Ludwig Schaaf

Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers

Objective  In multiple endocrine neoplasia type 1 (MEN1), age‐related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in‐depth. This study was conducted to examine whether carriers of out‐of‐frame/truncating and in‐frame MEN1 mutations differ in age‐related tumour penetrance.

Subclinical hyperthyroidism: Physical and mental state of patients

SummaryWe investigated whether subclinical hyperthyroidism [subnormal basal thyroid-stimulating hormone (TSH) level, attenuated TSH response to thyrotropin-releasing hormone (TRH) stimulation, peripheral thyroid hormones within normal range] is accompanied by physical and mental changes. Thirty-five subclinically hyperthyroid patients (27 female, 8 male) were compared with 60 overtly hyperthyroid patients (51 female, 9 male) and with 28 euthyroid control patients (18 female, 10 male) with respect to physical symptoms, affective state, short-term memory, ability to concentrate and psychomotor performance. Patients with subclinical hyperthyroidism ranged between the other two groups. The major difference between controls and subclinically hyperthyroid patients was an increase in frequency of nervous symptoms and symptoms due to an increase of metabolic rate and thermal regulation changes. The major differences between subclinically hyperthyroid and overtly hyperthyroid patients were psychomotor impairment and symptoms of increased metabolic rate. Self-ratings of affective state tended to be similar in patients with subclinical and overt hyperthyroidism. The ability to concentrate and short-term memory were not impaired in any group. Symptoms in patients with subclinical hyperthyroidism probably result from central changes which lead to attenuated TSH responses to TRH, or from elevated but still normal thyroxine levels, which possibly enhance the effect of catecholamines.

Glucose Metabolism and Antidepressant Medication

Impaired glucose tolerance is observed in depressed patients, and patients suffering from depression have an increased risk to develop diabetes mellitus. In depressed and diabetic patients, studies have shown both a beneficial effect of antidepressants on glucose homeostasis and the opposite. This review aims to structure the conflicting data and focuses on the question, which effect specific antidepressants have on glucose homeostasis. We therefore performed a systematic review of all available studies referenced in Medline from 1960 to 2011. We included antidepressant agents indexed in the Anatomical Therapeutic Chemical (ATC) classification system of the WHO in 2011 and searched for studies investigating their effects on glucose metabolism in clinical samples as well as in healthy subjects. Of 876 studies screened we included 66. Most studies had small sample sizes and lacked a placebo group limiting conclusions about antidepressant effects on glucose tolerance. However, some evidence points to beneficial effects on glucose homeostasis of hydrazine-type monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). In case of SSRIs, the effect is more pronounced in diabetic patients or patients with comorbid depression and diabetes mellitus. Noradrenegic substances (and possibly also dualacting antidepressants), in contrast, may deteriorate glucose tolerance. They can be used in depressed patients when favorable effects on mood outweigh adverse metabolic effects, but in depressed diabetics this can be at the expense of worsening of glycemic control. The effects of other antidepressants, like bupropione, mirtazapine or newer agents, require further investigation before reliable conclusions can be made. The synthesis of the findings is discussed in light of the specific pharmacodynamic properties of the antidepressants as well as the pathophysiological changes in depression and impaired glucose homeostasis, including animal studies.

Nocturnal secretion of TSH and ACTH in male patients with depression and healthy controls

Profound alterations of the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) systems at the hypophyseal level have been described in affective disorder. To precisely characterize the basal alterations of both axes during sleep, we simultaneously investigated sleep EEG and the secretion of thyrotropin, ACTH and cortisol in nine drug-free male patients with depression in comparison to 10 healthy age and sex matched controls. In depressed patients the nearly diametrical nocturnal secretion of thyrotropin and ACTH was disturbed by significantly blunted thyrotropin values (TSH AUC 51.96+/-5.68 vs. 87.23+/-13.63, P<0.05) and elevated ACTH values (ACTH AUC 1804+/-161 vs. 1538+/-130, P<0.05) compared to controls. Moreover, cross correlation analysis revealed a highly negative association of 0 lag between thyrotropin and ACTH and between thyrotropin and cortisol in the control sample, indicating a physiological nocturnal negative correlation of HPT and HPA system. In the patients sample these associations were weak and reached not statistical significance. Therefore, as a descriptive tool, the ratio TSH/ACTH revealed a significant group difference between controls and patients in the first half of the night (TSH/ACTH AUC 6.50+/-0.42 vs. 3.35+/-0.31, P<0.05). Sleep-EEG analysis showed a shortened REM latency, a decrease of stage 2 and an increase of awake time in the patients. Our data support the hypothesis that both hypophyseal hormones reflect a common dysregulation of both systems in depression probably due to impaired action of TRH-related corticotropin-release-inhibiting-factor (CRIF). The ratio TSH/ACTH might be a tool to characterize alterations of both the HPT and HPA axis in depression during the first half of the night.

Mirtazapine provokes periodic leg movements during sleep in young healthy men.

STUDY OBJECTIVES Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. DESIGN Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. SETTING Research institute. PARTICIPANTS Twelve healthy young (20-25 years) men. INTERVENTIONS Seven days of nightly intake (22:00) of 30 mg mirtazapine. MEASUREMENTS AND RESULTS Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. CONCLUSIONS Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls.

