On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study

Background: The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect. Methods: Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo. Results: The variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% highest density interval (HDI) [0.98, 1.02], REMA: 95% HDI [1.00, 1.02]). The between-study standard deviation tau under the REMA with respect to lnVR was found to be low (95% HDI [0.00, 0.02]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed. Conclusions: The published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated

Lithium Treatment Over the Lifespan in Bipolar Disorders

Lithium has been the treatment of choice for patients with bipolar disorder (BD) for nearly 70 years. It is recommended by all relevant guidelines as a first-line treatment for maintenance therapy. In this review, we outline the current state of evidence for lithium in the treatment of BD over the lifespan. First, we summarize the evidence on efficacy in general, from relapse prevention to acute anti-manic treatment and its role in treating mood episodes with mixed features and bipolar depression. As patients are often treated for many years and different aspects have to be considered in different phases of life, we discuss the particularities of lithium in the treatment of paediatric BD, in older aged individuals and in pregnant women. Lastly, we discuss the evidence on lithium's proposed suicide-preventive effects, the dangers of rapid discontinuation and lithium's adverse effects, particularly with regard to long-term treatment

Translatom-Analyse der entzündlichen Neurodegeneration

Multiple sclerosis (MS) is the most frequent inflammatory disease affecting the central nervous system (CNS). Alongside the inflammatory lesions due to infiltrating immune cells, there seems to be a chronic neurodegenerative process driving disease progression and longterm disability. Precise mechanisms contributing to neurodegeration are incompletely understood. The goal of this thesis was to investigate the underlying molecular mechanisms that mediate this progressive neuronal damage in a mouse model of MS (EAE). To accomplish this, a cell-specific translating mRNA extraction method termed bacTRAP was used to extract and consequently analyse whole tissue and neuronal mRNA of inflamed and healthy spinal cords. Using qPCR and deep sequencing analysis, multiple gene clusters that are activated in the CNS and particularly in motor neurons during experimental autoimmune encephalomyelitis (EAE) were identified. Gene signatures from immune cells and astrocytes were found to be enriched during inflammation and those from oligodendrocytes and neurons to be depleted. Through the analysis of the neuron-specific translatome during EAE, hundreds of de-regulated transcripts including key components of neurodegenerative pathways were identified. The most significant up-regulation was found for the presynaptic and intrinsically disordered protein Bassoon. Furthermore, among the top up- regulated candidates were several others with a high percentage of intrinsically disordered residues, a common feature of pathologically accumulating proteins. The neuronal deposition of misfolded proteins may result in an increased demand in protein clearance, signified by the activation of pathways involved in proteostasis including ubiquitin- and proteasome- dependent protein degradation. Moreover, evidence for neuronal energy deficit, reduced ATP synthesis, activation of glycolysis and mitochondrial dysfunction was found. This energy shortage may be the driver of impaired protein metabolism and the accumulation of misfolded proteins. These results imply hitherto unappreciated common pathological pathways of EAE/MS with other neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. More research is needed in order to illuminate the role of these de-regulated pathways and their contribution to inflammatory neurodegeneration in order to develop more efficacious treatments for MS patients.Multiple Sklerose (MS) ist die häufigste entzündliche Erkrankung des zentralen Nervensystems (ZNS). Neben entzündlichen Läsionen, welche durch migrierende Immunzellen verursacht werden, scheint es einen chronisch ablaufenden, neurodegenerativen Prozess zu geben, welcher das Fortschreiten der Erkrankung und die langfristige Behinderung be- dingt. Die genauen Mechanismen, welche zur Neurodegeneration beitragen, sind nicht vollständig verstanden. Das Ziel dieser Arbeit war es, die zugrundeliegenden molekularen Mechanismen, welche diesen progressiven neuronalen Verlust vermitteln, zu studieren. Um dies zu erreichen, wurde eine Methode namens bacTRAP genutzt, welche eine zell-spezifische Extraktion translatierender mRNA erlaubt, um neuronale mRNA aus entzündetem und gesundem Rückenmark zu extrahieren und zu analysieren. Mittels qPCR und deep-sequencing analysis konnten multiple Gen-Cluster identifiziert werden, welche im Gesamtgewebe sowie in Neuronen des Rückenmarks während der sogenannten experimental autoimmune encephalomyelitis (EAE) aktiviert werden. Insbesondere waren Signa- turen von Immunzellen und Astrozyten im entzündlichen Gewebe angereichert, während diejenigen von Neuronen und Oligodendrozyten reduziert waren. Durch die neuronenspezifische Translatomanalyse während der EAE gelang es, verschiedene Schlüsselbestandteile neurodegenerativer Signalwege zu identifizieren. Die stärkste Hochregulation wurde für das präsynaptische und intrinsisch ungeordnete Protein Bassoon gefunden. Unter den hochregulierten Genen waren einige weitere mit einem hohen Grad intrinsischer Unordnung, ein gemeinsames Merkmal pathologisch akkumulierender Proteine. Die neuronale Ablagerung dieser fehlgefalteten Proteine führt möglicherweise zu einem erhöhten Be- darf des Proteinabbaus, welcher in unserer Analyse durch die Aktivierung von Signalwegen der Proteostase, insbesondere Ubiquitin- und Proteasom-abhängiger Proteindegradation, angezeigt wurde. Des Weiteren fand sich Evidenz für ein neuronales Energiedefizit, eine reduzierte ATP-Produktion, die Aktivierung von Glykolyse und eine mitochondriale Dysfunktion. Dieser Energiemangel ist möglicherweise Ursache des gestörten Proteinmetabolismus und der Akkumulation fehlgefalteter Protein. Diese Ergebnisse implizieren bisher unbeachtete gemeinsame pathologische Signalwege zwischen EAE/MS und anderen neurodegenerativen Störungen wie der Parkinson-Krankheit und der Alzheimer-Krankheit. Weitere Forschung ist nötig, um die Rolle dieser fehlregulierten Signalwege und ihren Beitrag zur entzündlichen Neurodegeneration besser zu verstehen, mit dem Ziel, wirksamere Behandlungen für MS-Patienten zu entwickeln

