit of CYP genotyping for specific patients. Further validation of CYP2D6 and CYP2C19 testing in prospective, randomized trials is warranted.

Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. Numerous single nucleotide polymorphisms have been studied for association with antipsychotic-induced weight gain in an attempt to find genetic predictors of this side effect. An ability to predict this side effect could lead to personalized treatment plans for predisposed individuals, which could significantly decrease the prevalence and severity of weight gain. Variations in the serotonin receptor 2c gene (HTR2C) have emerged as promising candidates for prediction of antipsychotic-induced weight gain. Specifically, the well-studied −759C/T promoter polymorphism has been associated with weight gain in diverse populations, although some studies have reported no association. This discrepancy is likely due to heterogeneity in study design with respect to ethnicity, treatment duration, and other variables. Notably, the association between HTR2C and antipsychotic-induced weight gain appears strongest in short-term studies on patients with limited or no previous antipsychotic treatment. Other, less extensively studied promoter polymorphisms (−697C/G, −997G/A, and −1165A/G) have also emerged as potential predictors of antipsychotic-induced weight gain. Conversely, the well-studied intronic polymorphism Cys23Ser does not appear to be associated. With further research on both HTR2C and other genetic and environmental predictors of antipsychotic-induced weight gain, a predictive test could one day be created to screen patients and provide preventative or alternative treatment for those who are predisposed to this serious side effect.