Maria Gilles

Increased platelet aggregability in major depression

There is compelling evidence that depression constitutes an independent risk factor for cardiovascular morbidity and mortality. As exaggerated platelet reactivity is associated with an increased risk of intra-arterial thrombus formation, we studied platelet aggregability in patients with major depression both before and after 5 weeks of anti-depressant therapy as well as in healthy control subjects. Twenty-two depressed patients and 24 healthy control subjects participated in the study. Washed and rediluted platelets were stimulated with the agonists collagen and thrombin in three concentration steps. Depression was associated with a higher aggregability after stimulation with thrombin in the intermediate concentration and with collagen at the low concentration, with ceiling effects for the other concentrations. After 5 weeks of anti-depressant therapy, aggregability was somewhat less exaggerated, although this effect did not reach statistical significance. We thus conclude that major depression is associated with increased platelet aggregability, which seems to persist even under a marked improvement in depressive symptomatology. This effect may contribute to the increased cardiovascular morbidity in depressed patients.

Lipid metabolism and insulin resistance in depressed patients: significance of weight, hypercortisolism, and antidepressant treatment

Abstract: Major depression increases cardiovascular risk despite lower cholesterol levels. Little is known about effects of antidepressants on metabolic risk factors. We studied lipoprotein composition, insulin sensitivity (quantitative insulin sensitivity check index), and saliva cortisol in 78 depressed patients before and after 35 days of amitriptyline or paroxetin treatment. Data were analyzed by principal component factor analyses and analysis of variance (ANOVA). At baseline, quantitative insulin sensitivity check index was inversely correlated with cortisol (r = −0.46; P = 0.005) in normal weight patients, with body mass index in overweight patients (r = −0.50; P < 0.001). In overweight patients, hypercortisolemia correlated inversely with total and low density lipoprotein cholesterol (eg, cortisol at 4:00 PM and low density lipoprotein cholesterol: r = −0.49, P = 0.002). After treatment, quantitative insulin sensitivity check index was unchanged. Triglycerides increased in responders to amitriptyline only (P < 0.05). Parameters of cholesterol metabolism improved slightly without differences between treatment groups (eg, high density lipoprotein: pre 43.5 ± 12.0; post 47.6 ± 13.0 mg/dL; P = 0.01; low density lipoprotein triglycerides, a measure of low density lipoprotein atherogenicity: pre 458 ± 120; post 415 ± 130 mg/g; P < 0,01). The inverse correlation of cortisol and cholesterol, at least in the obese subgroup, proposes a mechanism for the known association of depression with low cholesterol. As determinants of plasma lipids in major depression, we identified body mass index, insulin sensitivity, and cortisol. Although uncontrolled, our data suggest that treatment of depression exerts a mainly beneficial effect on lipid regulation.Abbreviations: AMI = amitriptyline, BMI = body mass index, DSM IV = Diagnostic and Statistical Manual, IVth revision, HAMD = hamilton depression scale,HDL= high density lipoprotein, hypothalamus-pituitaryadrenal axis, LDL = low density lipoprotein, PAR = paroxetin, PPARa = peroxisome proliferation activator receptor a, QUICKI = quantitative insulin sensitivity check index, SSRI = selective serotonine reuptake inhibitor, TCA = tricyclic antidepressant, VLDL = very low density lipoprotein.

Oral administration of the NMDA receptor antagonist S-ketamine as add-on therapy of depression: a case series.

We intended to assess safety, response to treatment and time to response of 1.25 mg/kg oral S-ketamine as add-on to standard antidepressants in four depressed patients. Two patients with melancholic depression responded early and stayed in remission, while two patients with distinct somatic symptoms, chronicity or atypical features did not respond. The limited number of patients does not allow conclusions about efficacy. Oral S-ketamine was well tolerated and could merit being studied in randomised controlled trials due to its higher practicability compared to (S-)ketamine infusion therapy. Clinical subtyping should be considered.

MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD.