Impaired glucose tolerance and diabetes have been associated with depression, and antidepressant treatment is assumed to improve impaired glucose tolerance. However, antidepressant treatment is also considered as a risk factor for the development of diabetes. Reports about glucose tolerance under antidepressant treatment frequently lack appropriate control groups. We conducted the oral glucose tolerance test (OGTT) in 10 healthy controls selected from an epidemiological sample with a negative lifetime history of mental Axis I disorder. Controls were carefully matched to a sample of inpatients with major depression that participated in an OGTT before and after antidepressant treatment with mirtazapine. All participants underwent a standard OGTT protocol. In patients, a second (after 2 weeks) and a third (after 4-6 weeks) OGTT was performed under treatment with mirtazapine. Compared to healthy controls, we observed significantly impaired glucose tolerance in acutely depressed patients. Effect size calculation indicated a moderate to large effects on glucose and insulin concentrations in response to an OGTT. Although glucose tolerance improved under mirtazapine treatment, insulin sensitivity was still impaired and remained significantly lower in patients compared to controls.

Clinical and molecular diagnosis of multiple endocrine neoplasia type 1.

Abstract Multiple endocrine neoplasia type 1 (MEN1) is a classic hereditary tumor syndrome characterized by a genetic predisposition to develop a variety of neuroendocrine neoplasias and hormone excess syndromes. The disease is caused by inactivating mutations of the MEN1 tumor suppressor gene, detectable in >95% of MEN1 families. The distinction of MEN1-associated tumors from sporadic neuroendocrine neoplasias is clinically important for providing optimal surgical and medical therapy, appropriate clinical follow-up, and counsel for affected patients and their families. Since MEN1 gene analysis became available in 1997, new diagnostic approaches have evolved in clinical management, to be reviewed in this article. Genetic screening of MEN1 families will allow definition of individual disease risk at a preclinical stage, thus helping to allocate medical resources and treatment as individually needed. These new diagnostic approaches are expected to reduce MEN1-associated morbidity and mortality, health care expenses, and psychological disease burden.

The relationship between adult neuropsychological profiles and diabetic patients' glycemic control.

The purpose of this study was to assess, in relation to metabolic control, the cognitive, depressive, and anxiety symptoms among 40 adult patients (age: 18–60 years) with either type 1 (n = 28) or type 2 (n = 12) diabetes mellitus (DM1, DM2). Nineteen healthy subjects matched for age, gender, and education served as the control group. For most cognitive domains, no significant performance differences were found between subjects from the diabetic groups and control subjects. However, diabetes patients demonstrated reduced information processing accuracy along with impaired visual and verbal working memory performance. In addition, psychopathology scores were significantly elevated but did not reach the clinical criteria for depression or anxiety. Overall, there were no significant differences between diabetic subgroups, and no significant correlation was found between cognitive performance, psychopathology scores, and HbA1c values for either subgroup. Thus, patients with DM1 or DM2 may show mild-to-moderate cognitive impairment as well as subtle psychopathological symptoms. While cognitive impairments may be understood in terms of diabetes-associated cognitive dysfunction, psychopathological symptoms may also result from unsuccessful coping with high task demands in everyday life activities. The outcome of the current study underscores the importance of early clinical neuropsychological standardized assessment as well as the diagnosis of cognitive and psychopathological symptoms in adult patients with diabetes.

The influence of 4-week treatment with sertraline on the combined T3/TRH test in depressed patients.

AbstractIn the present study, the influence of a 4–week treatment with sertraline on the regulation of hypothalamic–pituitary–thyroid (HPT) axis activity in depression was investigated, in particular the impact of sertraline on the thyroid receptor (TR)–mediated negative feedback control as measured by the combined T3/TRH test. In 20 drug–free patients (8 men,12 women) suffering from a major depressive episode according to DSM-IV criteria the single TRH–stimulation test (administration of 200 µg TRH at 09:00h) was carried out followed by a combined T3/TRH test (pre–treatment with 40 µg 3,5,3’–triiodothyronine [T3] the night before; administration of 200 µg TRH at 09:00h the next day). After 4 weeks of treatment with sertraline at a standard dosage of 50 mg/day, both the single TRH test and the combined T3/TRH test were repeated in the depressed patients. Using repeated–measures ANOVA for statistical analysis, antidepressant therapy with sertraline did not have any significant impact on the TRH–induced TSH and prolactin stimulation (ΔTSH, ΔPRL) during the single TRH test nor during the combined T3/TRH test, neither in responders (n = 10) nor in non–responders (n = 10). Moreover, the percentage suppression of TRH–induced TSH stimulation (ΔTSH) after pre–treatment with 40 µg T3 was comparable before (–61.07 %) and after the 4–week treatment with sertraline (–58.92 %). Apparently, the therapeutic efficacy of antidepressants such as sertraline is not related to the regulation of HPT axis activity in depressed patients.

Erhöhtes Frakturrisiko bei Diabetikern

ZusammenfassungNoch zu wenig im Blick haben viele Ärzte ein möglicherweise erhöhtes Frakturrisiko bei Diabetikern. Im nachfolgenden Beitrag lesen Sie, welche Faktoren dafür verantwortlich sind und welche prophylaktischen Maßnahmen ergriffen werden können.