Sleep-related rhythmic movement disorder (SRRMD) is uncommon in adults. It can closely mimic nocturnal epilepsy and rapid eye movement (REM) sleep behavior disorder (RBD), creating significant diagnostic challenges. We report the case of a man in his mid-20s presenting with chief complaints of nightly head movements during sleep occurring multiple times each night. He intentionally shook his head to terminate these episodes, a volitional strategy he had developed to escape lucid dreams. Video-electroencephalogram (EEG) monitoring over two nights excluded epilepsy. Polysomnography (PSG) confirmed stereotyped lateral head rolling exclusively during REM sleep at approximately 1 Hz, without any loss of REM sleep atonia, thereby excluding RBD. Comorbid mild obstructive sleep apnea (apnoea-hypopnoea index (AHI) 8.7 events/hour) was also identified. Nasal septoplasty partially improved symptoms. He reported excessive daytime sleepiness, with an initial Epworth Sleepiness Scale (ESS) score of 22. Due to the presence of excessive daytime sleepiness, two Multiple Sleep Latency Tests (MSLTs) were performed at different time points to evaluate for a primary hypersomnia disorder. However, both studies were conducted under suboptimal conditions. The first was performed in the presence of untreated mild sleep apnea, and the second while the patient was receiving medications known to suppress REM sleep. Neither study demonstrated sleep-onset REM periods, and mean sleep latencies of 7.2 and 12 minutes did not meet the diagnostic criteria for narcolepsy. Nevertheless, narcolepsy could not be definitively excluded because of the suboptimal testing conditions. The patient did not report symptoms suggestive of cataplexy. He experienced rare episodes of isolated sleep paralysis and a single episode of hypnopompic hallucination. The patient denied experiencing sleep attacks. He managed daytime sleepiness by scheduling daytime naps, which could last up to one to two hours. Sequential pharmacotherapy with amitriptyline, followed by nortriptyline, and subsequently the addition of venlafaxine and bupropion, achieved complete resolution of rhythmic movements and excessive daytime sleepiness. We identified no previous reports describing a patient with successful management of rhythmic head movements during REM sleep using sequential tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), and serotonin-norepinephrine reuptake inhibitor (SNRI) therapy for this condition. At the six-month follow-up, the patient's ESS score improved from 22 to 3.

Background/Objectives: Migraine may be associated with structural changes in the brain, including the cerebellum and brainstem. Some of these changes reflect the brain's plasticity in adapting to migraine-related alterations, but others may influence the severity of migraines and resistance to treatment. Some studies report changes in cortical thickness among migraine patients, and focal cortical dysplasia (FCD) has been considered a possible cause of these changes. We argued that FCD could contribute to the development of migraine and the severity of its symptoms. To date, there has been no consistent report of FCD occurring in migraine patients. Case: A 29-year-old woman presented with a history of at least 19 years of high-frequency episodic migraine without aura. She experienced motion sickness during childhood and adolescence. Her condition worsened last year, evolving into chronic migraine, which was partially controlled by medications such as amitriptyline and rizatriptan, leading to high-frequency episodic migraines. An MRI conducted in 2024 showed a small area of signal abnormality in the left occipital lobe, believed to represent cortical dysplasia. A follow-up MRI after three months showed no changes in this area. She is currently diagnosed with high-frequency episodic migraine and demonstrated severe migraine-related disability, with a MIDAS score of 25, and a severe impact on daily functioning, with a HIT-6 score of 65. Conclusions: The case involves a worsening migraine that was somewhat alleviated by a pharmacological intervention. FCD may contribute to brain hyperexcitability in this case and her motion-related problems during childhood and adolescence. FCD could also play a role in the increasing severity of her migraines and her partial resistance to medication.

