Michael Colla

Hypercortisolemic Depression Is Associated With Increased Intra-abdominal Fat

Objective Similar to patients with a metabolic syndrome, patients with major depression are at increased risk of developing cardiovascular disorders. Interestingly, both disorders share a specific endocrine syndrome that promotes the accumulation of visceral fat, which again is considered a marker of increased cardiovascular morbidity and mortality. Methods Intra-abdominal fat was measured in 22 postmenopausal depressed women and 23 age-matched healthy women by computer tomography at the level of lumbar vertebrae 1 (L1) and 4 (L4). Saliva was taken in patients and control subjects at 08:00 hours over a period of 7 drug-free days for the measurement of free cortisol. In patients only we performed an oral glucose tolerance test. Results Compared with control subjects, depressed patients with elevated free cortisol concentrations showed similar visceral fat depots at L1 (113.0 ± 41.6 vs. 94.3 ± 53.2 cm2). Hypercortisolemic depressed patients also showed greater fat depots in this area (74.5 ± 55.5 cm2, p = .04) than the normocortisolemic patients. However, a comparison of all patients with control subjects revealed no difference in fat accumulation at either L1 or L4. Finally, glucose concentrations during the glucose tolerance test were higher in hypercortisolemic than in normocortisolemic patients, whereas their insulin levels showed only a tendency toward being increased. Conclusions Hypercortisolemic depressed patients suffer from resistance to insulin and increased visceral fat. The fact that hypercortisolemia reverses depression-related fat loss, particularly in the visceral area, might partially explain why major depression can be considered a risk factor for cardiovascular disorders.

Structured group psychotherapy in adults with attention deficit hyperactivity disorder: results of an open multicentre study.

Attention deficit hyperactivity disorder (ADHD) is a serious mental disorder that often persists in adulthood. In a pilot study, a structured skills training group program for adult ADHD led to significant symptomatic improvements. The present study evaluated the programs effectiveness, feasibility, and patient acceptability in a multicenter setting. Seventy-two adult ADHD patients were assigned to 13 two-hour weekly sessions at 4 different therapy sites. The therapy was well tolerated and led to significant improvements of ADHD, depressive symptoms, and personal health status (p < 0.001). The factors treatment site and medication did not contribute to the overall improvement. Patients regarded the program topics “behavioral analyses,” “mindfulness,” and “emotion regulation” as the most helpful. In this multicenter study, the therapy program showed therapist-independent effects and seemed to be disorder-specific. This warrants the effort of organizing further controlled studies.

Folic Acid, Neurodegenerative and Neuropsychiatric Disease

Folic acid plays an important role in neuroplasticity and in the maintenance of neuronal integrity. Folate is a co-factor in one-carbon metabolism during which it promotes the regeneration of methionine from homocysteine, a highly reactive sulfur-containing amino acid. Methionine may then be converted to S-adenosylmethionine (SAM), the principal methyl donor in most biosynthetic methylation reactions. On the cellular level, folate deficiency and hyperhomocysteinemia exert multiple detrimental effects. These include induction of DNA damage, uracil misincorporation into DNA and altered patterns of DNA methylation. Low folate status and elevated homocysteine increase the generation of reactive oxygen species and contribute to excitotoxicity and mitochondrial dysfunction which may lead to apoptosis. Strong epidemiological and experimental evidence links derangements of one-carbon metabolism to vascular, neurodegenerative and neuropsychiatric disease, including most prominently cerebral ischemia, Alzheimers dementia and depression. Although firm evidence from controlled clinical trials is largely lacking, B-vitamin supplementation and homocysteine reduction may have a role especially in the primary prevention of stroke and dementia as well as as an adjunct to antidepressant pharmacotherapy.

Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression

Hyperactivity of the HPA-system in major depression is reflected by an increased secretion of adrenal hormones especially cortisol and dehydroepiandrosterone (DHEA). In women for whom androgenicity is associated with cardiovascular disorders the dominant source of androstenedione and testosterone secretion are the adrenal glands. To date, there is only sparse information about the regulation of androstenedione, testosterone and dihydrotestosterone (DHT) concentrations in women with severe major depression.Therefore, 11 pre- and postmenopausal, severely depressed, hypercortisolemic women (Hamilton Depression Scale, 31.3+/-5.9; age, 28-77 yrs; mean, 48. 1+/-18.1 yrs) and 11 age-matched healthy female controls (age, 24-81 yrs; mean, 47.9+/-21.5 yrs) underwent a 24 hour (h) blood sampling starting at 0800 h with 30-minute sampling intervals. By applying multivariate analysis of covariance with age as covariate, androstenedione, testosterone and DHT plasma levels at 0900 h show a trend for elevated concentrations in depressed women compared to controls (F(1,19)=2.7; P=0.057). Univariate F tests reveal a significant difference between the groups for androstenedione (4. 19+/-1.571 vs 2.584+/-1.257 nmol/l; P<0.05) testosterone (1.110+/-0. 278 vs 0.833+/-0.347 nmol/l; P<0.05) and DHT (0.656+/-0.207 vs 0. 483+/-0.242 nmol/l; P<0.05). Mean ACTH (16.4+/-10.4 vs 10.4+/-2.4 pmol/l; P=0.89), LH (13.5+/-11.8 vs 8.9+/-9.2 IU/l; P=0.12), FSH (35. 2+/-33.1 vs 31.3+/-35.7 IU/l; P=0.67) and estradiol (135.4+/-157.4 vs 82.2+/-85.1 pmol/l; P=0.20) plasma levels did not differ between patients and controls. Further, there was a trend towards an age related decline in testosterone secretion in healthy controls (r=-0. 24; P=0.08) which did not occur in depressed patients (r=0.17; P=0. 96), while the calculated ratio of DHEA to testosterone was similar in both groups (0.2+/-0.14 vs 0.13+/-0.7; P=0.21, unpaired t-test). In conclusion, androstenedione, testosterone and DHT concentrations all were increased in hypercortisolemic women with severe major depression. These findings are best explained as a consequence of an overstimulation of the adrenal glands through pituitary and hypothalamic sites of the HPA-system.

