Stefan Kloiber

Max Planck Institute of Psychiatry, München, Bavaria, Germany

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Publications (69)372.41 Total impact

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    ABSTRACT: We read with great interest the study published by van Varsseveld et al. (van Varsseveld et al., 2015) on the relationship between IGF-I concentrations and depression in elderly subjects. The authors report on 1188 participants ≥ 65 years from a Dutch cohort study in which high IGF-I levels in men and low IGF-I levels in women were associated with prevalent depression. However, in the three-year follow-up period, no predictive associations between IGF-I levels and depressive disorder remained in men and in women (except for one association in women indicating that mid-range concentrations of IGF-I as compared to high IGF-I levels decreased the probability of minor depression). Therefore the authors conclude that IGF-I may play an important role in acute depression. On one hand, recently published findings from the Munich Antidepressant Response Signature (MARS) project underscore this notion regarding the importance of IGF-I in acute depression: In this study, we observed higher IGF-I levels at admission and after 6 weeks of treatment in 78 depressed inpatients compared to 92 healthy controls (Kopczak et al., 2015). Additionally, IGF-I levels at admission were higher in non-remitters after 6 weeks of psychopharmacological treatment than in remitters indicating even a potential role as a predictor for therapy response. On the other hand, we would like to strengthen the point that IGF-I may not only play a role in acute depression, but also as a predictor of depression per se. In our epidemiological study in the SHIP (Study of Health in Pomerania) cohort studying 3141 subjects with a similar study design and similar models as in the presented study, we observed high IGF-I levels in men and low IGF-I levels in women to be predictive for the incidence of depressive disorders in the 5-year follow-up period (Sievers et al., 2014) which was not seen by van Varsseveld et al. It is not clear why these results could not be confirmed in the Dutch cohort in elderly subjects. However, we believe that the results of the presented study in conjunction with previous and the studies of our group clearly emphasizes a yet to be elucidated role of IGF-I in depression and the need for further research of its relevance for etiology, prediction and therapy response.
    Psychoneuroendocrinology 04/2015; DOI:10.1016/j.psyneuen.2015.04.001 · 5.59 Impact Factor
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    ABSTRACT: Psychotropic medications target glycogen synthase kinase 3β (GSK3β), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3β at serine 9 (pGSK3β(S9)). FKBP51 associates with GSK3β mainly through its FK1 domain; furthermore, it also changes GSK3β's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3β on the downstream targets Tau, β-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3β(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3β pathway activity and by pGSK3β(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3β activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3β pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.Molecular Psychiatry advance online publication, 7 April 2015; doi:10.1038/mp.2015.38.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.38 · 15.15 Impact Factor
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    ABSTRACT: We analyzed insulin-like growth factor I (IGF-I) in serum of 78 inpatients with depression and 92 healthy controls. Patients were selected according to remission status after 6 weeks of antidepressant treatment with remission defined by Hamilton depression rating scale (HAM-D) 21-item score <10 (39 remitters and 39 non-remitters). IGF-I was analyzed in patients at admission and after 6 weeks of psychopharmacological treatment. IGF-I levels were compared between patients and controls and between remitters and non-remitters with general linear model using age, gender, and body mass index as covariates. In patients, IGF-I levels were significantly higher at admission (p=3.29E-04) and in week 6 (p=0.002) compared to controls. Furthermore, non-remitters showed significantly higher IGF-I levels at admission (p=0.046) and a trend for higher IGF-I levels in week 6 (p=0.11) compared to remitters. In remitters change in IGF-I levels during treatment was significantly correlated with change in cortisol levels (p=0.019). A genetic association analysis of polymorphisms in 10 genes contributing to the IGF-I system (IGF1, IGF1R, IGFBP1 to IGFBP7, and IGFBPL1) in the currently largest genetic databases for major depression (Psychiatric Genomics Consortium) revealed nominal associations with susceptibility for depression and treatment response, although results did not remain significant after multiple testing correction. In our study, elevated IGF-I levels were significantly associated with depression and impaired treatment response. Based on these findings IGF-I signaling could play a role in the pathophysiology of depression and could possibly influence the response to antidepressant treatment. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European Neuropsychopharmacology 01/2015; DOI:10.1016/j.euroneuro.2014.12.013 · 5.40 Impact Factor
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    ABSTRACT: Clear evidence has linked dysregulated hypothalamus–pituitary–adrenocortical (HPA) axis function to the aetiology and pathophysiology of major depression (MD), as observed in the majority of patients. Increased stress reactivity and hyperactivity of the HPA axis seem characteristic for psychotic/melancholic depression, while the atypical subtype of depression has been connected with the opposing phenotypes. However, the underlying molecular-genetic mechanisms are poorly understood. In the present study, mouse lines selectively bred for extremes in stress reactivity (SR), i.e. presenting high (HR) or low (LR) corticosterone secretion in response to stressors, were used to characterise the molecular alterations on all levels of the HPA axis. Results were contrasted with clinical phenotypes of MD patients from the Munich Antidepressant Response Signature project, stratified according to their cortisol response in the Dex/CRH test. Distinct differences between HR and LR mice were found in the expression of HPA axis-related genes in the adrenals, pituitary and selected brain areas. Moreover, HR animals presented an enhanced adrenal sensitivity, increased stress-induced neuronal activation in the PVN and an overshooting Dex/CRH test response, whereas LR animals showed a blunted response in these paradigms. Interestingly, analogous neuroendocrine, morphometric, psychopathological and behavioural differences were observed between the respective high and low HPA axis responder groups of MD patients. Our findings suggests that (i) the SR mouse model can serve as a valuable tool to elucidate HPA axis-related mechanisms underlying affective disorders and (ii) a stratification of MD patients according to their HPA axis-related neuroendocrine function should be considered for clinical research and treatment.
