Delirium is a common, acute confusional state that is associated with adverse patient, caregiver, and health system outcomes. All patients are at risk for delirium, although those with advanced age or acute infection and those taking sedatives and anticholinergics are at greater risk. The pathophysiology of delirium is complex and includes neuronal injury, inflammation, metabolic imbalance, and blood-brain barrier disruption. It is important to note that delirium is preventable; recognizing people at risk and identifying and addressing predisposing and precipitating factors is paramount. No single intervention or medication has been shown to be effective in treating delirium; therefore, standard-of-care treatments rely on multifaceted strategies to address contributing factors.

Plasma biomarkers, and the amyloid-β 42/40 ratio in particular, are increasingly used to stage Alzheimer's disease and to stratify and monitor clinical trials, on the tacit assumption that a single measurement reflects a stable, steady-state level of pathology. A recent micro-longitudinal study that sampled plasma weekly for five weeks in people with Alzheimer's disease challenged that assumption, reporting that most participants varied by more than half in the amyloid-β 42/40 ratio over that short window. The reflexive response is to treat such movement as measurement noise to be averaged away. Here I argue that a meaningful part of it is unlikely to be noise. In healthy adults the same ratio is among the most stable plasma analytes, so instability concentrated in disease is difficult to attribute to the assay alone. Brain-to-blood clearance of amyloid-β is itself dynamic over days, rising with sleep and falling with fragmentation, apnoea, poor cerebral perfusion, autonomic dysregulation, and sedating or anticholinergic drugs. An instantaneous plasma value therefore partly reports the clearance state of the preceding night. This clearance account is kept distinct from analytical and pre-analytical variance, and from oligomeric amyloid-β dynamics, which are considered separately. The practical problem is not the variance itself but that we measure the molecule without measuring the physiological state that moves it. I propose that an inexpensive, repeatable, bedside index of that state, illustrated here with the Systemic BenBrik Geriatric Score, could be recorded alongside each plasma draw and modelled as a covariate, converting nuisance variance into interpretable signal. The prediction is falsifiable, and a validation design is outlined. This is a hypothesis, not a validated result; the illustrative index used here, the Systemic BenBrik Geriatric Score, is not a validated measure.

The oculocardiac reflex (OCR) is well known in ophthalmic surgery, but its occurrence during neurosurgical procedures is rare and often unexpected. Mechanical stimulation of trigeminal pathways at the skull base can cause significant hemodynamic changes; however reflex activation during preparatory steps rather than tumor manipulation is rarely described. We report an intraoperative event in a 22-year-old male undergoing resection of a cystic trigeminal schwannoma via a subtemporal transcavernous approach under general anesthesia, during which periorbital needle electrodes were placed for cranial nerves III, IV, and VI monitoring. During electrode insertion, the patient developed sudden bradycardia from 72 to 34 beats per minute with a brief hypertensive response, followed by persistent bradycardia and eventual decrease in blood pressure. Immediate removal of the stimulus led to rapid recovery of hemodynamic stability without the need for anticholinergic therapy, and the surgery proceeded without further issues. This case shows that even minor periocular manipulation during neurosurgical preparation can trigger OCR. Early detection of unusual triggers, awareness of the characteristic biphasic cardiovascular response, and good communication between surgical and anesthesia teams are essential to prevent hemodynamic instability. Further documentation of similar cases may help identify contributing factors and improve preventive strategies.

Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive-protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)-induced amnesia model. Male Swiss albino mice were pretreated with BVC (10-40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y-maze, and Morris water maze. BVC attenuated SCP-induced memory deficits in a dose-dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater-than-additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC50 = 27.7 µM) and attenuates SCP-induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater-than-additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.

Bilastine is a second-generation H1-antihistamine considered to have minimal central nervous system penetration and low anticholinergic activity. Neuropsychiatric adverse drug reactions (ADRs), including hallucinations, are not expected with bilastine, although such reactions have been reported with other second-generation antihistamines (sgAH). We report the case of a 13-year-old girl who developed visual hallucinations and panic attacks shortly after starting treatment with bilastine, after having experienced a recurrent sensation of presence while taking desloratadine. The patient's symptoms resolved progressively after discontinuation of bilastine, with a Naranjo score of 6 indicating probable causality. VigiBase[®] analysis was also performed and identified a possible association between bilastine and hallucinations. This case, supported by pharmacovigilance data, although predominantly in older adults, suggests a potential pharmacovigilance signal with possible association between bilastine and hallucinations. Furthermore, similar neuropsychiatric ADRs have been reported with other second-generation antihistamines. Clinicians should be aware of this rare but potentially distressing ADR to ensure prompt recognition and discontinuation of treatment.