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

Cortisol Metabolism in Depressed Patients and Healthy Controls

Background: Chronic stress as well as major depressive disorders are associated with hypercortisolemia and impaired hypothalamic-pituitary-adrenocortical axis functioning. The aim of this study was to determine whether in major depression changes in the activity patterns of local modulators of glucocorticoid action might contribute to an increase in cortisol bioavailability and if they change during antidepressant treatment and clinical response. Methods: Concentrations of urinary total cortisol (UFF), urinary total cortisone (UFE), tetrahydrocortisone (THE), tetrahydrocortisol (THF) and allo-THF (5α-THF) were measured in 10-hour nocturnal urine samples of 19 depressed patients and 15 healthy controls. The activity of 11β-hydroxysteroid dehydrogenases (11β-HSD) as well as 5α- and 5β-reductases was assessed by calculating the ratios of glucocorticoid metabolites. Patients were treated for 28 days with either mirtazapine or venlafaxine. Enzyme activity was observed during the course of treatment and compared to healthy controls. Responders to treatment were selected for this analysis. Results: Depressed patients showed reduced 5α-reductase activity manifested as a significantly lower amount of 5α-THF (102.8 ± 167.2 vs. 194.6 ± 165.8 μg, p = 0.019). The increase in the UFF/UFE ratio (0.73 ± 0.32 vs. 0.29 ± 0.13, p < 0.0001) indicates reduced activity of renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). During pharmacological treatment, 5α-reductase activity in patients returned to the level of the control group, while the decrease in 11β-HSD2 activity persisted until day 28. Conclusions: Our results show changes in activity of intracellular modulators of steroid action in major depressive disorders, particularly a reduced activity of the intracellular cortisol-deactivating enzymes 5α-reductase and 11β-HSD2. These changes suggest an increase in cortisol bioavailability within tissues.

Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics.

Objective: Both conventional and second-generation antipsychotics have been associated with an increased risk for impaired glucose tolerance and diabetes mellitus. Though this has been largely attributed to weight gain, there may also be a direct, receptor-mediated effect of antipsychotics on glucose tolerance. We tested the hypothesis that antagonism of the serotonin (5-HT)-2 receptor impairs insulin sensitivity. Methods: Ten healthy male volunteers were included in a double-blind, placebo-controlled crossover study of a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic-hyperinsulinemic clamp technique. Subjects were treated with the α-1 adrenergic antagonist phenoxybenzamine in both parts of the study to control for ketanserin’s effects at the level of this receptor. Results: Compared with the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4 ± 3.6 mg/kg/min; ketanserin: 7.7 ± 2.1 mg/kg/min; p = .047). Conclusion: The selective 5-HT2 antagonist ketanserin impaired insulin sensitivity. This effect was possibly mediated by suppression of 5-HT2A receptor mediated glucose uptake in skeletal muscle. 5-HT = 5-hydroxytryptamine (serotonin); BMI = body mass index; FPG = fasting plasma glucose; IS = insulin sensitivity; BP = blood pressure.

Activity of the hypothalamus-pituitary-adrenal system and oral glucose tolerance in depressed patients.

We hypothesized that the activity of the hypothalamus-pituitary-adrenal system in depressed patients is related to oral glucose tolerance. In 70 moderately depressed inpatients, we measured morning saliva cortisol for 6 days and assessed oral glucose tolerance. We found glucose concentrations to be positively associated with mean morning cortisol concentrations (F3,236 = 2.86, p < 0.05). Also, the ISI, a measure of insulin receptor sensitivity, was negatively associated with mean morning cortisol concentrations (r = –0.25, p < 0.04). These findings support the hypothesis that hypercortisolemia may lead to disturbed glucose utilization in depressed patients.

Serum Lipoproteins Improve After Successful Pharmacologic Antidepressant Treatment: A Randomized Open-Label Prospective Trial