    Psychoneuroendocrinology 11/2014; 49(03):229–243. DOI:10.1016/j.psyneuen.2014.07.008 · 5.59 Impact Factor
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    ABSTRACT: FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, the underlying mechanisms remain elusive. The objective of this study was to elucidate the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy.
    PLoS Medicine 11/2014; 11(11):e1001755. DOI:10.1371/journal.pmed.1001755 · 14.00 Impact Factor
  • Biological psychiatry 10/2014; 76(7). DOI:10.1016/j.biopsych.2014.01.022 · 9.47 Impact Factor
  • Diabetologie und Stoffwechsel 05/2014; 9(S 01). DOI:10.1055/s-0034-1374917 · 0.31 Impact Factor
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  • Experimental and Clinical Endocrinology & Diabetes 03/2014; 122(03). DOI:10.1055/s-0034-1372321 · 1.76 Impact Factor
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    ABSTRACT: Major depressive disorder (MDD) is one of the leading causes of global disability. It is a risk factor for noncompliance with medical treatment, with about 40% of patients not responding to currently used antidepressant drugs. The identification and clinical implementation of biomarkers that can indicate the likelihood of treatment response are needed in order to predict which patients will benefit from an antidepressant drug. While analyzing the blood plasma proteome collected from MDD patients before the initiation of antidepressant medication, we observed different fibrinogen alpha (FGA) levels between drug responders and nonresponders. These results were replicated in a second set of patients. Our findings lend further support to a recently identified association between MDD and fibrinogen levels from a large-scale study.
    Translational Psychiatry 01/2014; 4(1):e352. DOI:10.1038/tp.2013.129 · 4.36 Impact Factor
  • Pharmacopsychiatry 09/2013; 46(06). DOI:10.1055/s-0033-1353288 · 2.17 Impact Factor
  • Pharmacopsychiatry 09/2013; 46(06). DOI:10.1055/s-0033-1353276 · 2.17 Impact Factor
  • Pharmacopsychiatry 09/2013; 46(06). DOI:10.1055/s-0033-1353352 · 2.17 Impact Factor
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    ABSTRACT: Dysfunctional limbic, paralimbic and prefrontal brain circuits represent neural substrates of major depression that are targeted by pharmacotherapy. In a high resolution structural magnetic resonance imaging (MRI) study we investigated the potential of variability of the cortex volume to predict the response to antidepressant treatment among patients with major depression. We enrolled 167 patients participating in the Munich Antidepressant Response Signature (MARS) study and employed voxel based morphometry to investigate covariation of gray matter (GM) maps with changes of depression severity over 5 weeks. Larger left hippocampal and bilateral posterior cingulate GM volumes and lower right temporolateral GM volumes were associated with beneficial treatment response. Subcallosal/orbitofrontal GM volumes were associated with treatment response mainly through gender-by-region interactions. A hippocampal/temporolateral composite marker proved robust in both first episode and recurrent unipolar patients and in bipolar patients. Compared with 92 healthy controls, abnormally low volumes were only detected in the left hippocampal area, particularly in recurrent unipolar patients. These findings indicate that variability of the cortex volume of specific brain areas is associated with different response to antidepressants. In addition, hippocampal findings recursively link together unfavorable treatment response and progressive hippocampal structural changes in recurrent depression.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 08/2013; 23(11). DOI:10.1016/j.euroneuro.2013.07.004 · 5.40 Impact Factor
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    ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
    Nature Genetics 12/2012; DOI:10.1038/ng.2500 · 29.65 Impact Factor
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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 (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.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2012; DOI:10.1016/j.euroneuro.2012.08.010 · 5.40 Impact Factor
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    ABSTRACT: Recent genome-wide association studies (GWAS) and metaanalyses revealed genetic associations for ANK3 (ankyrin 3) and CACNA1C (alpha 1C subunit of the L-type voltage gated calcium channel) with bipolar disorder (BPD). Several findings from clinical, epidemiological, and genetic studies point towards a common biological background of BPD and major depressive disorder (MDD). We were interested whether this also applies for ANK3 and CACNA1C and tested associations of single nucleotide polymorphisms (SNPs) in these genes with MDD in two Caucasian case-control samples. Sample 1 (Munich Antidepressant Response Signature Project/MARS - MDD) consisted of 720 depressed inpatients and 542 psychiatric healthy controls. Sample 2 (unipolar recurrent depression (URD)) consisted of 827 patients with URD and 860 psychiatric healthy controls. After stringent quality control we analyzed 262 SNPs (sample 1) and 504 SNPs (sample 2) and imputed further 5771 SNPs (sample 1) and 5534 SNPs (sample 2) from Hapmap Phase 2 data in the ANK3 and CACNA1C gene regions. Additionally, a metaanalysis of both samples was performed. Several SNPs in both genes were nominally associated with MDD with the highest association in the 3'-region of ANK3 (rs10994143, nominal p = 3.3*10(-4)) in the metaanalysis of both samples. None of these results remained significant after correction for multiple testing. No association of MDD with SNPs previously reported in BPD studies could be detected. By analyzing the LD-structure, our highest associated SNPs could not be linked to the SNPs previously reported in BPD. Regarding ANK3 and CACNA1C, our findings do not support a strong genetic link between BPD and MDD for these two genes.
