Fat Mass and Obesity-Related Gene Variants rs9939609 and rs7185735 are Associated with Second-Generation Antipsychotic-Induced Weight Gain.

INTRODUCTION: Weight gain is a limiting and frequent adverse effect of second-generation antipsychotic therapy. Identifying genetic risk factors would significantly improve pharmacotherapy. METHODS: We focused on rs7185735 and rs9939609, 2 common single nucleotide polymorphisms of the fat mass and obesity-associated (FTO) gene reported to be associated with obesity. Three-hundred fifty Caucasian inpatients were included in a naturalistic study. RESULTS: After 4 weeks of treatment, we did not observe any significant association of polymorphisms with weight change in the whole study population (p>0.05). In a subpopulation without additional weight-inducing comedication (n=178), G-allele carriers of rs7185735 gained 3.4 times more weight (1.69 kg±3.1 kg, p=0.019) than AA genotypes (0.49 kg±3.1 kg). A-allele carriers of rs9939609 gained 3.1 times more weight (1.65 kg±3.1 kg, p=0.029) than TT genotypes (0.54 kg±3.2 kg). DISCUSSION: Our findings confirm the role of the FTO gene as a high-potential risk factor for obesity and indicate a value for predicting a weight gain induced by second-generation antipsychotics. Further, we detected an additive effect of FTO rs7185735 and MC4R rs17782313.

CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations.

BACKGROUND: Although several polymorphisms in olanzapine-metabolizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in the UGT1A4 gene (*3), and in the POR gene (rs2302429) on olanzapine serum concentrations and the clinical outcome. METHODS: Ninety-eight white inpatients who received olanzapine as part of their treatment for at least 4 weeks were included in the retrospective investigation. Moreover, a sample of 209 inpatients receiving olanzapine or clozapine was built to investigate the influence of the relevant polymorphisms CYP1A2*1F, *1D, and CYP1A2 inducers on the clinical outcome. RESULTS: Carriers of the delT-allele (*1D) developed significantly higher dose-corrected olanzapine serum concentrations (analysis of covariance; P < 0.001, delT + delTdelT: 3.1, TT: 1.6 ng·mL·mg, adjusted model including the confounding factors age, sex, baseline weight, CYP1A2*1F genotype, and concomitant CYP1A2 inducers). Moreover, the CYP1A2*1F (AA) genotype also revealed a significant impact on olanzapine serum concentrations according to the analysis of covariance model (P = 0.028; CC + CA: 2.05, AA: 1.44 ng·mL·mg). The other polymorphisms studied revealed no significant influence. Regarding response and adverse effects, a higher increase of weight could be observed in schizophrenic Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005). CONCLUSIONS: We, for the first time, identified a significant influence of polymorphisms in CYP1A2 in combination with CYP1A2 inducer status on the clinical outcome. Therefore, genotyping for CYP1A2*1D and *1F may be a useful tool for dose optimization and identification of high-risk patients. Further and larger studies are needed before genotype-based dosage recommendations can help patients treated with CYP1A2 metabolized drugs.

MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain?

Weight gain is a therapy limiting and very frequent adverse effect of many second-generation antipsychotic (SGA) drugs. The human melanocortin four receptor (MC4R) is a very promising candidate gene possibly influencing SGA-related weight gain. The rs489693 polymorphism near the MC4R gene was associated with SGA-related weight gain in a genome-wide association study. We tried to replicate these results in our independent naturalistic study population. From 341 Caucasian inpatients receiving at least one SGA drug (olanzapine, clozapine, risperidone, paliperidone, quetiapine or amisulpride), carriers homozygous for the rs489693 A-allele (n = 35) showed a 2.2 times higher weight increase (+2.2 kg) than carriers of the CC-genotype (+1 kg) after 4 wk of treatment (analysis of covariance, p = 0.039). We revealed an even stronger effect in a subpopulation without weight gain inducing co-medication (factor 3.1, +2.8 kg, p = 0.044, (n = 16 of 169)) and in first episode patients (factor 2.7, +2.7 kg, p = 0.017, (n = 13 of 86)). Our results confirm the rs489693 A-allele as a possible risk factor for SGA-related weight gain.

Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain.

Weight gain is a frequent adverse effect of many second-generation antipsychotic (SGA) drugs. Although a number of candidate gene studies have focused on SGA-related weight gain, a clinical benefit for pharmacotherapy has not been achieved as yet. Genome-wide association studies offer great potential of identifying novel candidate genes and help to complete the search for relevant polygenetic risk factors. A polymorphism near the human melanocortin 4 receptor gene (MC4R) was associated with overweight and body mass index in recent studies. Owing to the central role of the MC4R receptor in energy homeostasis, we investigated the influence of the rs17782313 polymorphism on SGA-related weight gain. Three hundred forty-five white inpatients receiving different atypical antipsychotics (clozapine, olanzapine, risperidone, paliperidone, quetiapine, or amisulpride) were included in a naturalistic design. After 4 weeks of treatment, patients homozygous for the rs17782313 C-allele had a significantly higher risk of weight gain and body mass index increase, with a dose effect of the C-allele. In a subpopulation without additional weight gain-inducing comedication, the 106 TT-allele carriers gained on average 1.09% of their baseline weight within the 4 weeks of treatment, whereas the 57 CT-allele carriers and the 9 CC-allele carriers gained 3.28% and 5.47% (P = 0.003). Our findings indicate that the rs17782313 polymorphism could increase the amount of SGA-related weight gain and may influence MC4R expression, which could result in an imbalance of energy homeostasis. Nevertheless, further studies are needed to elucidate the role and mechanism of this polymorphism.