Polymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin
Introduction
Olanzapine and clozapine (CLZ) are the atypical antipsychotics (AAPs) with the highest propensity to induce body weight (BW) gain and metabolic dysfunction. A role for leptin (LEP) was suggested (Melkersson et al., 2000), but it was not confirmed either in cross-sectional (Haupt et al., 2005; Peña et al., 2008) or longitudinal studies (Baptista et al., 2007a).
Recent reports have focused on the association between BW gain and the LEP promoter 2548G/A (rs7799039, chromosome 7q31.3) and the leptin receptor (LEPR) Q223R (rs1137101, chromosome 1p31) single nucleotide polymorphisms (SNPs).
Regarding LEP 2548G/A SNPs, positive associations for BW gain were reported for AA (Zhang et al., 2003), G/A (Kang et al., 2008, Zhang et al., 2007 and GG (Templeman et al., 2005). A significant inverse association was found for the GG genotype (Calarge et al., 2009), and negative results were reported by Ellingrod et al., 2007, Gregoor et al., 2009, Ryu et al., 2006. Gregoor et al. (2009) reported that the QR and RR genotypes were associated with a lower risk of obesity in females but not in males during AAP treatment. These studies point to gender, age, and ethnicity among many other intervening variables.
This study was conducted in subjects who, after prolonged CLZ administration, entered a trial to assess the effects of metformin (MET) (Carrizo et al., 2009a, Carrizo et al., 2009b). Clinical (Baptista et al., 2007b, Eriksson et al., 2007, Fruehwald-Schultes et al., 2002, Marciniak et al., 2009, Sivitz et al., 2003) and experimental studies (Li et al., 2005, Kim et al., 2006, Klein et al., 2004, Mick et al., 2000, Mueller et al., 2000) suggest that MET decreases leptin synthesis and serum levels and improves leptin and insulin sensitivity.
We thus evaluated the frequency of the metabolic syndrome and obesity, anthropometric and biochemical variables before and after randomization to MET or placebo. Baseline values and post-treatment changes were compared between the genotypes.
Section snippets
Methods
The study was conducted in CATESFAM, Maracaibo, Venezuela, and was approved by the corresponding ethics committee. All participants signed a voluntary informed consent.
Inclusion criteria were to be under CLZ treatment for 3 or more consecutive months, over 18 years of age, free of hormone replacement therapy and have normal physical and laboratory tests.
Results
The baseline sample consisted of 61 CLZ-treated patients. Five subjects refused DNA analysis in phase 1, and four did not complete phase 2 due to pregnancy (1) and treatment refusal (3). Hence 56 patients completed phase 1 and 52 phase 2.
Discussion
No association was observed between the LEP 2548GALEPR Q223R SNPs and the anthropometric variables either at baseline or after treatment with MET or placebo. Gregoor et al. (2009) underlined the role of gender since the QR and RR genotypes showed less BW gain only in females. By contrast, Zhang et al. (2007) reported more BW gain in males with the GA genotype. Gender contribution was not evaluated in other reports (Zhang et al., 2003, Templeman et al., 2005, Kang et al., 2008, Calarge et al.,
Role of funding source
No intervention in the study accomplishment, results analysis and manuscript preparation.
Contributors
Erika Fernández, Edgardo Carrizo, Virginia Fernandez, Lisette Connell, Ignacio Sandia, Dexy Prieto, Johana Mogollon, Dennys Valbuena, Iliana Fernandez, Enma Araujo de Baptista and Trino Baptista.
Conflict of interest
None.
Acknowledgements
This study was funded by FONACIT, Caracas, Venezuela, grant no. 2005-000-384.
Thanks to Françoise Meyer for her editorial assistance.
References (27)
- et al.
Corrigendum to: Extended release metfomin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study
Schiz. Res.
(2009) - et al.
Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men
Metabolism
(2002) - et al.
Possible association between the − 2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2008) - et al.
Inhibition of leptin secretion by insulin and metformin in cultured rat adipose tissue
Biochim. Biophys. Acta
(2000) - et al.
Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment
Schiz Res.
(2008) - Ausubel, F., Brent, R., Kingston, R., Moore, D., Seidman, J., Smith, J., Struh, l .K., 1989. Preparation of genomic...
- et al.
Similar frequency of abnormal correlation between serum leptin levels and body mass index before and after olanzapine treatment in schizophrenia
Int. Clin. Psychopharmacol.
(2007) - et al.
Insulin counter-regulatory factors, fibrinogen and C-reactive protein during olanzapine administration: effects of the antidiabetic metformin
Int. Clin. Psychopharmacol.
(2007) - et al.
Leptin gene − 2548G/A variants predict risperidone-associated weight gain in children and adolescents
Psychiatr. Genet.
(2009) - et al.
Extended release metfomin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study
Schiz Res.
(2009)
Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia
Psychopharmacol. Bul.
Short-term effects of metformin in type 2 diabetes
Diab. Obes. Metab.
Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication
J. Clin. Psychopharmacol.
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Clozapine safety monitoring and related research in psychiatry and neurology in South America: A scoping review
2023, Schizophrenia ResearchAssociation between the -2548G/A polymorphism of the leptin gene and antipsychotic-induced weight gain: Analysis of the CATIE sample and meta-analysis
2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryA systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia
2016, Schizophrenia ResearchCitation Excerpt :Roffeei et al. (2014) found that the G-allele of LEPR rs1137101 may be associated with MetS in patients taking APs. Similar results were seen in a longitudinal study that investigated the effects of LEP and LEPR polymorphisms on metabolic profiles after prolonged CLZ administration and in response to MET treatment in a mixed Hispanic population from Venezuela (Fernandez et al., 2010). The authors found that in males the G-allele of LEPR rs1137101 was associated with metabolic derangements and that the A/A genotype was protective and also responded better to MET treatment.
Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats
2015, Brain ResearchCitation Excerpt :Moreover, SNPs identified in LEP, 2548 G/A and the leptin receptor gene (LEPR), Q223R were found to be irrelevant to weight gain after long-term clozapine treatment. Interestingly, metformin, an anti-diabetic drug, treatment for 14 weeks resulted in a reduction in triglyceride levels and insulin resistance due to antipsychotic treatment in patients with WT LEPR, while patients with the LEPR SNP did not show any change in these levels (Fernández et al., 2010). Among other serotonin receptor polymorphisms, 5-HT2A 102- C/C and 5-HT6 267- T/T variants were shown to predict lower body weight and also might predict a better treatment response for negative and positive symptoms, respectively (Lane et al., 2006).
Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain
2012, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :A summary of previous studies on rs7799039 is given in Table 1 where the inconsistent results regarding the observed risk alleles are listed in detail: While half of the studies found an association with the G-allele (Ellingrod et al., 2007; Gregoor et al., 2010a; Kang et al., 2008; Templeman et al., 2005; Yevtushenko et al., 2008) and weight gain or increased lipid/glucose measures, the other half of the studies reported significant results with the A-allele (Calarge et al., 2009; Wu et al., 2011; Zhang et al., 2003, 2007). Finally, some studies could not detect association of weight gain with the rs7799039 genotype (Fernandez et al., 2010; Opgen-Rhein et al., 2010; Perez-Iglesias et al., 2010; Ryu et al., 2006). Nonetheless, despite the general small sample sizes, it is unlikely that significant results are solely explained by type I or type II errors.