Objective: The aim of this study was to explore the clinical response and tolerability of topical 1% amitriptyline in patients with burning mouth syndrome in a real-world clinical setting. Methodology: A retrospective observational study was conducted through a review of the clinical histories of patients diagnosed with burning mouth syndrome, treated at the Dental Clinic of the Morales Meseguer Hospital (Murcia, Spain). All the patients were treated with topical amitriptyline for a period of four weeks. The following parameters were evaluated at the start of the treatment and at the end of the four weeks: pain or mouth burning, through the visual analog scale (VAS); anxiety and depression, with the Hospital Anxiety and Depression (HAD) scale; sleepiness, with the Epworth Sleepiness Scale (ESS); sensation of dry mouth (VAS) and basal sialometry for the objective measurement of salivary flow. Results: Of the 32 patients that were initially included, 27 were ultimately analyzed. After 4 weeks of treatment with 1% topical amitriptyline, a significant improvement was observed in mouth pain or burning, measured with the VAS, with a decrease in the median of 7.5 (IQR 6-9) to 5 (IQR 5-7) (p < 0.001). Likewise, significant improvements were recorded in the anxiety (HAD-A) and depression (HAD-D) scores, with significant reductions after the treatment (p = 0.019 and p = 0.009, respectively). No statistically significant differences were observed in the subjective sensation of dry mouth (VAS) (p = 0.054) or in the total production of saliva (p = 0.477). Conclusions: Treatment with 1% topical amitriptyline for four weeks was associated with a reduction in pain and emotional distress in patients with burning mouth syndrome, with very few reported adverse effects. As an exploratory retrospective study with a limited sample size reflecting real-world clinical practice, these findings suggest that 1% topical amitriptyline may represent a useful therapeutic option in the management of burning mouth syndrome. However, the results should be interpreted with caution, and further prospective controlled studies are needed to confirm these findings.

BackgroundNew daily persistent headache (NDPH) is a primary headache disorder that often presents in adolescence. Presently, there is no effective treatment for NDPH and a paucity of clinical trials exploring therapeutic options. In this study, we explored the relative benefit of currently used treatments to help inform future trials and clinical decision-making.MethodsIn this retrospective chart review study, patients aged 5-17 years with abrupt onset continuous headache and headache duration of at least one month (constituting NDPH or probable NDPH) were identified based on responses to a Headache Questionnaire in child neurology clinic and confirmed with chart review. We included all treatments (transitional therapy, preventive supplement, preventive medication and preventive non-medication therapy) started during continuous headache until both break in continuous headache and sustained improvement in headache were achieved. For treatments tried by at least 10 patients and for the first treatment tried in each category, we calculated proportions of any documented benefit, including "Significant" (≥30% improvement lasting ≥4 weeks) and "Some improvement" (all other improvement) and proportions of negative outcome (those with worsened headaches or side effects warranting discontinuation), as well as median time to treatment. We used multivariable regression modeling to examine for factors associated with headache outcomes. Treatments may have overlapped.ResultsOf the 165 patients, the largest proportion of patients experienced benefit with the first transitional therapy (62/108; 57%), which was usually intravenous medications ± oral corticosteroids. The first supplement tried, usually riboflavin ± magnesium, offered benefit in (36/118; 31%), with few negative outcomes (3/118; 3%). The first prescription preventive tried, usually amitriptyline or topiramate, offered similar benefit (37/106; 35%) as the first supplement, but with more negative outcomes (25/106; 24%). Despite being tried after oral preventives, onabotulinumtoxinA injections offered benefit to the largest proportion of patients (14/20; 70%) without negative outcomes (0%). Overall, the time to first therapy was weeks to months into continuous headache: shortest for transitional therapies (median = 49 days, interquartile range = 17-92 days), and longest for non-medication therapies (median = 144 days, interquartile range = 61-381 days). Increased time to any first treatment was associated with decreased odds of headache improvement at one-year follow-up (odds ratio = 0.823, 95% confidence interval = 0.715-0.946, p = 0.006).ConclusionsChildren and adolescents with new onset continuous headache experience treatment delays which are associated with worse outcomes. Clinicians should consider use of transitional therapies in combination with preventive treatments as early as possible. Prospective natural history studies and trials are needed to improve treatment outcomes for pediatric patients with NDPH.

Zebrafish larvae are increasingly used in behavioural pharmacology because of their translational relevance and suitability for anxiety- and stress-related studies. However, it remains unclear whether commonly used behavioural assays and molecular stress markers provide convergent evidence of anxiolytic-like drug activity. This study therefore aimed not to validate a single predictive screening platform, but to assess the concordance and interpretative value of behavioural and molecular endpoints in larval zebrafish anxiety-related drug screening. Reference compounds with established anxiolytic or antidepressant activity, including diazepam, amitriptyline, and fluoxetine, were used to anchor assay performance. TP003, a GABAergic modulator, and three serotonergic psychedelic compounds, DOI, 5-MeO-DMT, and psilocybin, were included to challenge the assays with pharmacologically diverse mechanisms relevant to stress- and anxiety-related responses. Diazepam showed the strongest cross-assay behavioural consistency compatible with an anxiolytic-like profile. However, this response was not accompanied by reduced cortisol levels or straightforward normalisation of stress-related gene expression. Amitriptyline reduced cortisol but produced only partial behavioural effects, whereas DOI affected selected behavioural preference endpoints and transcriptional markers without significantly reducing cortisol. Fluoxetine and 5-MeO-DMT altered locomotor activity in patterns requiring cautious interpretation, as reduced movement may reflect locomotor suppression or sedation rather than anxiolysis alone. These findings indicate that behavioural and molecular endpoints should not be treated as interchangeable measures of a single anxiety construct. Instead, combined behavioural and molecular assessment is most useful as a profiling framework to identify endpoint-dependent responses, detect sedative or nonspecific locomotor confounds, and support more cautious interpretation of putative anxiolytic-like effects in larval zebrafish.