On the treatment effect heterogeneity of antidepressants in major depression. A Bayesian meta-analysis

AbstractBackgroundThe average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect.MethodsBayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo.ResultsThe variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% HPD [0.98, 1.02], REMA: 95% HPD [1.00, 1.02]). The between-study variance τ2 under the REMA was found to be low (95% HPD [0.00, 0.00]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed.ConclusionsThe published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated.</jats:sec

On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study

Background The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect. Methods Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo. Results The variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% highest density interval (HDI) [0.98, 1.02], REMA: 95% HDI [1.00, 1.02]). The between-study standard deviation τ under the REMA with respect to lnVR was found to be low (95% HDI [0.00, 0.02]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed. Conclusions The published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated. </jats:sec

Suizidpräventive Effekte von Ketamin und Esketamin

Ketamin und Esketamin werden als rasch und stark wirksame Mittel zur Reduktion von Depressivität und Suizidalität beschrieben. Dieser Beitrag gibt einen Überblick zur Wirksamkeit von Ketamin und Esketamin zur Reduktion von suizidalen Gedanken und Handlungen, basierend auf randomisierten kontrollierten Studien, die bis Dezember 2021 publiziert wurden. Für Ketamin gibt es Hinweise für eine beträchtliche Reduktion von Suizidgedanken, aber nur in den ersten 3 Tagen und die tatsächliche Effektstärke ist aufgrund der Schätzunsicherheit ungewiss. Für suizidale Handlungen fehlen zudem Daten. Die wenigen, aber qualitativ hochwertigeren Studien zu Esketamin fanden bestenfalls schwache Effekte bezüglich Suizidgedanken, auch unter Berücksichtigung der Schätzunsicherheit, und für suizidale Handlungen können keine gesicherten Aussagen getroffen werden. Das Nutzen-Schaden-Verhältnis von Ketamin und Esketamin in der Suizidprävention ist deshalb ungewiss