Preoperative Depression and Plasma Cortisol Levels as Predictors of Delirium after Cardiac Surgery.

BACKGROUND: Delirium is common in old patients who undergo cardiac surgery, and it is associated with adverse outcomes. The genesis of delirium is thought to be multi-factorial, but it is still not well understood. Symptoms of depression and elevated cortisol level have been described in some previous studies as factors associated with delirium, suggesting a shared pathophysiology. AIMS: The objective of the present study was to determine whether preoperative depression symptoms and increased cortisol level represent risk factors for delirium after cardiac surgery. METHODS: We performed a prospective cohort study in 183 patients aged >50 years undergoing elective cardiac surgery. The Geriatric Depression Scale (GDS) was used to assess patients for depressive symptoms before surgery. Preoperative plasma cortisol levels were available in 145 participants. Delirium was diagnosed using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) during the first 7 days after surgery. Spearman correlation was used for correlations between GDS, Mini-Mental State Examination (MMSE), Charlson comorbidity index, and age. Binary logistic regression was used to determine whether GDS and cortisol levels predict postoperative delirium. RESULTS: Delirium occurred in 60 patients out of 183 (32.8%) included and lasted 2.3 days (SD 1.36). GDS was correlated with age (p = 0.001) and comorbidity index (p = 0.003) and inversely correlated with MMSE score (p < 0.001). Higher preoperative GDS scores were associated with incidence of delirium in the postoperative period (p = 0.002). The association was significant after controlling for age, MMSE score, history of stroke, and Charlson comorbidity index (p = 0.045). Preoperative cortisol level was not associated with the development of postoperative delirium. CONCLUSION: Our results suggest that a higher preoperative depression score is associated with an increased risk of postoperative delirium. On the other hand, preoperative plasma cortisol level does not seem to be a predictor of delirium after surgery. Further studies are needed to determine the potential of preoperative depression treatment to prevent postoperative delirium.

CETP polymorphisms influence cholesterol metabolism but not Alzheimer's disease risk.

Cholesteryl ester transfer protein (CETP) is a component of the high density lipoprotein (HDL). Variations in the CETP gene may cause CETP deficiency, which is characterized by decreased mass and activity of the protein as well as altered HDL and LDL levels. We investigated the effect of three putative functional CETP polymorphisms (-1946 VNTR, C-629A and I405V) on the risk of Alzheimer's disease (AD) and on cholesterol, lathosterol and 24S-hydroxycholesterol levels in CSF and plasma of AD patients and controls. None of the investigated CETP polymorphisms or haplotypes had any effect on the risk of AD. However, we found that a three marker CETP haplotype (L/C/V) influenced CSF levels of lathosterol and 24S-hydroxycholesterol as well as plasma levels of total cholesterol in controls but not in AD patients. Our data suggest that CETP gene variations influence cerebral and peripheral cholesterol metabolism, but not AD risk.

Platelet 5-HT2A receptor binding and tryptophan availability in depression are not associated with recent history of suicide attempts but with personality traits characteristic for suicidal behavior.

BACKGROUND: Abnormalities in the serotonergic (5-HT) system have been implicated in the pathogenesis of suicidal behavior. Studies on peripheral serotonergic parameters as a measure for central serotonergic function in suicidal patients appear to be promising, yet failed to show a clear association with suicidality. The objective of this study was to elucidate the role of serotonergic blood parameters in depressed suicidal patients and to examine their usefulness as a potential biological marker for suicidality. A number of personality traits were assessed in order to provide a basis for a psychobiological model of suicidal behavior. METHODS: Depressed patients with a recent suicide attempt (SA; n = 59) were compared to those without history of suicide attempts (NSA; n = 28). 5-HT2A receptor binding in platelets and tryptophan/amino acid ratio in plasma were measured. Acute psychopathology and personality traits as well as characteristics of suicide attempts were assessed. RESULTS: There was no significant difference between SA and NSA in terms of peripheral serotonergic parameters as well as personality traits. However, the whole sample showed associations between certain personality traits and serotonergic platelet parameters. Furthermore, we observed a relation between suicidal ideation, lethality of suicide attempts and peripheral serotonergic markers. LIMITATIONS: The number of cases with data on peripheral markers is relatively low. The potential influence of antidepressant medication previous to study inclusion has to be taken into account. The study focussed on depressed patients only. CONCLUSIONS: Low serotonergic function is involved in the pathogenesis of suicidality, whereas the use of platelet 5-HT2A receptor activity and tryptophan availability as biological markers for suicidality in depressed patients could not be proven an appropriate tool. Alterations in the serotonergic system are associated with trait aggression and other character dimensions.

Analysis of eighteen antidepressants, four atypical antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring.