OBJECTIVE Despite reports of lower plasma cholesterol in depressed patients, major depressive disorder has been shown to increase cardiovascular risk. Our objective was to study the composition of lipoproteins in depressed patients and controls and to examine the effects of pharmacologic treatment and treatment response on lipoprotein composition. METHOD Lipoprotein composition was analyzed in 65 adult inpatients at a university psychiatric hospital in Germany with DSM-IV major depressive disorder and 33 healthy controls (recruited via newspaper and radio ads) matched for age and sex. After the cross-sectional study phase, the patients were randomized in an open-label prospective trial to treatment with either mirtazapine or venlafaxine. Lipoproteins were reanalyzed after 4 weeks of treatment. Main outcome measures were total cholesterol, the low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol ratio, and the LDL triglycerides to apolipoprotein B ratio. Secondary outcome measures were total triglycerides, HDL and LDL cholesterol levels, and apolipoproteins A1 and B levels. Comparisons were made between the 2 drug groups and between remitters and nonremitters as measured by the 21-item Hamilton Depression Rating Scale. The study was conducted from April 2003 through December 2007. RESULTS Total cholesterol at baseline was lower in patients than in controls (mean ± SD = 4.99 ± 0.98 mmol/L vs 5.63 ± 1.01 mmol/L; P = .003), with significantly lower HDL cholesterol (P < .001) and LDL cholesterol (P = .03) in patients. However, the ratio of LDL triglycerides to apolipoprotein B, an index of size and atherogenic potential of LDL particles, was higher in depressed subjects (mean ± SD = 0.46 ± 0.14 mmol/g vs 0.38 ± 0.09 mmol/g; P = .002). Irrespective of treatment allocation, we found significant improvement of cardiovascular risk parameters in remitters but found deterioration in nonresponders. The LDL cholesterol mean change from baseline (remitters vs partial responders vs nonresponders) was -0.06 mmol/L versus +0.39 mmol/L versus +0.56 mmol/L (P = .014); the mean change in LDL/HDL cholesterol ratio was -0.50 versus +0.14 versus +0.80 (P = .002); and the mean change in the LDL triglycerides per apolipoprotein B ratio was -0.01 versus -0.01 versus +0.08 (P = .045). No drug-specific changes in lipid concentrations during treatment were observed except for total cholesterol (venlafaxine group mean = -0.02 mmol/L and mirtazapine group mean = +0.37 mmol/L; P = .033). CONCLUSIONS In depressed patients, lipoprotein structure is changed toward LDL particles with a higher atherogenic potential. Remission from depression is associated with an improvement of the LDL/HDL cholesterol ratio, shifting lipoproteins toward a less atherogenic composition. Our findings should be confirmed in a larger study, as they have relevance for both researchers and clinicians. TRIAL REGISTRATION German Clinical Trial Registry Identifier: DRKS00000008.

Cognition and Sensation in Very High Static Magnetic Fields: A Randomized Case-Crossover Study with Different Field Strengths

PURPOSE To establish the extent to which representative cognitive functions in subjects undergoing magnetic resonance (MR) imaging are acutely impaired by static magnetic fields of varying field strengths. MATERIALS AND METHODS This study was approved by the local ethics committee, and informed consent was obtained from all subjects. In this single-blind case-crossover study, 41 healthy subjects underwent an extensive neuropsychologic examination while in MR units of differing field strengths (1.5, 3.0, and 7.0 T), including a mock imager with no magnetic field as a control condition. Subjects were blinded to field strength. Tests were performed while subjects were lying still in the MR unit and while the examination table was moved. The tests covered a representative set of cognitive functions, such as memory, eye-hand coordination, attention, reaction time, and visual discrimination. Subjective sensory perceptions were also assessed. Effects were analyzed with a repeated-measures analysis of variance; the within-subject factors were field strength (0, 1.5, 3.0, and 7.0 T) and state (static, dynamic). RESULTS Static magnetic fields were not found to have a significant effect on cognitive function at any field strength. However, sensory perceptions did vary according to field strength. Dizziness, nystagmus, phosphenes, and head ringing were related to the strength of the static magnetic field. CONCLUSION Static magnetic fields as high as 7.0 T did not have a significant effect on cognition.

Insulin-like Growth Factor-I (IGF-I) Serum Concentrations in Depressed Patients: Relationship to Saliva Cortisol and Changes during Antidepressant Treatment

INTRODUCTION The present study was designed to test the hypothesis that total and free insulin-like growth factor-I (IGF-I) serum concentrations in depressed patients are related to hypothalamus-pituitary-adrenal (HPA) system activity and show a longitudinal decline in patients responding to treatment as well as to declining HPA system activity. METHODS We measured total and free IGF-I as well as IGF-binding protein-3 in 77 depressed patients after wash-out of pre-medication and again after 28 or 35 days of treatment with paroxetine or amitriptyline. RESULTS Total but not free IGF-I serum concentrations are related to saliva cortisol concentrations in drug-free depressed patients. In responders to both amitriptyline and paroxetine, total IGF-I serum concentrations declined during treatment. DISCUSSION Our findings show IGF-I to be related to HPA system activity and to decline in responders to treatment while serum concentrations of the biologically active free IGF-I are neither related to HPA system activity nor do they change during the course of treatment. Our data do not support the hypothesis that free IGF-I may play a major role in physical disturbances in depressed patients.