Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels

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Abstract

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10−5) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STARD) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.

Introduction

The discovery of the protein leptin (Zhang et al., 1994), secreted from adipose tissue to signal the amount of peripheral fat stores to the brain (Schwartz et al., 2000), was a breakthrough for understanding the central regulation of energy metabolism. The human leptin gene (MIM 164160) is located on chromosome 7q31.3 spanning over 15 kb and encodes a 167-amino-acid secreted protein. Deficiency of leptin or its receptor (LEPR) have been described as monogenic causes of severe obesity and pituitary dysfunction (Schwartz et al., 2000, Zhang et al., 1994).

Major depressive disorder (MDD) is characterized by symptoms of depressed mood and anhedonia, but also vegetative symptoms like appetite loss, weight loss, sleep disturbances, and cognitive impairment in different domains (Cohen et al., 2001, Zihl et al., 1998). Consistent with these findings smaller hippocampal volumes have been reported in patients with MDD (Sheline et al., 1996). Impaired hypothalamic glucocorticoid signaling and a dysregulated hypothalamus-pituitary-adrenocortical (HPA) axis are further well established findings in MDD (de Kloet et al., 2005). Recent genome wide association studies regarding antidepressant treatment outcome failed to identify genome wide significant results but confirmed a complex genetic contribution (Garriock et al., 2010, Ising et al., 2009, Uher et al., 2010). Candidate gene studies investigating the outcome following antidepressant treatment have shown associations with specific genotypes (Horstmann and Binder, 2009) in genes involved in HPA-axis or serotonergic system.

Several clinical and epidemiological studies described a comorbidity between MDD and obesity (Luppino et al., 2010), but previous studies on MDD reported inconsistent results concerning plasma leptin levels (Deuschle et al., 1996, Kraus et al., 2002). Associations of leptin levels in the course of antidepressant treatment (Dryden et al., 1999, Kraus et al., 2002) suggest a link between antidepressant action, resolution of psychopathology and regulation of leptin.

Besides its effects upon appetite and weight, leptin influences numerous other central nervous system (CNS) functions like sleep and cognition and has been shown to influence HPA-axis regulation (Flier, 1998, Heiman et al., 1997, Sinton et al., 1999). As systemic and hippocampal administration of leptin in rodents significantly reduced depression-like behavior and influenced hippocampal gene expression, leptin has been suggested to exert antidepressant-like effects (Lu, 2007, Lu et al., 2006).

Pursuing our findings of an impaired response to antidepressants and differentially regulated HPA-axis in overweight and obese patients with MDD (Kloiber et al., 2007), we investigated a possible association of DNA polymorphisms in the leptin gene with the causality of MDD and with response to antidepressant treatment. Recent findings in the large Genome-based Therapeutic Drugs for Depression (GENDEP) study showing an association of a SNP (rs10487506) in the leptin gene and response to tricyclic antidepressants (Uher et al., 2010) encouraged us to substantiate our investigations by additionally analyzing leptin mRNA expression in lymphocytes and leptin serum levels in patients with MDD and in the course of antidepressant treatment. We also tested SNPs in the leptin gene region in a meta-analysis including data from GENDEP and the Sequenced Treatment Alternatives to Relieve Depression (STARD) study.

Section snippets

Exploration sample

338 inpatients participated in the Munich Antidepressant Response Signature (MARS) Project (Binder et al., 2004) from 2000 until 2006. Patients presented with a single or recurrent unipolar depressive episode (85.2%) or a depressive episode in bipolar disorder (14.8%). The details of the study were explained and written informed consent was obtained. Patients were diagnosed by trained psychiatrists according to the DSM-IV criteria (APA, 1994). Depressive disorders due to a medical or

Exploration sample

We detected nominally significant associations with treatment response in 10 SNPs (Supplementary Table 3). Associations with 7 SNPs (rs4731423, rs10487506, rs2278815, rs4731426, rs12706832, rs11763517, and rs3828942) remained significant after correction for multiple testing for the number of SNPs (Supplementary Table 3). The strongest association after correction for multiple testing for the number of SNPs, all phenotypes and genetic models, (p(nominal)=3.9×10−5) was detected for rs10487506

Discussion

Our data suggest an association of polymorphisms in the leptin gene with resistance to antidepressant treatment, the failure to achieve remission, and disturbed cognitive function in depressed patients. Furthermore, we detected decreased leptin serum levels and reduced leptin mRNA expression in patients with impaired treatment response independent of their genotype configuration. These findings probably point towards a connection of leptin deficiency and impaired treatment response to

Role of the funding source

The MARS-Study was funded by the Max Planck Society and in part by a research grant from the German Federal Ministry for Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481) and by the BMBF Program “Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression” (01ES0811). The authors' research on personalized medicine is supported by the Max Planck Excellence Foundation.

The STARD study was

Contributors

Stefan Kloiber has written the first draft of the manuscript. Stefan Kloiber, Stephan Ripke, Benno Pütz, Bertram Müller-Myhsok, Marcus Ising and Daria Salyakina undertook the statistical analysis and wrote parts of the manuscript. Martin A. Kohli, Manfred Uhr, and Thomas Bettecken carried out genotyping and bioinformatic analyses. Elisabeth Binder, Johannes Hennings, Torsten Klengel, and Benno Pütz performed gene expression experiments and statistical analysis of gene expression data. Simone

Conflict of interest

Dr. Perlis has received consulting fees or served on scientific advisory boards for Genomind, Healthrageous, Pamlab, Proteus Biomedical, and RIDVentures. He receives royalties from Concordant Rater Systems (now a Medco subsidiary).

Acknowledgments

We thank S. Damast, S. Sauer, M. Ködel, M. Rex-Haffner, G. Ernst-Jansen, E. Kappelmann and B. Siegel for their excellent technical assistance.

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