Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.
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PMID:Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. 1556 10

Bipolar disorder (BPD) is a devastating psychiatric illness marked by recurrent episodes of mania and depression. While the underlying pathophysiology of BPD remains elusive, an abnormal hypothalamic-pituitary-adrenal (HPA) axis and dysfunctional glucocorticoid receptor (GR) signaling are considered hallmarks. This review will examine how targeting resiliency signaling cascades at the cellular level may serve as a mechanism to treat BPD. Here, cellular resiliency is defined as the ability of a cell to adapt to an insult or stressor. Such resiliency at the cellular level could confer resiliency at the systems level and, ultimately, help individuals to cope with stressors or recover from depressive or manic states. This review will focus on four molecular targets of mood stabilizers that are known to play integral roles in these cellular resiliency signaling pathways: (1) B-cell CLL/lymphoma 2 (Bcl-2), (2) Bcl-2-associated athanogene (BAG-1), (3) glucocorticoid receptors (GRs), and (4) 51 kDa FK506-binding protein (FKBP5). These targets have emerged from neurobiological and human genetic studies and employ mechanisms that modulate GR function or promote anti-apoptotic processes critical to affective resilience. Future research should focus on elucidating sustainable treatments that target resiliency factors-such as BAG-1 or FKBP5-which could ultimately be used to treat individuals suffering from BPD and prevent relapses in afflicted individuals. Further identification of resiliency and susceptibility factors will also be vital. Ultimately, these developments would allow for the treatment of susceptible individuals prior to the development of BPD.
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PMID:Cellular mechanisms underlying affective resiliency: the role of glucocorticoid receptor- and mitochondrially-mediated plasticity. 1959 76

Recent reports suggest that FKBP5 gene and its corresponding FKBP5 protein play a relevant role in the regulation of anxiety and depression in animal models and human stress-related disorders. In the present study, FKBP5 and glucocorticoid receptor (GR) gene and protein expression were analyzed in the amygdala (AMY) of suicide victims (n=13 males, without clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and its corresponding controls (n=13 males) by real-time PCR and Western blotting. The results revealed that FKBP5 and GR gene expression were significantly reduced in the AMY (-38% and -48%, respectively) of suicide victims compared with controls. Interestingly, FKBP5 and GR protein expression were also significantly decreased (-41% and -42%, respectively) in the AMY of suicide victims compared with controls. These results suggest that the FKBP5 plays a relevant role in human emotional responses and suggest this receptor as a new promising target in the treatment of suicide behavior.
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PMID:Gene and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of suicide victims. 2321 23

The gene that encodes the FK506-binding protein 5 (FKBP5) is regarded as a candidate for investigating how negative life events interact with a genetic predisposition to stress-related disorders, such as depression and anxiety. Given the role of FKBP5 as an important regulator of stress responses, we aimed to investigate if single-nucleotide polymorphisms (SNPs) in FKBP5-in the presence/absence of exposure to violence-are associated with symptoms of depression and anxiety. Data from two community-based samples of adolescents (n=1705) and young adults (n=1800) regarding ratings on depression, anxiety, exposure to violence and FKBP5 genotype were collected. A risk haplogenotype including the minor alleles of seven common SNPs in the FKBP5 (rs3800373, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080 and rs4713916) conferred higher ratings on anxiety among females, but not males, in the presence of violence. Exposure to violence and female sex were associated with higher ratings on both depression and anxiety, with the exception of ratings on depression among young adults, on which sex had no effect. Ratings on depression were not associated with the haplogenotype. These findings may correspond to differences in the regulation of the HPA axis and with the higher vulnerability to anxiety in females.
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PMID:Associations between the FKBP5 haplotype, exposure to violence and anxiety in females. 2744 12

Increased expression of the FK506-binding protein 5 (FKBP5) gene has been associated with a number of diseases, but most prominently in connection to psychiatric illnesses. Many of these psychiatric disorders present with dementia and other cognitive deficits, but a direct connection between these issues and alterations in FKBP5 remains unclear. We generated a novel transgenic mouse to selectively overexpress FKBP5, which encodes the FKBP51 protein, in the corticolimbic system, which had no overt effects on gross body weight, motor ability, or general anxiety. Instead, we found that overexpression of FKBP51 impaired long-term depression (LTD) as well as spatial reversal learning and memory, suggesting a role in glutamate receptor regulation. Indeed, FKBP51 altered the association of heat-shock protein 90 (Hsp90) with AMPA receptors, which was accompanied by an accelerated rate of AMPA recycling. In this way, the chaperone system is critical in triage decisions for AMPA receptor trafficking. Imbalance in the chaperone system may manifest in impairments in both inhibitory learning and cognitive function. These findings uncover an unexpected and essential mechanism for learning and memory that is controlled by the psychiatric risk factor FKBP5.
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PMID:The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling. 3096 2

The FKBP5 protein is of importance for the function of the glucocorticoid receptor. The purpose of the present study was to examine the possible association between the different genotypes of rs1360780 in the FKBP5 gene, and clinical symptoms in patients with unipolar depression. Seven hundred eighteen patients and 673 controls from the Danish Psychiatric Biobank were participated. No association was found between any genotype and diagnosis of unipolar depression. It was found that the group of depressed patients with the CC genotype showed significantly earlier start of treatment with medicine, had a significantly greater tendency to be treated with electroconvulsive therapy and showed a significantly higher frequency of family history of depression compared with the combined group of patients with the CT and TT genotypes. The only informations about controls were their sex and that they were recruited from the blood bank. The clinical data were not complete for all patients.
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PMID:Clinical association to FKBP5 rs1360780 in patients with depression. 3121 60