The His452Tyr variant of the gene encoding the 5-HT2A receptor is specifically associated with consolidation of episodic memory in humans

Basic research has shown that serotonin plays an important role in memory formation. Accordingly, genetic variation of serotonin receptors can be expected to affect memory and to underlie, in part, the heritability of memory capacity. A study by de Quervain and colleagues found a highly significant association of the functional 5-HT2A receptor variant His452Tyr (rs6314) with long-term memory. We replicated this finding in a cohort of 133 adults (mean age 43.5 yr). Carriers of the Tyr allele showed poorer verbal delayed recall and recognition, while immediate recall and additional measures of attentional and executive function were not affected by the His452Tyr genotype. Results suggest a possible role of 5-HT2A receptors in memory consolidation. Serotonergic drugs may have the potential to improve memory

The association between overcommitment to work and depression is moderated by the polymorphic region of the 5-HTT gene

To the Editors: The associationbetweenovercommitmentto work anddepressivesymptomsismoderated by thepolymorphicregionofthe5-HTTgene

Serotonintransportergen und stressreagibilität bei unipolarer depression

Background A length polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with both depression and hypothalamic-pituitary-adrenal (HPA) system activity. A dysregulation of the HPA system is considered to be a candidate endophenotype of depression. The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5-HTTLPR and HPA system activity in a sample of inpatients with major depression. Materials and methods A total of 237 inpatients with major depression were genotyped for 5-HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) as well as using the Hamilton score (Hamilton rating scale for depression) to determine the severity of the psychopathology. Results Patients with the ss-genotype showed a significantly higher HPA -system activity in comparison to patients with the lI-genotype, but no association between 5-HTTLPR and the severity of psychopathology could be detected. Conclusions The results of the current study demonstrate an influence of 5-HTTLPR on dysregulation of the HPA system in patients with major depression and support the hypothesis that 5-HTTLPR- and HPA-system-interaction constitutes an important component in the pathogenesis of depression

PCLO rs2522833 modulates HPA system response to antidepressant treatment in major depressive disorder

Variant rs2522833 of the Piccolo-encoding gene PCLO has recently been found to be associated with major depressive disorder (MDD). PCLO encodes a presynaptic cytomatrix protein which influences monoamine neurotransmitter release. Piccolo could therefore play an important role in treatment response to antidepressant therapy and the improvement of alterations in HPA system reactivity. We investigated the influence of the coding variant rs2522833 in the PCLO gene on treatment response in 205 in-patients with unipolar depression. Treatment response was measured (1) at the level of psychopathology using the Hamilton Depression Rating Scale (HAMD) and (2) with the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which is a refined tool for showing dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, a neurobiological finding in depression. While we did not find an association between variation in PCLO and HAMD scores, HPA dysregulation was less pronounced in carriers of the AA genotype than in carriers of one or two C alleles. HPA activity of individuals with the AA genotype only marginally changed during 4-wk antidepressant treatment, whereas C allele carriers showed a higher hormonal secretion at admission than carriers of the AA genotype but lower responsivity to the Dex/CRH challenge after 4 wk. Our results point to a moderating role of PCLO SNP rs2522833 on HPA regulation during antidepressant treatment, which may represent a neurobiological feature of stability of clinical response

Higher overcommitment to work is associated with higher plasma cortisol but not ACTH responses in the combined dexamethasone/CRH test in apparently healthy men and women

BACKGROUND: Overcommitment (OC) is a pattern of excessive striving that has been associated with alterations in the hypothalamus-pituitary-adrenal (HPA) system. To investigate whether overcommitment is associated with alterations in HPA system function we measured cortisol and adrenocorticotropin (ACTH) release in response to the combined dexamethasone/CRH test. METHODS: We recruited 92 men and 108 women of a wide range of OC scores including the minimum (6) and maximum (24) of possible OC scores (mean+/-SEM: 13.25+/-.27). We repeatedly measured plasma cortisol and ACTH levels in the combined dexamethasone/CRH test after injection of 100mul CRH preceded by administration of 1.5mg dexamethasone the night before. Moreover, we assessed depressive symptoms (Beck Depression Inventory, BDI) and work stress (effort-reward-imbalance, ERI). RESULTS: Independent of age and gender, higher OC was associated with higher repeated cortisol (interaction time-by-OC: p=.014, f=.15) but not ACTH (p=.22) secretion in the combined dexamethasone/CRH test. Similarly, higher cortisol (beta=.16, p=.029, R(2)=.02) but not ACTH (p=.47) increase following CRH injection was predicted by higher OC. Depressive symptoms (BDI score) and work stress scores (effort-reward-ratio) did not relate to neuroendocrine responses to the dexamethasone/CRH test. Controlling for depressive symptoms and work stress scores in addition to age and gender did not change results. OC was not associated with ACTH or cortisol pre-test levels. DISCUSSION: Whereas OC was not associated with alterations in negative feedback sensitivity after dexamethasone administration, our findings indicate that with increasing OC scores, a higher reactivity of the adrenal cortex together with a normal reactivity of the pituitary is observed following subsequent stimulation by CRH injection

Influence of 5-HTTLPR polymorphism on resting state perfusion in patients with major depression

Neuroimaging studies in major depressive disorder (MDD) have indicated dysregulation in a network involving prefrontal cortex, subgenual cingulate and the amygdalae, which is known to be modulated by serotonin. The serotonergic system is the principal target for pharmacological treatment in MDD and the functional variable serotonin promoter polymorphism (5-HTTLPR) influences susceptibility, course and treatment response of MDD. Using data from a previously published sample of 89 MDD-patients, we examined post hoc the effect of 5-HTTLPR status on resting state perfusion, as measured with 99mTc-HMPAO-SPECT. MDD patients were stratified according to receptor polymorphism, both using a bi-allelic (group A: L/L vs. group B: S/S and S/L genotype) and a tri-allelic approach (Group A′: LA/LA vs. Group B′: non-LA/LA genotype). There were no significant differences between both subgroups regarding age, gender, severity of depression, medication, or treatment response (p \u3e 0.1). Using the bi-allelic approach, Group B, compared to group A, revealed a significantly higher resting state perfusion in medial prefrontal cortex (pvoxel (FWE) \u3c 0.05). Additional ROI analyses showed relative overactivity of the amygdalae in group B (pvoxel (FWE) \u3c 0.05). Similar effects were observed in the tri-allelic approach. The opposite contrasts (Group A \u3e Group B) revealed no significant effects. We demonstrate that in patients with MDD, 5-HTTLPR gene polymorphism modulates resting state perfusion in key structures of mood processing. While the clinical impact of these findings will need to be further investigated in larger cohort studies, the necessity to monitor and to account for individual 5-HTTLPR-status in future MDD imaging studies is highly recommended

Association of amygdala volumes with cortisol secretion in unipolar depressed patients

Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes

DNA sequence variants of the FKBP5 gene are associated with unipolar depression

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

Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP)

A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10-9) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10-5). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies