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

Stefan Kloiber; Stephan Ripke; Martin A. Kohli; Simone Reppermund; Daria Salyakina; Rudolf Uher; Peter McGuffin; Roy H. Perlis; Steven P. Hamilton; Benno Pütz; Johannes Hennings; Tanja Brückl; Torsten Klengel; Thomas Bettecken; Marcus Ising; Manfred Uhr; Tatjana Dose; Paul G. Unschuld; Josef Zihl; Elisabeth Binder; Bertram Müller-Myhsok; Florian Holsboer; Susanne Lucae

doi:10.1016/j.euroneuro.2012.08.010

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

Stefan Kloiber, Stephan Ripke, Martin A. Kohli, Simone Reppermund, Daria Salyakina, Rudolf Uher, Peter McGuffin, Roy H. Perlis, Steven P. Hamilton, Benno Pütz, Johannes Hennings, Tanja Brückl, Torsten Klengel, Thomas Bettecken, Marcus Ising, Manfred Uhr, Tatjana Dose, Paul G. Unschuld, Josef Zihl, Elisabeth BinderBertram Müller-Myhsok, Florian Holsboer, Susanne Lucae

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35 Citas (Scopus)

Resumen

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 (STAR^*D) 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.

Idioma original	English
Páginas (desde-hasta)	653-662
Número de páginas	10
Publicación	European Neuropsychopharmacology
Volumen	23
N.º	7
DOI	https://doi.org/10.1016/j.euroneuro.2012.08.010
Estado	Published - jul. 2013
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
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.

Funding Information:
The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428), the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and South London, and the Maudsley National Health Service Foundation Trust (National Institute for Health Research, United Kingdom) and the Medical Research Council, United Kingdom (G0701420).

Funding Information:
The STAR ⁎ D study was supported by funds from NIMH under contract N01 MH-90003 to the University of Texas Southwestern Medical Center at Dallas (A. John Rush, M.D., P.I.). Genotyping of STAR ⁎ D samples was funded by NIMH (R01 MH-072802; Steven P. Hamilton, M.D., Ph.D., P.I.).

ASJC Scopus Subject Areas

Pharmacology
Neurology
Clinical Neurology
Psychiatry and Mental health
Biological Psychiatry
Pharmacology (medical)

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Kloiber, S., Ripke, S., Kohli, M. A., Reppermund, S., Salyakina, D., Uher, R., McGuffin, P., Perlis, R. H., Hamilton, S. P., Pütz, B., Hennings, J., Brückl, T., Klengel, T., Bettecken, T., Ising, M., Uhr, M., Dose, T., Unschuld, P. G., Zihl, J., ... Lucae, S. (2013). Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels. European Neuropsychopharmacology, 23(7), 653-662. https://doi.org/10.1016/j.euroneuro.2012.08.010

Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels. / Kloiber, Stefan; Ripke, Stephan; Kohli, Martin A. et al.
En: European Neuropsychopharmacology, Vol. 23, N.º 7, 07.2013, p. 653-662.

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

Kloiber, S, Ripke, S, Kohli, MA, Reppermund, S, Salyakina, D, Uher, R, McGuffin, P, Perlis, RH, Hamilton, SP, Pütz, B, Hennings, J, Brückl, T, Klengel, T, Bettecken, T, Ising, M, Uhr, M, Dose, T, Unschuld, PG, Zihl, J, Binder, E, Müller-Myhsok, B, Holsboer, F & Lucae, S 2013, 'Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels', European Neuropsychopharmacology, vol. 23, n.º 7, pp. 653-662. https://doi.org/10.1016/j.euroneuro.2012.08.010

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

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 (STAR*D) 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.",

author = "Stefan Kloiber and Stephan Ripke and Kohli, {Martin A.} and Simone Reppermund and Daria Salyakina and Rudolf Uher and Peter McGuffin and Perlis, {Roy H.} and Hamilton, {Steven P.} and Benno P{\"u}tz and Johannes Hennings and Tanja Br{\"u}ckl and Torsten Klengel and Thomas Bettecken and Marcus Ising and Manfred Uhr and Tatjana Dose and Unschuld, {Paul G.} and Josef Zihl and Elisabeth Binder and Bertram M{\"u}ller-Myhsok and Florian Holsboer and Susanne Lucae",

note = "Funding Information: 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. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428), the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and South London, and the Maudsley National Health Service Foundation Trust (National Institute for Health Research, United Kingdom) and the Medical Research Council, United Kingdom (G0701420). Funding Information: The STAR ⁎ D study was supported by funds from NIMH under contract N01 MH-90003 to the University of Texas Southwestern Medical Center at Dallas (A. John Rush, M.D., P.I.). Genotyping of STAR ⁎ D samples was funded by NIMH (R01 MH-072802; Steven P. Hamilton, M.D., Ph.D., P.I.). ",

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AU - Ripke, Stephan

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AU - Reppermund, Simone

AU - Salyakina, Daria

AU - Uher, Rudolf

AU - McGuffin, Peter

AU - Perlis, Roy H.

AU - Hamilton, Steven P.

AU - Pütz, Benno

AU - Hennings, Johannes

AU - Brückl, Tanja

AU - Klengel, Torsten

AU - Bettecken, Thomas

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AU - Dose, Tatjana

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AU - Binder, Elisabeth

AU - Müller-Myhsok, Bertram

AU - Holsboer, Florian

AU - Lucae, Susanne

N1 - Funding Information: 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. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428), the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and South London, and the Maudsley National Health Service Foundation Trust (National Institute for Health Research, United Kingdom) and the Medical Research Council, United Kingdom (G0701420). Funding Information: The STAR ⁎ D study was supported by funds from NIMH under contract N01 MH-90003 to the University of Texas Southwestern Medical Center at Dallas (A. John Rush, M.D., P.I.). Genotyping of STAR ⁎ D samples was funded by NIMH (R01 MH-072802; Steven P. Hamilton, M.D., Ph.D., P.I.).

PY - 2013/7

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N2 - 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 (STAR*D) 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.

AB - 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 (STAR*D) 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.

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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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