KarXT (marketed as Cobenfy™), a fixed-dose combination of xanomeline and trospium chloride, represents the first new mechanism of action of an antipsychotic used for adult schizophrenia approved by the US Food and Drug Administration (FDA) in over 30 years. While mainstream drugs (e.g. haloperidol, chlorpromazine, risperidone, olanzapine, quetiapine, aripiprazole) mainly antagonize dopamine D2 or serotonin 5-HT2A receptors, KarXT acts through transient activation of muscarinic M1 and M4 receptors. M4 stimulation influences the functioning of mesolimbic dopaminergic pathways, providing an indirect means of regulating dopamine release that bypasses D2 blockade. Trospium, a peripherally acting muscarinic receptor antagonist, was used to reduce anticholinergic adverse effects (AEs). It does not cross the blood-brain barrier and therefore minimizes central adverse events. In a series of randomized placebo-controlled phase 2 and 3 studies, the KarXT significantly and clinically meaningfully reduced Positive and Negative Syndrome Scale (PANSS) total scores. The effect sizes were moderate to large with few extrapyramidal symptoms (EPS), minimal metabolic disturbances and no significant prolactin level increases. In this narrative review, we discuss in detail the pharmacological mechanism, basis of preclinical development, and clinical outcomes of KarXT. We also contextualize this drug within the development of a new wave of non-D2 antipsychotics, highlighting cholinergic dysfunction as one important mechanistic pathway within the broader multidimensional neurobiology of schizophrenia.

Depression is a major and under-recognized comorbidity in Sjögren's disease, contributing to disease burden and impaired quality of life. This narrative review summarizes current evidence regarding the prevalence, pathophysiological mechanisms, clinical impact, assessment, and treatment of depression in patients with Sjögren's disease. Reported prevalence rates range widely from 3.2% to 78.6%, largely owing to methodological heterogeneity, although meta-analytic data demonstrate a significantly increased risk of depression in patients with Sjögren's disease than in healthy controls. Etiology is multifactorial, involving chronic pain, fatigue, dryness, psychosocial stressors, and immune-mediated mechanisms. Elevated inflammatory cytokines, altered serotonergic pathways, antibodies, gut dysbiosis, and neuroimaging abnormalities are the potential underlying links to depression. Furthermore, depression is associated with greater symptom burden, autonomic dysfunction, sleep disturbances, fatigue, reduced health-related quality of life, and impaired functional status. Patient-reported outcomes often correlate more closely with depression than with systemic disease activity. Although several screening instruments are available, their validation in patients with Sjögren's disease remains limited. Management requires a multidisciplinary approach integrating psychological interventions, lifestyle modification, and pharmacologic treatment. Selective serotonin reuptake inhibitors and other agents with low anticholinergic burden are preferred. Optimization of systemic disease control may provide additional benefits. Early recognition and comprehensive management of depression are essential to improve outcomes in patients with Sjögren's disease.

Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.

Myasthenia gravis (MG) is a heterogeneous neuroimmune disorder in which pathogenic autoantibodies impair neuromuscular junction transmission and produce fluctuating skeletal muscle weakness. Although conventional therapy with acetylcholinesterase inhibitors, corticosteroids, and broad immunosuppressants remains effective for many patients, its limitations are increasingly evident, including delayed onset, cumulative toxicity, and inadequate control in refractory disease. These challenges have accelerated the transition from non-selective immunosuppression to biologic and other targeted therapies. Recent advances in MG have revealed that treatment response is strongly shaped by disease heterogeneity across molecular, cellular, and structural levels. Antibody-defined subtypes, including acetylcholine receptor (AChR)-positive, muscle-specific tyrosine kinase (MuSK)-positive, low-density lipoprotein receptor-related protein 4 (LRP4)-positive, and seronegative MG, differ in immune mechanism, complement dependence, and therapeutic vulnerability. On this basis, neonatal Fc receptor (FcRn) antagonists, complement inhibitors, and B-cell-directed therapies have emerged as major biologic classes that increasingly enable mechanism-informed treatment selection. At the same time, resistance remains an important clinical problem, arising from persistent autoreactive immune compartments, pathway-level escape, and irreversible neuromuscular junction damage that may sustain disability despite immunological control. In this review, we discuss how immunological heterogeneity provides the biological rationale for targeted therapy in MG and synthesize current evidence for established and emerging biologics, including FcRn antagonists, complement inhibitors, B-cell- and plasma-cell-directed strategies, and cell-based immunotherapies. We further examine the major barriers that now define the field, particularly long-term safety, infection risk, treatment resistance, incomplete biomarker frameworks, and the distinction between active immune refractoriness and fixed structural impairment. Finally, we outline how biomarker-guided stratification, dynamic monitoring, and integration of neuroprotective or regenerative approaches may help move MG management from empiric escalation toward safer and more precise individualized care.