Work often leads to better outcomes in terms of health, nutrition, and reproductive success, suggesting that work execution should be favored by natural selection. However, work also involves expending energy and time, costs that biological systems aim to limit. Indeed, work is often accompanied by the subjectively aversive experience of effort, which motivates work avoidance. Accordingly, decision-makers need to trade off the expected benefits of the goal their work aims to achieve with the anticipated effort costs before engaging in any action. While such trade-offs are relatively well-characterized, effort-based decision-making involve several other essential components, including the representation of anticipated effort and its comparison with experienced effort, which allows learning. These components and their relation to arousal received considerably less attention. To thoroughly dissect effort-based decision-making, we here synthesize the framework of value-based decision-making and expand it with work preparation, execution and recovery subprocesses. This systematizes existing research, highlights the specificities of effort-based decision-making, and identifies understudied components. Moreover, we use this framework to analyze (neuro)physiological commonalities and differences between motor and cognitive effort. Finally, we propose a novel, arousal-based model of effort suggesting that required increases in arousal give rise to effort and serve as a common currency that effort indexes and effort-based decisions aim to minimize.
The systematic use of alcohol is a frequent behaviour on a world-wide scale. Some of the users develop an abuse pattern of consumption and an alcohol use disorder (AUD). This is considered as a major psychiatric disorder causing significant suffering for the individual and society. As yet, there are no satisfactory and broadly working treatment options for AUD available, which has sparked research in a better understanding of neurobiological mechanism of alcohol and AUD and the search for an evidence-based treatment rational. Here we review the development of neuropharmacological insights focusing on selected brain mechanisms that have recently experienced significant progress and which give rise to new pharmaco-development ideas for AUD. Those include alcohol action and AUD mechanisms in the actin cytoskeleton system, in the nociceptin/orphanin system, and in the endocannabinoid system. Besides progress in pharmacotherapeutic targets, there are developments in how this therapy may be better applied in a personalized and addiction phase-sensitive way. This embraces new technologies like Ecological Momentary Assessment (EMA) for near real-time AUD symptom diagnosis, treatment allocation, and success monitoring. Emergence and future potential of this combination are discussed here. Altogether, current research in alcohol and AUD shows significant progress in our understanding of disease mechanisms and may spark the implementation of a new generation of technology supplemented pharmacotherapies of AUD.
Opioids are effective for severe pain but are limited by adverse effects and the risk of opioid use disorder (OUD), while non-opioid analgesics may provide insufficient relief. Neurotensin (NT), an endogenous neuropeptide, has attracted interest as a potential analgesic, with encouraging findings mainly from preclinical studies. This review summarizes advances in NT-based analgesic development, focusing on the pain-modulatory mechanisms of NTSR1 and NTSR2, the two principal neurotensin G protein-coupled receptors recognized by IUPHAR/BPS, and receptor-directed drug-design strategies. Sortilin, historically termed NTSR3 in some literature, is discussed separately because it is structurally distinct from these GPCRs. We examine NT-derived ligands, opioid-NT bifunctional compounds such as BNT-12, and combination approaches involving NT and opioid therapies. Their potential benefits are considered alongside safety concerns and translational limitations, including opioid-related adverse effects and pruritus. Although preclinical studies suggest promising analgesic effects, the comparative safety advantages of these strategies remain unestablished. NT may also influence mood regulation, making it relevant to the frequent co-occurrence of chronic pain with depression and anxiety. Overall, receptor-selective, multitarget, and combination approaches based on NT may offer complementary strategies for treating pain and associated affective symptoms. Further research is needed to establish their efficacy, safety, and clinical applicability, including whether they can reduce adverse effects and abuse liability.
Introduction Obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) are common in schizophrenia spectrum disorders (SCZ), yet their aetiology remains unclear. Antipsychotics, particularly clozapine (CLZ), have been implicated, but the strength and consistency of this association remain uncertain. Methods A systematic review and random-effects meta-analysis was conducted to evaluate the incidence and prevalence of OCS and OCD in psychosis, comparing people treated with CLZ and other antipsychotics, including first and second generation. Results The search identified thirty two studies. The prevalence of OCS was similar between the CLZ-treated and the non-CLZ groups [41%, 95% CI: 28–54% vs. 30%, 95% CI: 22–38%; p = 0.183]. In contrast, OCD prevalence was significantly higher in the CLZ group [25%, 95% CI: 18–33% vs. 12%, 95% CI: 7–18%; p = 0.007]. De novo outcomes did not differ significantly between groups, de novo OCS was 26% [95% CI: 17–36%] with CLZ versus 14% [95% CI: 7–21%] with non-CLZ antipsychotics (p = 0.239), and de novo OCD was 22% [95% CI: 9–36%] versus 19% [95% CI: 17–21%] (p = 0.458). In the two studies that had measured the incidence of de novo OCS or OCD, the incidence rate was zero in all groups. Conclusions These findings suggest a potential association between CLZ and increased rates of OCS and OCD in cross-sectional studies, though longitudinal evidence is lacking. Methodological limitations, including detection bias, confounding by indication and limited prospective data, highlight the need for further longitudinal and pharmacoepidemiologic research to clarify causal pathways.
