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 geneti...
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| Veröffentlicht in: | European neuropsychopharmacology 2013-07, Vol.23 (7), p.653-662 |
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| creator | Kloiber, Stefan Ripke, Stephan Kohli, Martin A Reppermund, Simone Salyakina, Daria Uher, Rudolf McGuffin, Peter Perlis, Roy H Hamilton, Steven P Pütz, Benno Hennings, Johannes Brückl, Tanja Klengel, Torsten Bettecken, Thomas Ising, Marcus Uhr, Manfred Dose, Tatjana Unschuld, Paul G Zihl, Josef Binder, Elisabeth Müller-Myhsok, Bertram Holsboer, Florian Lucae, Susanne |
| description | 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. |
| doi_str_mv | 10.1016/j.euroneuro.2012.08.010 |
| format | Article |
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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.</description><identifier>ISSN: 0924-977X</identifier><identifier>EISSN: 1873-7862</identifier><identifier>DOI: 10.1016/j.euroneuro.2012.08.010</identifier><identifier>PMID: 23026132</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antidepressive Agents - therapeutic use ; Cognition - drug effects ; Databases, Genetic ; Depression ; Depression - blood ; Depression - drug therapy ; Depression - genetics ; Depression - psychology ; Drug Resistance - genetics ; Female ; Gene expression ; Gene Expression - drug effects ; Humans ; Internal Medicine ; Leptin ; Leptin - biosynthesis ; Leptin - blood ; Leptin - genetics ; Male ; Middle Aged ; Pharmacogenetics ; Polymorphism, Single Nucleotide - genetics ; Psychiatry ; RNA, Messenger - analysis ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Treatment Outcome ; Treatment response</subject><ispartof>European neuropsychopharmacology, 2013-07, Vol.23 (7), p.653-662</ispartof><rights>Elsevier B.V. and ECNP</rights><rights>2012 Elsevier B.V. and ECNP</rights><rights>Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.</rights><rights>2012 Elsevier B.V. and ECNP. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-3ced9ff9d355dae70f9b6f960d0e5caca1d6dac49cacbb2630834a1adb94211a3</citedby><cites>FETCH-LOGICAL-c596t-3ced9ff9d355dae70f9b6f960d0e5caca1d6dac49cacbb2630834a1adb94211a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.euroneuro.2012.08.010$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23026132$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kloiber, Stefan</creatorcontrib><creatorcontrib>Ripke, Stephan</creatorcontrib><creatorcontrib>Kohli, Martin A</creatorcontrib><creatorcontrib>Reppermund, Simone</creatorcontrib><creatorcontrib>Salyakina, Daria</creatorcontrib><creatorcontrib>Uher, Rudolf</creatorcontrib><creatorcontrib>McGuffin, Peter</creatorcontrib><creatorcontrib>Perlis, Roy H</creatorcontrib><creatorcontrib>Hamilton, Steven P</creatorcontrib><creatorcontrib>Pütz, Benno</creatorcontrib><creatorcontrib>Hennings, Johannes</creatorcontrib><creatorcontrib>Brückl, Tanja</creatorcontrib><creatorcontrib>Klengel, Torsten</creatorcontrib><creatorcontrib>Bettecken, Thomas</creatorcontrib><creatorcontrib>Ising, Marcus</creatorcontrib><creatorcontrib>Uhr, Manfred</creatorcontrib><creatorcontrib>Dose, Tatjana</creatorcontrib><creatorcontrib>Unschuld, Paul G</creatorcontrib><creatorcontrib>Zihl, Josef</creatorcontrib><creatorcontrib>Binder, Elisabeth</creatorcontrib><creatorcontrib>Müller-Myhsok, Bertram</creatorcontrib><creatorcontrib>Holsboer, Florian</creatorcontrib><creatorcontrib>Lucae, Susanne</creatorcontrib><title>Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels</title><title>European neuropsychopharmacology</title><addtitle>Eur Neuropsychopharmacol</addtitle><description>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.