Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels
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 (STAR⁎D) 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 STAR⁎D 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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