Der Einfluss klinischer, sozialer und biologischer Faktoren auf metabolische Komorbiditäten der Depression und Therapieerfolg

Die Major Depression zählt zu den weltweit wichtigsten Ursachen für gesundheitliche Beeinträchtigungen und ist mit vielen psychischen und körperlichen Folgeerkrankungen assoziiert. Metabolische Erkrankungen zählen zu den häufigsten Komorbiditäten der Depression und beeinflussen das unmittelbare Behandlungsergebnis und die Langzeitprognose negativ. Longitudinale Studien belegen den bidirektionalen Zusammenhang zwischen Depression und metabolischen Erkrankungen. Verschiedene klinische, psychosoziale und biologische Mechanismen erklären diese bidirektionale Relation. Chronizität ist ein wichtiger Faktor, der mit schlechterem Behandlungsergebnis nach multimodaler Behandlung der Depression einhergeht. Im Hinblick auf metabolische Auffälligkeiten bei depressiven Patient:innen ist dieser Befund von hoher Relevanz, da Chronizität eine Konsequenz vom Zusammenspiel von Depression und metabolischen Dysregulationen sein könnte. Dieser Zusammenhang konnte am Beispiel der Altersdepression gezeigt werden. Die Zunahme von metabolischen Auffälligkeiten mit längerer Dauer der depressiven Erkrankung geht mit negativen Auswirkungen auf das Therapieergebnis einher. Diese Ergebnisse unterstreichen die Notwendigkeit der Prävention von metabolischen Risikofaktoren und Chronizität bei der Depressionsbehandlung. Das Risiko für die Entwicklung von metabolischen Erkrankungen ist bei Patient:innen mit MDD außerdem bereits im jüngeren Alter erhöht. Neuroendokrine Veränderungen könnten eine Erklärung dafür sein. Daher sollten in Zukunft Modulatoren der Steroidhormonsysteme bezüglich ihres Potenzials Depressionssymptome und metabolische Risikofaktoren zu reduzieren weitererforscht werden. Für die effektive Prävention von Depression bei komorbider Adipositas sollten spezifisch zugeschnittenen Maßnahmen insbesondere für Frauen mit niedrigem sozioökonomischem Status und geringer sozialer Unterstützung entwickelt werden. Aus sozialer Benachteiligung ergibt sich häufig ein Circulus vitiosus mit wechselseitiger Verstärkung von Depression und metabolischen Erkrankungen. Die Verbesserung der sozialen-, emotionalen- und finanziell-ausreichenden Unterstützung von sozial benachteiligten Menschen könnte das Problem Depression bei komorbider Adipositas in seinem gesellschaftlichen Kontext adressieren. Schließlich wurde unter Berücksichtigung von potenziellen Störfaktoren ein stärkerer Zusammenhang von Adipositas mit CRP im Vergleich zu Depression gefunden. Dieser Befund korrespondiert mit Ergebnissen aus aktuellen Untersuchungen, die zeigen, dass CRP im nicht-klinischen Sample eher mit komorbiden und konfundieren Faktoren der Depression assoziiert ist als mit Depression selbst. Zusätzlich wurde ein spezifischer positiver Zusammenhang zwischen Fatigue und CRP gefunden. Zusammenfassend deuten diese Ergebnisse darauf hin, dass die chronische Inflammation als pathophysiologischer Mechanismus für diejenigen mit bestimmten Symptomen der Depression, die Veränderungen der Energiehomöostase ausweisen (z.B. Fatigue), und mit komorbiden metabolischen Erkrankungen (z.B. Adipositas), relevant sein könnte. Für zukünftige Interventionen lässt sich ableiten, dass gezielte Maßnahmen für adipöse Patient:innen mit MDD notwendig sind, um die chronische Inflammation zu reduzieren, die ein Treiber für die wechselseitige Verstärkung von Depression und metabolischen Erkrankungen ist

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age- and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others’ emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-angstrom sberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