</description><subject>Antidepressive Agents - therapeutic use</subject><subject>Cognition - drug effects</subject><subject>Databases, Genetic</subject><subject>Depression</subject><subject>Depression - blood</subject><subject>Depression - drug therapy</subject><subject>Depression - genetics</subject><subject>Depression - psychology</subject><subject>Drug Resistance - genetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Leptin</subject><subject>Leptin - biosynthesis</subject><subject>Leptin - blood</subject><subject>Leptin - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pharmacogenetics</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Psychiatry</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Treatment Outcome</subject><subject>Treatment response</subject><issn>0924-977X</issn><issn>1873-7862</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUsuOEzEQtBCIzQZ-AebIYRP8mJcvK0UrWJBWIC0gcbMcu2fjMDMe3J5AvoZfxUNCxOMAF7ttV1W7u4uQp4wuGWXl8-0SxuD7aVlyyviS1kvK6D0yY3UlFlVd8vtkRiXPF7KqPp6Rc8QtpawQQj4kZ1xQXjLBZ-TbLaDDqHsDWfSZ7qOzMARATGEWA-jYQYocZhrRG6cj2OyLi5ts8O2-82HYOOwwc30WN5C1MMQU3kEPF5kFkwQwEY7X3e2bVQZff-g731-kfPZvFEIYu3TYQYuPyINGtwiPj_ucfHj54v3Vq8XN2-vXV6ubhSlkGRfCgJVNI60oCquhoo1cl40sqaVQGG00s6XVJpcpXq95KWgtcs20XcucM6bFnFwedIdx3YE1qeagWzUE1-mwV1479ftL7zbqzu9UzjkrUy_n5NlRIPjPI2BUnUMDbat78CMqVnAqJM3z_N_QnFdpmKKqE7Q6QE3wiAGa048YVZMT1FadnKAmJyhaq4k8J09-LejE-zn6BFgdAKnLsHMQFBoHyQfWBTBRWe_-I8nlHxqmdb0zuv0Ee8CtH0OfpqaYwsRR7yZDTn5knFLOayG-A8Ag5Qo</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Kloiber, Stefan</creator><creator>Ripke, Stephan</creator><creator>Kohli, Martin A</creator><creator>Reppermund, Simone</creator><creator>Salyakina, Daria</creator><creator>Uher, Rudolf</creator><creator>McGuffin, Peter</creator><creator>Perlis, Roy H</creator><creator>Hamilton, Steven P</creator><creator>Pütz, Benno</creator><creator>Hennings, Johannes</creator><creator>Brückl, Tanja</creator><creator>Klengel, Torsten</creator><creator>Bettecken, Thomas</creator><creator>Ising, Marcus</creator><creator>Uhr, Manfred</creator><creator>Dose, Tatjana</creator><creator>Unschuld, Paul G</creator><creator>Zihl, Josef</creator><creator>Binder, Elisabeth</creator><creator>Müller-Myhsok, Bertram</creator><creator>Holsboer, Florian</creator><creator>Lucae, Susanne</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>5PM</scope></search><sort><creationdate>20130701</creationdate><title>Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels</title><author>Kloiber, Stefan ; Ripke, Stephan ; Kohli, Martin A ; Reppermund, Simone ; Salyakina, Daria ; Uher, Rudolf ; McGuffin, Peter ; Perlis, Roy H ; Hamilton, Steven P ; Pütz, Benno ; Hennings, Johannes ; Brückl, Tanja ; Klengel, Torsten ; Bettecken, Thomas ; Ising, Marcus ; Uhr, Manfred ; Dose, Tatjana ; Unschuld, Paul G ; Zihl, Josef ; Binder, Elisabeth ; Müller-Myhsok, Bertram ; Holsboer, Florian ; Lucae, Susanne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c596t-3ced9ff9d355dae70f9b6f960d0e5caca1d6dac49cacbb2630834a1adb94211a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antidepressive Agents - therapeutic use</topic><topic>Cognition - drug effects</topic><topic>Databases, Genetic</topic><topic>Depression</topic><topic>Depression - blood</topic><topic>Depression - drug therapy</topic><topic>Depression - genetics</topic><topic>Depression - psychology</topic><topic>Drug Resistance - genetics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Leptin</topic><topic>Leptin - biosynthesis</topic><topic>Leptin - blood</topic><topic>Leptin - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pharmacogenetics</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Psychiatry</topic><topic>RNA, Messenger - analysis</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Treatment Outcome</topic><topic>Treatment response</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kloiber, Stefan</creatorcontrib><creatorcontrib>Ripke, Stephan</creatorcontrib><creatorcontrib>Kohli, Martin A</creatorcontrib><creatorcontrib>Reppermund, Simone</creatorcontrib><creatorcontrib>Salyakina, Daria</creatorcontrib><creatorcontrib>Uher, Rudolf</creatorcontrib><creatorcontrib>McGuffin, Peter</creatorcontrib><creatorcontrib>Perlis, Roy H</creatorcontrib><creatorcontrib>Hamilton, Steven P</creatorcontrib><creatorcontrib>Pütz, Benno</creatorcontrib><creatorcontrib>Hennings, Johannes</creatorcontrib><creatorcontrib>Brückl, Tanja</creatorcontrib><creatorcontrib>Klengel, Torsten</creatorcontrib><creatorcontrib>Bettecken, Thomas</creatorcontrib><creatorcontrib>Ising, Marcus</creatorcontrib><creatorcontrib>Uhr, Manfred</creatorcontrib><creatorcontrib>Dose, Tatjana</creatorcontrib><creatorcontrib>Unschuld, Paul G</creatorcontrib><creatorcontrib>Zihl, Josef</creatorcontrib><creatorcontrib>Binder, Elisabeth</creatorcontrib><creatorcontrib>Müller-Myhsok, Bertram</creatorcontrib><creatorcontrib>Holsboer, Florian</creatorcontrib><creatorcontrib>Lucae, Susanne</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European neuropsychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kloiber, Stefan</au><au>Ripke, Stephan</au><au>Kohli, Martin A</au><au>Reppermund, Simone</au><au>Salyakina, Daria</au><au>Uher, Rudolf</au><au>McGuffin, Peter</au><au>Perlis, Roy H</au><au>Hamilton, Steven P</au><au>Pütz, Benno</au><au>Hennings, Johannes</au><au>Brückl, Tanja</au><au>Klengel, Torsten</au><au>Bettecken, Thomas</au><au>Ising, Marcus</au><au>Uhr, Manfred</au><au>Dose, Tatjana</au><au>Unschuld, Paul G</au><au>Zihl, Josef</au><au>Binder, Elisabeth</au><au>Müller-Myhsok, Bertram</au><au>Holsboer, Florian</au><au>Lucae, Susanne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels</atitle><jtitle>European neuropsychopharmacology</jtitle><addtitle>Eur Neuropsychopharmacol</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>23</volume><issue>7</issue><spage>653</spage><epage>662</epage><pages>653-662</pages><issn>0924-977X</issn><eissn>1873-7862</eissn><abstract>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.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>23026132</pmid><doi>10.1016/j.euroneuro.2012.08.010</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European neuropsychopharmacology, 2013-07, Vol.23 (7), p.653-662 |
| issn | 0924-977X 1873-7862 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Antidepressive Agents - therapeutic use Cognition - drug effects Databases, Genetic Depression Depression - blood Depression - drug therapy Depression - genetics Depression - psychology Drug Resistance - genetics Female Gene expression Gene Expression - drug effects Humans Internal Medicine Leptin Leptin - biosynthesis Leptin - blood Leptin - genetics Male Middle Aged Pharmacogenetics Polymorphism, Single Nucleotide - genetics Psychiatry RNA, Messenger - analysis RNA, Messenger - biosynthesis RNA, Messenger - genetics Treatment Outcome Treatment response |
| title | 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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