Therapeutic drug monitoring necessitates efficient, fast and reliable analytical methods validated by external quality control. We therefore devised an isocratic reversed-phase HPLC method with ultraviolet detection and optimised this to quantify mirtazapine, reboxetine, moclobemide, venlafaxine, O-desmethylvenlafaxine, paroxetine, fluvoxamine, fluoxetine, norfluoxetine, sertraline, citalopram, amitriptyline, nortriptyline, imipramine, desipramine, doxepin, nordoxepin, clomipramine, norclomipramine, trimipramine, mianserine, maprotiline, normaprotiline, amisulpride, clozapine, norclozapine, quetiapine, risperidone and 9-OH-risperidone in human serum. After solid-phase extraction of the drugs and metabolites, the chromatographic separation was achieved on a Nucleosil 100-Protect 1 column with acetonitrile-potassium dihydrogenphosphate buffer as mobile phase. The method was validated for therapeutic and toxic serum ranges. A linear relationship (r>0.998) was obtained between the concentration and the detector signal. Recoveries were between 75 and 99% for the drugs and metabolites. The accuracy of the quality control samples, expressed as percent recovery, ranged from 91 to 118%; intra- and inter-assay-relative standard deviations were 0.9-10.2% and 0.9-9.7%, respectively. Additional external quality control is carried out since 3 years. This method is applicable to rapidly and effectively analyze serum or plasma samples for therapeutic drug monitoring of about 30 antidepressants and atypical antipsychotics.

Polymorphism in the BACE gene influences the risk for Alzheimer's disease.

Pathological characteristics of Alzheimer's disease (AD) are neurofibrillary tangles and amyloid-beta (Abeta) plaques. Abeta is generated by cleavage of the amyloid precursor protein by beta- and gamma-secretases. BACE (beta-site APP cleaving enzyme) was identified as the beta-secretase. Variations of the BACE gene might influence activity and function of the protein and, thus, might influence the pathogenesis of AD. Consequently, we investigated the association of different BACE polymorphisms with AD. BACE exon 5 polymorphism influenced the risk of AD. This effect was most pronounced in apolipoprotein E4 allele carriers. Furthermore, Abeta(42) CSF levels were influenced by BACE genotype. It appears that BACE polymorphism plays a more important role in the development of AD than previously assumed, possibly by influencing Abeta(42) levels.

Association of an interleukin-1beta gene polymorphism at position -511 with Alzheimer's disease.

Inflammation is thought to promote neuronal cell death in Alzheimer's disease (AD). The proinflammatory interleukin-1 is a main component in inflammatory pathways and is overexpressed in the brain of AD patients. Investigation of different polymorphisms in the interleukin-1 genes (IL-1alpha -889, IL-1beta -511, IL-1beta +3953) revealed associations between specific alleles and AD in that they increased the risk or modified the age at onset of AD. However, there are controversial findings from other studies which revealed no significant associations between these polymorphisms and AD; thus further evaluation of the association of IL-1 gene polymorphisms with AD and their role in pathogenesis is needed. In this study we examined the distribution of the IL-1beta -511 alleles in AD patients and a control sample of healthy individuals. An additional control population of non-demented depressive inpatients was recruited to exclude a confounding bias. The cerebrospinal fluid (CSF) levels of Abeta42 in AD patients were investigated to assess the influence of IL-1beta -511 genotypes. We found no significant association of the IL-1beta -511 polymorphism with AD, suggesting that the IL-1beta -511 polymorphism is no risk factor for AD. However, we found the Abeta42 CSF levels to be lower in carriers of the IL-1beta CC-genotype compared to carriers of the T-allele. Even though IL-1beta -511 polymorphism did not influence the risk of AD it might have a pathophysiological influence on the disease process.

FcepsilonRI induces the tryptophan degradation pathway involved in regulating T cell responses.

FcepsilonRI is suspected to play a pivotal role in the pathophysiology of atopic disorders such as atopic dermatitis. In search for genes differentially regulated by FcepsilonRI on APCs, a differential cDNA bank of receptor-stimulated and unstimulated monocytes was established. By means of suppression subtractive hybridization, we identified kynurenine 3-monooxygenase and subsequently indoleamine 2,3-dioxygenase (IDO) to be overexpressed in FcepsilonRI-activated monocytes. IDO is the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan. We show that cross-linking of FcepsilonRI on monocytes results in low tryptophan concentrations associated with impaired T cell stimulatory capacity. Importantly, T cell suppression could be prevented by the addition of tryptophan or inhibition of IDO. Moreover, stimulation of T cells by FcepsilonRI-activated monocytes was increased compared with T cell stimulation by nonactivated monocytes if exogenous supply of tryptophan was available. We speculate that the expression of IDO by FcepsilonRI(+) APCs in vivo allows these cells to regulate T cell responses in atopic disorders by inhibiting or stimulating T cell proliferation, depending on the metabolic environment.