Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site

Are scientific findings exaggerated? study finds steady increase of superlatives in PubMed abstracts.

Are scientists using language aimed at convincing editors and reviewers to publish their work? Joeri Tijdink, Christiaan Vinkers and Wim Otte present findings which suggest a rise in potentially exaggerated language. Potentially conflicting with the core values of science, the pressure to publish in high impact publications may be contributing to a paradigm of over-interpretation, overstatement and misreporting of scientific results

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive syniptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MOD recurrence (P = 0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T + and TCE +); 461 days for T - and TCE + patients; 773 days for T + and TCE - patients and 866 days for T - and TCE - patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P = 0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MOD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MOD recurrence after exposure to childhood trauma

Een onderzoek naar de compatibiliteit van de Nederlandse wet- en regelgeving met Europese Richtlijn 2013/48/EU en laatste jurisprudentie van het EHRM inzake de rol van de raadsman tijdens het politieverhoor.

Richtlijn 2013/48/EU verplicht lidstaten verhoorbijstand wettelijk te regelen. Is de Nederlandse wet en de bijbehorende regelgeving inzake de rol van de raadsman tijdens politieverhoor conform de Europese Richtlijn 2013/48/EU en de laatste jurisprudentie van het EHRM? In mijn onderzoek kwam ik tot de volgende selectie van onderwerpen binnen de verhoorbijstand op basis waarvan ik mijn rechtsvergelijkende onderzoek vorm heb gegeven, te weten; de verdachte, moment van toegang, wijze van toegang, rechtsbijstandverlener, regels verhoorbijstand en de rechtsgevolgen. Ik omschrijf telkens op basis van de geselecteerde onderwerpen achtereenvolgens het Europese kader, de Nederlandse situatie en ik maak een rechtsvergelijking met de buurlanden België en Engeland & Wales. Ik beoordeel of de onderwerpen in de Nederlandse wet voldoen aan hetgeen geïmplementeerd moest worden volgens de Richtlijn en of er stringentere voorwaarden zijn gesteld in jurisprudentie van het EHRM waarmee Nederland rekening zou moeten houden. Op basis van de toetsing kom ik tot de conclusie dat de huidige wetgeving tegemoet komt aan de minimum eisen gesteld in de Richtlijn, maar heb ik ook aanbevelingen kunnen doen

Atheroslerosis, cognitive impairment, and depression in old age.

Pathofysiologie, epidemiologie en therapie bij verouderin

The validity of the BDHI translated into Papiamento in pre-trial defendants in Curaçao

The Buss-Durkee Hostility Inventory (BDHI) is an important assessment scale of hostility in forensic psychiatry. We analyzed the validity and reliability of a Papiamento translation of the BDHI in 134 pre-trial defendants in Curaçao using Exploratory Structural Equation Modeling (ESEM). The reliability of the Direct and Indirect Hostility BHDI-P subscales were good and the reliability of the Social Desirability poor. There was a negative correlation between Direct Hostility and Agreeableness and a positive correlation between Indirect Hostility and Anxiety. We conclude that the BDHI-P has an acceptable measurement quality when used in defendants.</p

Childhood trauma and dysregulation of multiple biological stress systems in adulthood:Results from the Netherlands Study of Depression and Anxiety (NESDA)

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive. Methods: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood. Results: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems’ activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β =.088, p =.007; AUCi, β =.084, p =.010), cumulative HPA-axis markers (β =.115, p =.001), C-reactive protein (β =.055, p =.032), interleukin-6 (β =.053, p =.038), cumulative inflammation (β =.060, p =.020), and cumulative markers across all systems (β =.125, p =.0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases. Conclusion: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health