Perspectives on advance research directives from individuals with mild cognitive impairment and family members: a qualitative interview study.

Background: Advance research directives (ARDs) provide a promising way to involve individuals with mild cognitive impairment (MCI) in research decisions before they lose the capacity to consent. At the same time, the views of people with MCI on ARDs are underexplored. This study assesses the perceptions of people with MCI and family members on the benefits and challenges associated with ARDs. Aims: The aim of this study was to investigate the perspectives of individuals with MCI and family members of individuals with MCI on ARDs. We focus specifically on willingness to participate in nontherapeutic research, understanding of ARDs and the ethical considerations involved. Methods: Thirteen open-ended, face-to-face interviews were conducted using a semi-structured format. Seven interviews were conducted with individuals with MCI, and six with family members of individuals with MCI. The narratives were transcribed verbatim and qualitative content analysis was carried out. Results: Research participation and ARDs were viewed positively, largely based on altruistic motives and the desire to contribute to society. The participants recognized the potential advantages of ARDs in reducing the decision-making burden on family members and maintaining personal autonomy. They also highlighted challenges in comprehending ARDs and navigating the complexities surrounding potential conflicts between current preferences versus preferences described in an ARD. Conclusions: ARDs were predominantly seen as valuable instruments that enable individuals with MCI to participate in research. This study provides insights into the reasons why affected individuals are interested in drafting ARDs. These insights can guide the development of supportive interventions that are tailored to assist individuals with MCI and their families in navigating ARD processes.

When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia.

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry.

PURPOSE OF REVIEW: Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS). Although the evidence base for its wide-ranging, unique efficacy continues to expand, clozapine remains alarmingly underutilized in industrialized countries. Analyzing the causes and consequences of this problem is crucial for substantially improving the quality of care for TRS patients. RECENT FINDINGS: Clozapine is the most effective antipsychotic for reducing all-cause mortality in TRS. In most cases, treatment resistance emerges during the first psychotic episode. Delaying clozapine treatment has a negative impact on long-term outcome. Patients' experience with clozapine treatment is largely positive despite a comparatively high rate of side effects. Patients prefer clozapine, while psychiatrists regard it as a burden due to concerns regarding safety and side effect management. Shared decision-making (SDM), which increases the likelihood of a clozapine recommendation, is not routinely used, possibly due to stigmatization of TRS patients. SUMMARY: The mortality-reducing effects of clozapine alone warrant its regular use. Therefore, psychiatrists must not exclude patients from the decision regarding a clozapine trial by not even offering it. Rather, they have a clear obligation to align their actions more closely with the existing evidence and patients' needs and to facilitate the timely initiation of clozapine.

Impact of insulin and insulin resistance on brain dopamine signalling and reward processing - An underexplored mechanism in the pathophysiology of depression?

Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.

Improved correspondence of fMRI visual field localizer data after cortex-based macroanatomical alignment.

Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.

Supported Decision-Making in Persons With Dementia: Development of an Enhanced Consent Procedure for Lumbar Puncture.

The right to make autonomous decisions is enshrined in law. However, the question how persons with cognitive deficits can be enabled to make autonomous decisions has not been satisfactorily addressed. In particular, the concept of supported decision-making and its implementation into practice has been poorly explored for persons with dementia (PwD).This article describes the empirical development and implementation of support tools to enhance informed consent processes (so called enhanced consent procedures/ECP) for PwD on whether to undergo lumbar puncture. In the end of the process of pilot testing and further development of the tools, the following tools were defined: (1) Standardized Interview Structure, (2) Elaborated Plain Language, (3) Ambience and Room Design, (4) Keyword Lists, (5) Priority Cards, (6) Visualization, and (7) Simplified Written Informed Consent (Patient Information), as well as the general attitude (8) Person-Centered Attitude of the facilitator. As the development, implementation and evaluation of ECP tools is one objective of the transnational ENSURE project, we also include an overview of future empirical procedures. So far, our findings can serve as a selection of possibilities to support PwD in decision-making and help practitioners achieve an appropriate balance between the autonomy and protection of PwD in complex decision-making situation. Future studies should address the question if the proposed set of tools is effective to enhance informed consent processes in PwD.