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.

Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders

Significance Electroconvulsive therapy is controversial: How does a major electrical discharge over half the brain result in recovery in disorders such as refractory major depression and manic depression, which are apparently different diseases? We find local but not general brain anatomy changes following electroconvulsive therapy that are differently distributed in each disease, and the areas affected are those implicated as abnormal in each disorder. An interaction between electroconvulsive therapy and specific pathology appears to be responsible for the therapeutic effect. Our results have implications for other electrically based brain treatments, such as deep brain stimulation and transcranial magnetic stimulation. There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a “barbaric” form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.

Reduced amygdala volume in newly admitted psychiatric in-patients with unipolar major depression

Structural neuroimaging studies investigating amygdala volumes in patients suffering from major depression have yielded variable results. Discrepant findings across studies may be attributable in part to heterogeneity with respect to antidepressant medication and to lack of adequate control for the effects of total brain volume and age. Here, 24 unipolar depressed in-patients newly admitted to a psychiatric unit and 14 healthy control participants matched for age, gender, and years of education underwent quantitative magnetic resonance imaging (MRI) toward the end of a one-week washout period. Saliva cortisol was measured at 08.00 and at 16.00h in patients during washout. Absolute amygdala volumes were significantly reduced in the patient group (by 13% in left amygdala and 12% in right amygdala). The effect of reduced amygdala volumes in patients remained significant after correction for brain volume (BV) and age. Furthermore, amygdala volume measurements in the patient sample showed a significant inverse relationship to the number of preceding depressive episodes. In patients, severity of disease (baseline HAMD scores) and baseline cortisol levels were not related to amygdala volume. This study of a sample of unmedicated depressed in-patients adds to the small, yet growing, body of evidence linking untreated major depression to reduced amygdala volume.

Antidepressive treatment with amitriptyline and paroxetine: Effects on saliva cortisol concentrations

With regard to the course of basal human hypothalamus-pituitary-adrenal (HPA) system activity, there is a lack of data for comparing different classes of antidepressants. Ninety-four patients were included in a study comparing standardized treatment with paroxetine (PAROX) and amitriptyline (AMI) after a drug-free period of at least 6 days. Saliva for measurement of cortisol concentrations was obtained daily at 0800, 1600, and 2200 during the 6 days of drug-free washout and 35 days of active treatment. The course of HPA system activity and psychopathology, as assessed by the Hamilton Depression Scale, was compared by means of repeated-measurement analyses of variance (ANOVA-rm). Only AMI responders—not PAROX responders or nonresponders to either antidepressant—had a significant decline in saliva cortisol concentrations. In hypercortisolemically depressed patients, treatment with AMI may be preferable to PAROX in order to lower HPA system activity.

Mineralocorticoid Receptor also Modulates Basal Activity of Hypothalamus-Pituitary-Adrenocortical System in Humans

Hippocampal mineralocorticoid (MRs) and glucocorticoid receptors (GRs) have been demonstrated to regulate the activity of the hypothalamus-pituitary-adrenocortical (HPA) system. To elucidate the role of the hippocampal MR in the circadian activity of the human HPA system, we studied diurnal secretory profiles of corticotropin (ACTH) and cortisol in 10 healthy male humans before and after an 8-day treatment with the MR antagonist spironolactone. 24-hour blood sampling at 30-min intervals was performed for estimation of cortisol (q30) and ACTH (q120). Saliva cortisol was measured for estimation of unbound cortisol. At the end of the 24-hour sampling period a corticotropin-releasing hormone (CRH) challenge was performed. High plasma concentrations of the active metabolite canrenone were achieved (begin of sampling: 2,653 ± 693 nmol/l; end of sampling: 747 ± 177 nmol/l). There was a significant increase in the diurnal minima (37.1 ± 13.3 vs. 23.7 ± 8.9 nmol/l, p < 0.02) and mean cortisol (193.5 ± 25.8 vs. 173.0 ± 23.0 nmol/l, p < 0.03) plasma concentrations. However, the diurnal peak concentrations and pulsatile secretory features were unchanged after spironolactone treatment. For saliva cortisol, the only significant treatment difference was a decrease in the diurnal amplitude of cortisol relative to the diurnal mean concentration (2.56 ± 0.47 vs. 3.11 ± 0.87, p < 0.03). After spironolactone treatment there was a decrease in diurnal mean ACTH concentrations (46.2 ± 14.4 vs. 41.8 ± 10.3 pmol/l). There was no difference in the ACTH and cortisol response after infusion of CRH before and after spironolactone treatment. CBG plasma concentrations were significantly increased (22.4 ± 2.3 vs. 19.2 ± 2.7 mg/l, p < 0.01) after spironolactone treatment, which possibly contributed to the observed increase in plasma cortisol. In summary, as predicted from animal studies we found significant effects of MR antagonization to be restricted to time windows of low HPA system activity. These findings are similar to the effects of aging upon the HPA system. However, the effect of spironolactone treatment was small, suggesting that the HPA system activity in humans is modulated but not regulated by the hippocampal MR.

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol.

While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T 1H-magnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus–pituitary–adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients>controls) and laterality (left hippocampus>right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.