Tiredness of Life - Conceptualizing a Complex Phenomenon.

A phenomenon referred to as 'tiredness of life' or 'weariness of life' appears in current discussions on the legitimacy of euthanasia for relatively healthy older adults as well as in research on suicidality more broadly. However, a consensus conceptualization of the phenomenon is lacking. In the current paper, we offer such a conceptualization by reviewing and integrating knowledge from terminology, available descriptions, and first qualitative findings. Boredom with life, aversion towards life, meaninglessness, and fatigue are identified as central components of the phenomenon. Per component, we describe how the component was identified, our definition of the component and its foundation in descriptions in the literature, and empirical studies on how the component relates to euthanasia requests and suicidality. Moreover, hypotheses on the structure of the phenomenon are outlined, such as on interactions among and the importance of the different components.

Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial.

BACKGROUND: Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. METHODS: We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. RESULTS: Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. CONCLUSIONS: This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development.

Older Adults Who Experience Their Lives to Be Completed and No Longer Worth Living: A Systematic Mini-Review Into Used Terminology, Definitions, and Interpretations.

In the Netherlands and in Belgium, a political debate emerged regarding the possibility of euthanasia and assisted suicide (EAS) for older adults who experience their lives as completed and no longer worth living, despite being relatively healthy. This mini-review aimed to (1) present an overview of the terms used to denote this phenomenon as well as their definitions and to (2) explore how the underlying experiences are interpreted by the study authors. A systematic search was performed in Web of Science, MEDLINE, PsycINFO, and CINAHL, yielding 35 articles meeting the selection criteria. We selected empirical, English-language articles published in peer-reviewed journals. Participants had to have a first-person experience of the phenomenon or be assessed for it, or have a third-person experience of the phenomenon. Results show that the terms tiredness of life (ToL) and weariness of life (WoL) were used most frequently, also in the broader literature on suicidal expressions across the life span. Many studies mentioned operational definitions or synonyms rather than theoretical definitions. Moreover, inside the EAS debate, the term ToL was more common, its definition incorporated death wishes, and it was regularly framed existentially. Outside of this debate, the phenomenon was generally considered as a part of suicidal ideation distinct from death wishes, and its experience was often associated with underlying psychopathology. We discuss the need to establish consensus definitions and conclude that only a multidimensional view may be suitable to capture the complex nature of the phenomenon.

The Role of Perseverative Cognition for Both Mental and Somatic Disorders in a Naturalistic Psychiatric Patient Sample.

OBJECTIVE: Perseverative cognition (PC) is the repeated or long-term activation of the cognitive representation of psychological stressors and is associated with prolonged stress including somatic and mental consequences. Hence, PC might represent a cognitive process linking mental and somatic pathology, but current research on this link is limited by investigating healthy samples, markers of somatic disease, and single disorders. The present study explored the importance of PC for different mental and somatic disorders in psychiatric patients. METHODS: Data from 260 naturalistic psychiatric outpatients were used. Psychiatric diagnoses were based on structured clinical interviews. Somatic diseases were assessed using a well-validated questionnaire and were clustered into (cardio)vascular and immune/endocrine diseases. PC was operationalized using the Perseverative Thinking Questionnaire (PTQ). RESULTS: Multiple regression complemented with relative importance analyses showed that the PTQ total and subscale scores were associated with the presence of mood disorders, addiction, and anxiety. Unexpectedly, no relatively important associations were found between the PTQ and autism spectrum disorder, attention-deficit/hyperactivity disorder, or somatic disease. CONCLUSIONS: Our data complement previous work linking PC to stress-related mental disorders but question its immediate role in neurodevelopmental and somatic disorders. Targeting PC in the treatment of mood disorders and perhaps also in addiction seems promising.

Histamine deficiency in gene-targeted mice strongly reduces antigen-induced airway hyper-responsiveness, eosinophilia and allergen-specific IgE.

Histamine is an important mediator released from activated mast cells provoked by allergen and has a substantial role in the pathophysiology of asthma. However, several lines of evidence indicate that histamine could also have important functions in the regulation of basic cell biological processes. We have used histidine decarboxylase gene-targeted (HDC-KO) mice, lacking histamine, to investigate the effect of histamine deficiency in an animal model of asthma. Our previous investigations revealed that HDC-KO mice had fewer mast cells with reduced granular content and defective degranulation characteristics. Ovalbumin (OVA)-sensitized and challenged HDC-KO mice had significantly reduced airway hyper-responsiveness, lung inflammation, bronchoalveolar lavage eosinophilia, and OVA-specific IgE compared with congenic wild-type littermates treated in the same way. Comparing the expression profiles of cytokines, the levels of IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IFN-gamma were significantly lower in the HDC-KO mice in asthmatic late phase, indicating a significantly altered immune response to OVA provocation and challenge. Evaluation of chemokine gene expression revealed that OVA treatment caused elevation of both T(h)1- and T(h)2-type chemokines in wild-type mice, while the chemokine expression was polarized toward a T(h)1 response in HDC-KO mice. According to our results we can suggest that the possible causes of the reduced asthma symptoms in the HDC-KO mice may be the imperfect mast and eosinophil cell system, and an altered immune response to OVA provocation and challenge.