a study of emotions in dreams in bipolar disorder

Die bipolaren Störungen sind gekennzeichnet durch das rezidivierende Auftreten von affektiven Episoden, die das Leben der Betroffenen auf verschiedenen psychischen, körperlichen und sozialen Ebenen erheblich beeinflussen. Als Träumen wird die psychische Aktivität während des Schlafs bezeichnet. Ob dem Träumen eine bestimmte Funktion zugeschrieben werden kann, ist gegenwärtig Gegenstand der Kontroverse. Nichtsdestotrotz scheinen sich die Forscher darüber einig zu sein, dass sich Aspekte des Wachlebens im Traum widerspiegeln. Diese sogenannte Kontinuitätshypothese treffe insbesondere für Emotionen sowie für psychopathologische Symptome zu. In der vorliegenden Dissertation wurden daher die Traumemotionen der bipolaren Patienten untersucht, und zwar in der Annahme, dass ihre affektiven Symptome in den Träumen kontinuierlich fortgesetzt werden. Erstmalig in der Geschichte der Traumforschung wurden mit der Central Image Methode Traumemotionen der nach der aktuellen Störungsphase unterteilten bipolaren Patienten im Vergleich zu einer gesunden Kontrollgruppe analysiert. Nach der Contemporary Theory of Dreaming wird im Traum der emotionale Zustand des Träumers bildlich dargestellt. Die dominierende Emotion kontextualisiert dabei das Central Image (CI), dessen Intensität Rückschlüsse auf den emotionalen Zustand des Träumers erlaubt. Konkret bewerteten zwei unabhängige Beurteiler aus jedem Traumbericht, sofern ein Central Image (CI) vorhanden war, die Intensität des CI (CI-Intensität) und die am wahrscheinlichsten kontextualisierende Emotion (CI-Emotion). Die Schwere der affektiven Symptome wurde zeitgleich mit der HAMD-21 und YMRS erfasst. Insgesamt wurden 419 Träume von 33 Kontrollprobanden und 27 bipolaren Patienten über einen Erfassungszeitraum von 3 Wochen akquiriert. Im Vergleich der depressiven Gruppe mit der manischen Gruppe wiesen die Traumemotionen der depressiven Patienten einen größeren Negativitätsindex und die Traumemotionen der manischen Patienten einen größeren Positivitätsindex auf. Wider Erwarten zeigte sich kein Unterschied bezüglich der CI-Intensität zwischen den Probandengruppen. Depressive und manische Patienten berichteten signifikant mehr Träume als euthyme Patienten und Kontrollprobanden. In den Träumen der depressiven Patienten befanden sich signifikant häufiger Furcht/Entsetzen, Schuld sowie Sehnsucht. Dagegen kennzeichnete das signifikant häufigere Vorkommen von Scheu/Verwunderung/Geheimnis und Glück/Freude/Erregung die Träume der manischen Patienten. Insgesamt wurden in der vorliegenden Arbeit neue Erkenntnisse über CI-Emotion und CI-Intensität sowie Traumerinnerungsfähigkeit der bipolaren Patienten gewonnen. Nichtsdestotrotz bedürfen die hier gewonnenen Befunde einer Bestätigung durch weitere Studien mit einer größeren Stichprobe. Weiterhin besteht Forschungsbedarf bezüglich der Art und Weise, wie Emotionen des Wachlebens in den Träumen reflektiert werden. Ferner könnte die Untersuchung von Traumserien im Hinblick auf intraindividuelle Veränderungen über verschiedene Störungsphasen weitere wichtige Erkenntnisse liefern. Auf diesen Grundlagen könnten schließlich die Möglichkeiten der diagnostischen, prognostischen sowie psychotherapeutischen Anwendung von Träumen für die moderne Psychiatrie diskutiert und weiterentwickelt werden.Bipolar disorders are characterized by fluctuation of mood states with serious consequences for several aspects of the lives of those affected. According to the Continuity Hypothesis of Dreaming the content of dreams is largely continuous with waking concepts and emotional concerns of the dreamer. Therefore, if a clear relationship exists between mood and dream content, qualitative changes in dreams of bipolar patients should be evident. Ernest Hartmann proposed a theory called Contemporary Theory of Dreaming in which underlying emotions of the dreamer shape dream imagery. Among the dream images Hartmann identified the Central Image (CI) to be the most powerful image of all which is contextualized by the dominant emotion of the dreamer. Moreover, a high intensity of CI seemed to be related to dreams of people with high levels of emotional arousal. The present study investigated dream reports of bipolar patients in depressive, euthymic and manic phases and healthy controls by scoring dreams regarding to proportion of positive and negative emotions, intensity of CI, type of emotion contextualized and dream recall frequency. Two independent raters evaluated 419 dreams of 33 healthy controls and 27 bipolar patients for a period of 3 weeks. Alongside the dream content analysis, severity of affective symptoms was measured by the Hamilton Rating Scale for Depression and Young Mania Rating Scale. Even though there was a preponderance of negative dream emotions in all groups, dreams of depressive patients showed a significantly higher negativity score than those of manic patients. Correspondingly, the dreams of manic patients had a significantly higher positivity score than those of depressive patients. Contrary to our second hypothesis, intensity of the CI didn’t differ between the groups. In addition, analysis showed that depressive and manic patients reported significantly more dreams than euthymic patients and controls. Furthermore, three types of emotions, namely fear/terror, guilt and longing, were significantly predominant in dreams of depressive patients. On the other hand, manic patients reported significantly more dreams with awe/wonder/mystery as well as happiness/joy/excitement. Together these findings support the Continuity Hypothesis of Dreaming and pave the way for dreams to be used as a diagnostic, prognostic and therapeutic tool. However, further investigations regarding changes in dream recall and content over the course of symptom remission together with an examination about the exact mechanism of the continuity of emotions in waking and dreaming states are essential for the reintroduction of dreams into the modern psychiatry