    Journal of Psychiatric Research 05/2012; 46(8):973-9. DOI:10.1016/j.jpsychires.2012.04.017 · 4.09 Impact Factor
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    ABSTRACT: Glutamate has been implicated in the pathophysiology and treatment of mood disorders possibly by affecting the regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Growing evidence suggests an important role of the metabotropic glutamate receptor 1 (mGlu1) in depression-related phenotypes. To test whether these findings can also be supported by human genetics data, we explored polymorphisms within the metabotropic glutamate receptor 1 gene (GRM1) for their association with unipolar depression (UPD) as well as with biological phenotypes of this disorder. We first tested the association of 43 tag-SNPs covering the GRM1 locus with UPD in 350 patients and 370 matched controls. We then investigated the effects of the associated SNPs on hippocampal glutamate levels estimated using ¹H-MR-spectroscopy (¹H-MRS) and on endocrine measures from the combined dexamethasone-suppression/CRH stimulation (dex/CRH) test. Within the GRM1 locus, 22 SNPs showed nominally significant association with UPD, of which 6 withstood corrections for multiple testing (rs2268666 with best allelic p=7.0×10⁻⁵). Supportive evidence for an association with UPD was gained from a second independent sample with 904 patients and 1012 controls. Furthermore, patients homozygous for the non-risk genotypes showed reduced hippocampal glutamate levels as measured by ¹H-MRS, a more pronounced normalization of HPA-axis hyperactivity as well as a better antidepressant treatment outcome. These results suggest that the combination of genetic and biological markers may allow to subgroup patients into etiopathogenetically more relevant subcategories which could guide clinicians in their antidepressant treatment choices.
    Psychoneuroendocrinology 09/2011; 37(4):565-75. DOI:10.1016/j.psyneuen.2011.09.003 · 5.59 Impact Factor
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    ABSTRACT: Although there are indications for modulatory effects of PUFA on associations between SNP and obesity risk, scientific evidence in human subjects is still scarce. The present analyses investigated interaction effects between SNP in candidate genes for obesity and PUFA in erythrocyte membranes on obesity risk. Within the second Bavarian Food Consumption Survey (cross-sectional, population-based), 568 adults provided blood samples. Fatty acid composition of erythrocyte membranes was analysed by means of GC. Genotyping was performed for twenty-one genes, including cytokines, adipokines, neurotransmitters and transcription factors. In addition, plasma IL-6 concentrations were analysed. For the statistical analysis, a logistic regression model assuming additive genetic effects was chosen. About 20 % of the study participants were classified as obese (BMI ≥ 30 kg/m(2)). Several significant gene-PUFA interactions were found, indicating regulatory effects of PUFA by gene variants of IL-2, IL-6, IL-18, TNF receptor family member 1B and 21, leptin receptor and adiponectin on obesity risk. After stratification by genotype, the strongest effects were found for rs2069779 (IL-2) and all tested PUFA as well as for rs1800795 (IL-6) and linoleic or arachidonic acid. The obesity risk of minor allele carriers significantly decreased with increasing fatty acid content. The genetic PUFA-IL-6 interaction was also reflected in plasma IL-6 concentrations. If replicated in a prospective study with sufficient statistical power, the results would indicate a beneficial effect of high PUFA supply for a substantial proportion of the population with respect to obesity risk.
    The British journal of nutrition 05/2011; 106(8):1263-72. DOI:10.1017/S0007114511001541 · 3.34 Impact Factor
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    Molecular Psychiatry 11/2010; 15(11):1123. DOI:10.1038/mp.2009.8 · 15.15 Impact Factor