Consent in psychiatric biobanks for pharmacogenetic research.

In psychiatric practice, pharmacogenetics has the potential to identify patients with an increased risk of unsatisfactory drug responses. Genotype-guided treatment adjustments may increase benefits and reduce harm in these patients; however, pharmacogenetic testing is not (yet) common practice and more pharmacogenetic research in psychiatric patients is warranted. An important precondition for this type of research is the establishment of biobanks. In this paper, we argue that, for the storage of samples in psychiatric biobanks, waiving of consent is not ethically justifiable since the risks cannot be considered minimal and the argument of impracticability does not apply. An opt-out consent procedure is also not justifiable, since it presumes competence while the decisional competence of psychiatric patients needs to be carefully evaluated. We state that an enhanced opt-in consent procedure is ethically necessary, i.e. a procedure that supports the patients' decision-making at the time when the patient is most competent. Nevertheless, such a procedure is not the traditional exhaustive informed consent procedure, since this is not feasible in the case of biobanking.

The association between CYP2D6 genotype and switching antipsychotic medication to clozapine.

PURPOSE: Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics. METHODS: CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics. RESULTS: A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively). CONCLUSIONS: Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes.

Combined HTR2C-LEP genotype as a determinant of obesity in patients using antipsychotic medication.

Obesity is one of the most serious common somatic adverse effects of atypical antipsychotic agents. Genetic factors partly determine the individual patients risk of developing obesity during treatment. As weight-regulating mechanisms, such as the leptinergic and serotonergic system, may be interdependent, genetic polymorphisms in these systems also may show interactions. To determine whether combined HTR2CLEP genotype or HTR2C-LEPR genotype are associated with obesity in patients using atypical antipsychotic drugs, a cross-sectional study design was used. The study population included 200 patients aged between 18 and 65 years of age, diagnosed with a psychotic disorder, all of whom had been using an atypical antipsychotic for at least 3 months. Primary outcome measure was presence of obesity (body mass index, >30). Determinants were the combined (HTR2C -759C/T-LEPR Q223R), (HTR2C -759C/T-LEP -2548G/A, (HTR2C rs1414334-LEPR Q223R) and (HTR2C rs1414334-LEP -2548G/A) genotypes. Of the 200 included patients, 61 (31%) were obese. In patients without the HTR2C -759T allele, presence of the LEP -2548G allele was associated with obesity (odds ratio, 2.88; 95% confidence interval, 1.05-7.95). The results of the other analyses showed some nonsignificant trends. The combined (HTR2C -759C/TYLEP -2548G/A) genotype may be a determinant of obesity in patients during treatment with atypical antipsychotic drugs.

Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication.

Weight gain is one of the most serious adverse effects of atypical antipsychotic agents. Genetic factors influence the risk of an individual to gain weight. The objective of our study was to determine whether the LEPR Q223R polymorphism and the LEP promoter 2548G/A polymorphism are associated with obesity in a group of male and female patients using atypical antipsychotic drugs. A cross-sectional study design was used. The study population consisted of 200 patients aged between 18 and 65 years, diagnosed with a psychotic disorder, all of whom had been using an atypical antipsychotic for at least 3 months. The primary outcome measure was the presence of obesity. Determinants were the LEPR Q223R (rs1137101) polymorphism and the LEP promoter 2548G/A single nucleotide polymorphism ([SNP] rs7799039). Of the 200 included patients, 61 (31%) were obese. In females, the LEPR 223QR (adjusted odds ratio, 0.11; 95% confidence interval [CI], 0.02-0.54) and LEPR 223RR (adjusted odds ratio, 0.07; 95% CI, 0.01-0.63) genotypes were associated with a lower risk of obesity. In males, this association was not found. In females, the average body weight was 13.6 kg more (95% CI, 1.11-26.1) in the LEPR 223QQ group compared with the LEPR 223RR group. No significant association was found between the LEP promoter 2548G/A polymorphism and obesity. Taken together, the results of our study show that the LEPR Q223R polymorphism may be associated with obesity in women with a psychotic disorder treated with atypical antipsychotic drugs and stress the importance of stratification for gender when investigating the role of variations of the LEP- and LEPR genes on the metabolic side effects of antipsychotic medications.

Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting.

UNLABELLED: Weight gain is a frequently occurring serious somatic adverse effect of atypical antipsychotic agents. Genetic factors influence the risk of an individual to gain weight. OBJECTIVES: To determine whether LEPR Q223R, LEP -2548G/A and HTR2C -759C/T polymorphisms are associated with obesity and weight change in patients using atypical antipsychotic drugs. METHODS: A longitudinal study design was used in a naturalistic setting. The study population included 141 patients, all of whom were using an atypical antipsychotic drug. The body mass index was measured twice. Primary outcome measures were obesity at the moment of first measurement and body mass index change during treatment. Determinants were the LEPR Q223R (rs1137101), the LEP -2548G/A SNP (rs7799039) and the HTR2C -759C/T (rs3813929) polymorphisms. RESULTS: Of the 141 included patients, 35 (24.8%) were obese. In females, presence of the LEPR 223R allele was associated with an increased risk of obesity (47.6 vs 17.6%; p = 0.03). In males this association was not found. None of the SNPs were significantly associated with weight change during treatment. CONCLUSIONS: The LEPR Q223R polymorphism may be a risk factor for obesity in women with a psychotic disorder treated with atypical antipsychotic drugs. This is in line with earlier findings of our group.

Association between LEP and LEPR gene polymorphisms and dyslipidemia in patients using atypical antipsychotic medication.

BACKGROUND: Treatment with atypical antipsychotic agents is often complicated by dyslipidemia, which is a risk factor for cardiovascular disease. OBJECTIVES: To determine whether the LEPR Q223R, the LEP -2548G/A, and the HTR2C -759C/T polymorphisms are associated with dyslipidemia in patients using atypical antipsychotic drugs. METHODS: A cross-sectional study design was used. The study population included all patients who had been screened for dyslipidemia between January 2008 and March 2009 and had been using an atypical antipsychotic for at least 3 months at the moment of screening. Primary outcome measure was the mean total cholesterol (TC)/HDL ratio. Determinants were the LEPR Q223R (rs1137101), the LEP -2548G/A SNP (rs7799039), and the HTR2C -759C/T (rs3813929) polymorphisms. RESULTS: A total of 353 patients was included in the study, of which 184 (52.1%) were men and 169 (47.9%) were women. Overall, no significant differences were found between the different genotype groups. However, in patients with a first admission to the hospital less than a year ago, the LEP -2548G allele had a lower mean TC/HDL ratio compared with patients without the LEP -2548G allele (6.41 vs. 4.12, P-adj: 0.017) and patients with the LEPR 223R allele had a lower mean TC/HDL ratio compared with patients without the LEPR 223R allele (5.04 vs. 3.92, P-adj: 0.019). The association between the LEP -2548G/A allele and the TC/HDL ratio in recent patients was present only in men. CONCLUSION: Genetic variation in the LEP and LEPR gene may be associated with short-term dyslipidemia in patients using atypical antipsychotic agents.