Pressure-Free Assembling of Poly(methyl methacrylate) Microdevices via Microwave-Assisted Solvent Bonding and Its Biomedical Applications

Poly(methyl methacrylate) (PMMA) has become an appealing material for manufacturing microfluidic chips, particularly for biomedical applications, because of its transparency and biocompatibility, making the development of an appropriate bonding strategy critical. In our research, we used acetic acid as a solvent to create a pressure-free assembly of PMMA microdevices. The acetic acid applied between the PMMA slabs was activated by microwave using a household microwave oven to tightly merge the substrates without external pressure such as clamps. The bonding performance was tested and a superior bond strength of 14.95 &plusmn; 0.77 MPa was achieved when 70% acetic acid was used. Over a long period, the assembled PMMA device with microchannels did not show any leakage. PMMA microdevices were also built as a serpentine 2D passive micromixer and cell culture platform to demonstrate their applicability. The results demonstrated that the bonding scheme allows for the easy assembly of PMMAs with a low risk of clogging and is highly biocompatible. This method provides for a simple but robust assembly of PMMA microdevices in a short time without requiring expensive instruments

Early treadmill exercise increases macrophage migration inhibitory factor expression after cerebral ischemia/reperfusion

The neuroprotective function of macrophage migration inhibitory factor (MIF) in ischemic stroke was rarely evaluated. This study aimed to investigate the effects of early treadmill exercise on recovery from ischemic stroke and to determine whether these effects are associated with the expression levels of MIF and brain-derived neurotrophic factor (BDNF) in the ischemic area. A total of 40 male Sprague-Dawley rats were randomly assigned to the ischemia and exercise group [middle cerebral artery occlusion (MCAO)-Ex, n = 10), ischemia and sedentary group (MCAO-St, n = 10), sham-surgery and exercise group (Sham-Ex, n = 10), or sham-surgery and sedentary group (Sham-St, n = 10). The MCAO-Ex and MCAO-St groups were subjected to MCAO for 60 minutes, whereas the Sham-Ex and Sham-St groups were subjected to an identical operation without MCAO. Rats in the MCAO-Ex and Sham-Ex groups then ran on a treadmill for 30 minutes once a day for 5 consecutive days. After reperfusion, the hanging time tested by the wire hang test was longer and the relative fractional anisotropy determined by MRI was higher in the peri-infarct region of the MCAO-Ex group compared with the MCAO-St group. The expression levels of MIF and BDNF in the peri-infarct region were upregulated in the MCAO-Ex group. Increased MIF and BDNF levels were positively correlated with relative fractional anisotropy changes in the peri-infarct region. There was no significant difference in the levels of MIF and BDNF in the peri-infarct region between the Sham-Ex and Sham-St groups. Our study demonstrated that early exercise (initiated 48 hours after the MCAO) could improve motor and neuronal recovery after ischemic stroke. Furthermore, the increased levels of MIF and BDNF in the peri-infarct region (penumbra) may be one of the mechanisms of enhanced neurological function recovery. All experiments were approved by the Institutional Animal Care and Use Committee in Asan Medical Center in South Korea (2016-12-126)

Neonatal-Onset PIGT Encephalopathy: A Rare Korean Case with Hypophosphatasia

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Effects of glucocorticoid and noradrenergic activity on spatial learning and spatial memory in healthy young adults

Background: Acute stress leads to a rapid release of noradrenaline and glucocorticoids, which in turn influence cognitive functions such as spatial learning and memory. However, few studies have investigated noradrenergic and glucocorticoid effects on spatial learning and memory in humans. Therefore, we examined the separate and combined effects of noradrenergic and glucocorticoid stimulation on spatial learning and memory. Methods: One hundred and four healthy men (mean age = 24.1 years +/- SD 3.5) underwent the virtual Morris Water Maze (vMWM) task to test spatial learning and spatial memory retrieval after receiving either 10 mg hydrocortisone or 10 mg yohimbine (an alpha 2-adrenergic receptor antagonist that increases noradrenergic activity), 10 mg hydrocortisone and 10 mg yohimbine combined, or placebo. The vMWM task took place 90 min after yohimbine was administered and 75 min after hydrocortisone was administered. Placebo was given at the same times. Salivary cortisol and alpha amylase levels were measured to check pharmacological stimulation. Results: Hydrocortisone and yohimbine increased salivary cortisol and alpha amylase levels. Participants' task performance improved over time, suggesting successful spatial learning. However, separate and combined noradrenergic and glucocorticoid stimulation had no effect on spatial learning and spatial memory retrieval compared with placebo. Conclusions: In healthy young men, hydrocortisone and/or yohimbine did not alter spatial learning or spatial memory retrieval. Importantly, pharmacological stimulation took place prior to learning. Further studies should examine the effects of glucocorticoid and noradrenergic stimulation during encoding, consolidation, and retrieval