FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.
As gyrification is an ontogenetic stable feature unaffected by atrophic processes during aging, the gyrification abnormalities of the prefrontal region provide further evidence of the importance of a neurodevelopmental mechanism in the etiology of schizophrenia, at least in males.
This constellation may propose that HPA dysregulation is the endocrinological basis for neuroticism and depressive temperament; this result supports the view that distinct personality factors and HPA vulnerability interact in mediating depression.
Excess comorbidity between depression and epilepsy proposes common pathophysiological patterns in both disorders. Neuroendocrine abnormalities were often observed in depression as well as in epilepsy. Lack of inhibitory control of the hypothalamic pituitary adrenocortical (HPA) system is a core feature of depression; main relay stations of this system are located in the amygdala and hippocampus, which are key regions for both disorders. Therefore we explored the feedback mechanism of the HPA system in epilepsy. In order to control for the impact of depression we focused on epilepsies without depression. We compared patients with epilepsy (subdivided by medication with or without hepatic enzyme inducing antiepileptic medication) with 16 healthy controls and 16 patients with unipolar major depression but without epilepsy. We observed a lack of inhibitory control of the HPA system in patients with epilepsy, also in the absence of enzyme inducing medication. An impact of the temporal lobe location of the epileptic focus could not be observed. Thus, epilepsies share with depression the deficiencies in the feedback mechanism of the HPA system, proposing common pathophysiological features of up to now unknown nature.
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