Temporomandibular disorders (TMDs) comprise a group of multifactorial conditions involving the masticatory muscles, temporomandibular joint, and associated structures influenced by biomechanical, neuromuscular, and biopsychosocial factors. Myogenous TMDs may involve muscle hyperactivity, parafunction, and central sensitization, contributing to chronic pain and functional limitation. Oral skeletal muscle relaxants (SMRs) are commonly used as adjunctive pharmacologic therapy; however, these agents vary considerably in mechanism, efficacy, and safety. This review summarizes the pharmacology, clinical evidence, and risk profiles of commonly prescribed SMRs-including cyclobenzaprine, baclofen, tizanidine, and others-within the context of chronic TMD management. Evidence supports short-term benefit for select agents, though data for chronic daily use remain limited. Given concerns regarding sedation, dependence, hepatotoxicity, and interactions with polypharmacy, clinicians should employ these medications judiciously and primarily for acute exacerbations rather than long-term therapy. An evidence-based, multimodal approach remains essential for optimizing care in patients with chronic TMDs.

The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases.

The executive functions are a suite of cognitive-control processes that enable goal-directed behaviour. Executive functioning is vital in allowing animals to adapt their behaviour to changing environmental conditions, which is a key determinant of the success of individuals, populations, and species under anthropogenic change. Despite this, very little is known about the mechanisms that underpin executive functioning in animals and how it manifests in behaviour. Moreover, whether and how executive functioning is impacted by environmentally realistic levels of chemical pollution is completely unknown, despite neuroactive pollutants, such as pharmaceuticals, having become widespread in ecosystems around the globe. We employed the Free Movement Pattern Y-maze to investigate how executive functioning manifests in decision-making and behaviour in a wild population of guppies (Poecilia reticulata), and whether this was disrupted by exposure to two environmentally realistic concentrations (9 ng/L or 309 ng/L) of the neuroactive pharmaceutical pollutant amitriptyline. We found that two of the three domains of executive function-working memory and cognitive flexibility-actively regulated cognition to inform behaviour during maze exploration. However, the role of executive functioning in directing navigation behaviour was not affected by exposure to amitriptyline. Given that neuroactive pharmaceuticals are increasingly detected in waterways, and executive functioning is critical for behaviours that dictate fitness, it is crucial that we better understand whether and how these contaminants affect executive functioning, and what implications this may have for wildlife living in human-impacted ecosystems.

Drug overdose remains a major public health challenge, particularly for non-opioid substances that lack effective antidotes and are often treated through gastrointestinal decontamination with activated charcoal. While activated charcoal is broadly effective, its use is associated with aspiration risks and gastrointestinal complications. Here, we report a class of synthetic poly(glutamic acid-block-tyrosine) (EY) peptide adsorbent materials designed as biocompatible, tuneable alternatives for gastrointestinal drug adsorption. EY polypeptides were synthesized via N-carboxyanhydride ring-opening polymerization with systematically varied tyrosine block lengths to investigate how amino acid composition and length govern adsorption. Adsorption kinetics and capacity were evaluated under simulated gastric (pH 1.2) and intestinal (pH 6.8) conditions for clinically relevant drugs commonly implicated in overdose: amitriptyline (AMI), bupropion (BUP), hydroxychloroquine (HCQ), and strychnine (STR). Increasing tyrosine content enhanced drug uptake, with the top-performing formulation (E30Y129) achieving high adsorption capacities and binding affinities comparable to reported adsorbent biopolymers and competitive with activated charcoal for certain drugs. Langmuir isotherm analysis revealed maximum adsorption capacities of 40-238 mg g[-1] and binding affinities up to 0.214 L g[-1], with adsorption behavior dependent on drug characteristics. Exploratory fed-state experiments demonstrated that adsorbent properties are retained in the presence of a complex nutrient matrix and vary depending on drug properties. Preliminary enzyme degradation studies indicated gradual proteolysis under gastrointestinal conditions, and cytocompatibility assays with fibroblasts and macrophages showed no overt toxicity across relevant concentrations. Collectively, these results demonstrate that synthetic polypeptides can be engineered to achieve efficient, clinically relevant drug adsorption while offering advantages in biocompatibility, degradability, and tunability. This work establishes a foundation for next-generation gastrointestinal decontamination materials beyond activated charcoal.

