Daniel Kopf

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.

Hypertension in rats induced by renal grafts from renovascular hypertensive donors.

Renal transplantations were performed, using microsurgical techniques, with adult male two-kidney, one clip hypertensive rats (n = 9) and sham-operated normotensive Wistar-Kyoto rats (n = 8) as kidney donors and with F1 hybrids, bred from Wistar-Kyoto and stroke-prone spontaneously hypertensive rat parents, as recipients. Systolic blood pressure before surgery was 200 +/- 2.7 mm Hg in hypertensive and 115 +/- 1.7 mm Hg in normotensive donors and 144 +/- 7.1 and 138 +/- 3.5 mm Hg in the two groups of recipients. Renal hypertension in donors was maintained for 14 weeks before surgery was performed and the nonischemic kidneys were transplanted. Bilaterally nephrectomized recipients of renal grafts from hypertensive donors developed sustained hypertension (185 +/- 3.9 mm Hg). In contrast, in recipients of renal grafts from normotensive donors, blood pressure decreased significantly to the level of the donors (111 +/- 3.7 mm Hg). Posttransplantation hypertension in recipients of renal grafts from hypertensive donors was associated with intrarenal vascular hypertrophy, smaller kidneys, a decreased glomerular filtration rate, an increased plasma urea concentration, and polydipsia as compared with normotensive transplanted controls. Renal pyelograms revealed no gross anatomic alterations of transplanted kidneys. Our data indicate that secondary damage to the renal grafts caused by high perfusion pressure before transplantation can induce hypertension in recipients of these kidneys. Furthermore, our data suggest that renal mechanisms may be necessary to maintain borderline hypertension in F1 hybrids.

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.

Improving care for patients with dementia hospitalized for acute somatic illness in a specialized care unit: a feasibility study.

BACKGROUND Persons with dementia hospitalized for an acute illness have a high risk of poor outcomes and add to the burden on acute care systems. We developed a segregated Special Care Unit (SCU) in a somatic hospital for patients with challenging behavior resulting from dementia and/or delirium. This pilot study evaluates the feasibility and patient outcomes. METHODS The SCU was established with environmental features that allow for safe and unrestricted ambulation within the unit and create a home-like atmosphere. Daytime activities structure the day and assure additional professional presence. The staff received intensive specialized training. Feasibility criteria were: acceptance by the staff, avoidance of transfers to geriatric psychiatry, lack of serious falls and mortality. Patient outcome criteria were ADL (Barthel index), mobility scores and behavior scores (Wilcoxons, McNemar tests, pre-post design). RESULTS 332 consecutively admitted patients were enrolled. The SCU has been well received by the staff. Length of hospital stay did not differ from other hospital patients (15.3 +/- 8.3 vs. 15.0 +/- 10.3 days, p = 0.54). Six patients were transferred to geriatric psychiatry. Two patients suffered a fall-related hip fracture. The median Barthel Index improved significantly (admission 30, discharge 45, p < 0.001), with only 8.5% of patients suffering functional loss. Wandering, aggression and agitation were significantly reduced (p < 0.001). CONCLUSIONS The SCU has improved the care of patients with challenging behavior. Decline in ADL function and institutionalization occurred to a lesser degree than would be expected in this group of patients. Despite the selection of patients with behavioral problems, transfer to psychiatry was rare.

Role of the kidney in the pathogenesis of primary hypertension.

Primary hypertension in animals and humans probably represents several different pathophysiological states rather than being a uniform nosological entity. Among other factors, renal mechanisms may be primarily and secondarily involved. The availability of genetically homologous animal models for hypertension has greatly promoted studies on the etiology and pathogenesis of high blood pressure disease. In particular, renal transplantation studies between genetically hypertensive and normotensive rats from three different models have provided strong evidence for a primary role of the kidney in genetic hypertension. Other factors, such as vascular, neural, and humoral mechanisms have also been shown to be involved and may be particularly effective in increasing blood pressure, when they act through the kidney. Several functional and biochemical differences have been identified between kidneys from genetically hypertensive and normotensive animals. However, the relative contribution of each of these factors to the development of primary hypertension remains to be determined. Evidence from studies on human renal graft recipients also indicates that, among other factors, the kidney plays an important role in the development of primary hypertension in humans.

Impact of early parental child-rearing behavior on young adults' cardiometabolic risk profile : a prospective study

Objective: To examine prospectively whether early parental child-rearing behavior is a predictor of cardiometabolic outcome in young adulthood when other potential risk factors are controlled. Metabolic factors associated with increased risk for cardiovascular disease have been found to vary, depending on lifestyle as well as genetic predisposition. Moreover, there is evidence suggesting that environmental conditions, such as stress in pre- and postnatal life, may have a sustained impact on an individual’s metabolic risk profile. Methods: Participants were drawn from a prospective, epidemiological, cohort study followed up from birth into young adulthood. Parent interviews and behavioral observations at the age of 3 months were conducted to assess child-rearing practices and mother-infant interaction in the home setting and in the laboratory. In 279 participants, anthropometric characteristics, low-density lipoprotein and high-density lipoprotein cholesterol, apolipoproteins, and triglycerides were recorded at age 19 years. In addition, structured interviews were administered to the young adults to assess indicators of current lifestyle and education. Results: Adverse early-life interaction experiences were significantly associated with lower levels of high-density lipoprotein cholesterol and apolipoprotein A1 in young adulthood. Current lifestyle variables and level of education did not account for this effect, although habitual smoking and alcohol consumption also contributed significantly to cardiometabolic outcomes. Conclusions: These findings suggest that early parental child-rearing behavior may predict health outcome in later life through its impact on metabolic parameters in adulthood. MetS = metabolic syndrome; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SGA = small for gestational age; SUQ = Substance Use Questionnaire; TLFB = timeline followback; BMI = body mass index.

Are renal mechanisms involved in primary hypertension? Evidence from kidney transplantation studies in rats

SummaryPrevious renal transplantation experiments in genetically hypertensive and normotensive rat strains indicated that a genetic defect in the kidney may be primarily involved in the pathogenesis of primary hypertension. In order to investigate whether this is also true for the most widely used animal model of primary hypertension, the spontaneously hypertensive rat (SHR), we performed renal transplantations using SHR and normotensive Wistar-Kyoto rats (WKY) as kidney donors and bilaterally nephrectomized F1 hybrids, bred from SHR×WKY parents as renal graft recipients. Our studies were also designed to differentiate between primary and secondary renal mechanisms as a possible cause of posttransplantation hypertension. Recipients of renal grafts from adult, naive SHR but not from adult normotensive WKY kidney donors developed posttransplantation hypertension. Permanent blood pressure normalization by antihypertensive treatment in adult SHR kidney donors and prehypertensive, young age of SHR kidney donors reduced, but did not prevent, posttransplantation hypertension. Increasing renal perfusion pressure in WKY kidney donors (2-kidney 1-clip hypertension) also resulted in posttransplantation hypertension in recipients of the non-clipped kidneys. Blood pressure remained normal in recipients of renal grafts from young WKY kidney donors. These data suggest that SHR kidneys carry a genetic defect which may be primarily involved in the pathogenesis of primary hypertension.