Depression causes distress, dysfunction, and disability in terms of physical, mental, and social wellbeing. The challenges of late presentation, no-compliance of patients, and time-lag of antidepressants persist, despite advances. The objective was to determine the efficacy of antidepressants in combination with magnesium, compared to antidepressant monotherapy for treating depression. Forty-four patients with depression (6A70, 6A71, and 6A72 according to ICD-11) were divided into two equal groups, in an open label nonrandomized clinical trial. All patients received evidence-based antidepressants (either escitalopram, sertraline, duloxetine, amitriptyline, or fluoxetine). The experimental group additionally received 800 mg of magnesium glycinate (112 mg elemental magnesium). The psychometric testing was done by Patient Health Questionnaire (PHQ-9) at days 0, 14, and 28. Primary outcome was to see improvement at day 28, while secondary outcomes included time lag and remission (PHQ-9 scores < 4) at day 14 and 28, respectively. Paired sample t-test and Student t-test were applied for within-group and between-group differences using SPSSv27.0. The p-value ≤ 0.05 was considered statistically significant. The improvement in the PHQ-9 scores in groups A and B was 26.42% and 72.17%, respectively, by day 28, and effect size (Cohen's d = 1.76) was in the favor of adjunct therapy. Group B showed 41.34% improvemnet and large effect size (d = 1.29) on day 14 as well. All these values were statistically significant (p ≤ 0.05). The remission rate (44 patients) was higher with adjunt therpay (10.23%), versus 2.27% with monotherapy. Adjunct antidepressant therapy with magnesium is a preliminary effective strategy for patients with depression, potentially augmenting treatment response and decreasing time lag of antidepressants. ClinicalTrials.gov ID: NCT05931965 (https://clinicaltrials.gov/study/NCT05931965?cond=Depression&intr=magnesium,%20methylfolate,%20B12&rank=1), 14-06-2023 (retrospectively registered).

Since the 2018 valsartan recall, the genotoxic impurity N-nitrosodimethylamine (NDMA) has been frequently detected in various pharmaceuticals. Matrix variability often complicates routine testing, requiring customized analyses. We developed a universal LC-MS/MS method enabling consistent NDMA detection across diverse pharmaceuticals. Separation utilized a C30 column (150 mm × 4.6 mm I.D., 5 µm), offering superior retention and shape selectivity for polar nitrosamines compared to conventional reversed phases. Unlike C18 or pentafluorophenyl phases, which often exhibit limited retention for NDMA, the C30 phase provides exceptional shape selectivity and enhanced hydrophobic interactions. This structural advantage, supplemented by its resistance to phase dewetting under highly aqueous conditions further ensures robust resolution between NDMA and complex drug matrices. The mobile phase consisted of 0.1% v/v formic acid in water and methanol under gradient elution at 1.0 mL/min. Detection used atmospheric pressure chemical ionization in positive ion mode. The method demonstrated a linear range of 2.0-100.0 ng/mL (r2 > 0.999), with a limit of detection of 1.0 ng/mL and a limit of quantification of 2.0 ng/mL. Validation per International Council for Harmonisation (ICH) guidelines confirmed accuracy (87.7%-115.5%) and precision (coefficient of variation, CV ≤ 10.7%). Application to 30 diverse pharmaceutical products, including sartans and ranitidine, showed robust resolution (> 2.0) between the analyte and active pharmaceutical ingredients (APIs). Notably, NDMA was quantified in historical batches of ranitidine (164.83 ± 5.68 ng/mL), nizatidine (10.25 ± 0.52 ng/mL), and amitriptyline (2.28 ± 0.19 ng/mL). While the histamine type 2 receptor antagonists significantly exceeded the acceptable daily intake limit, the remaining 27 products showed no detectable NDMA. These findings highlight the method's effectiveness for real-world surveillance and the critical risk of post-manufacturing NDMA generation during prolonged storage. This universal C30-based method provides a practical, reliable tool for routine screening, facilitating regulatory compliance and improved patient safety without drugspecific method development.