Tricyclic antidepressant (TCA) overdose is a potentially life-threatening condition characterized by anticholinergic, cardiotoxic, and neurotoxic effects. Amitriptyline is a highly lipophilic TCA metabolized by cytochrome (CYP)2C19, CYP3A4, and CYP2D6 and may be associated with altered metabolism with concurrent use of cannabinoids, mutations of the CYP enzymes, and elevated body mass index (BMI). With higher levels of adipose tissue, elevated BMI can lead to a larger volume of distribution for lipophilic drugs. Deviations from expected drug clearance may prolong toxicity and complicate management. We describe a 15-year-old female with obesity (BMI of 36 kg/m[2]) and a complex psychiatric history who presented after an intentional overdose of approximately 750 mg of amitriptyline. On arrival, she was unresponsive with a Glasgow Coma Scale (GCS) score of 3, tachycardia, respiratory distress, and electrocardiographic evidence of TCA cardiotoxicity, including a wide complex tachycardia and QRS prolongation. She required emergent intubation, sodium bicarbonate therapy, seizure prophylaxis, serial electrocardiograms, laboratory monitoring, and intensive care monitoring. Despite appropriate supportive management and based on typical half-life estimates under therapeutic conditions, QRS prolongation persisted, and serum amitriptyline/nortriptyline levels remained markedly elevated on day seven (combined level 612 ng/mL) and detectable on day ten (combined level 131 ng/mL). The prolonged elimination observed in this case was likely multifactorial, with cannabinoid use potentially contributing to prolonged toxicity through interactions with CYP enzymes. Additional contributing factors may have included elevated BMI or CYP enzyme polymorphisms. Although CYP testing was not performed in this case, consideration of testing in similar presentations in the future may aid in clinical management if a mutation is identified. The contribution of elevated BMI in this case remains speculative, as current evidence regarding its effects on the pharmacokinetics of lipophilic drugs is inconsistent, highlighting the importance of further studies on this topic. This case illustrates the impact of cannabinoid use and other factors on the pharmacokinetics of amitriptyline and underscores the need for prolonged monitoring, serial electrocardiograms, and consideration of extended drug clearance in cases of pediatric patients with TCA overdose. Clinicians should be aware that standard half-life estimates may underestimate the duration of toxicity in populations that have factors influencing metabolism.

Mental and neurologic disorders are a growing global health concern. Psychotropic medicines are vital for the treatment of these disorders, but issues such as inappropriate prescribing and polypharmacy are prevalent, especially in low- and middle- income countries like Ethiopia. This study assessed psychotropic medicine use patterns in public hospitals of Hadiya zone, Southern Ethiopia. A facility-based cross-sectional study was conducted from June 15 to December 30, 2019, involving the review of 1200 patients medical charts. Data were collected by reviewing the medical charts of patients with mental and neurologic disorders using a data abstraction format. Data were entered and analyzed using SPSS version 26. The results showed that, the most commonly treated mental and neurologic disorders were psychosis (27.50%), followed by schizophrenia (15.67%), epilepsy (13%), and depression (11.92%). Antipsychotics (48.1%) and antidepressants (25.7%) were the most commonly used psychotropic medicines. Chlorpromazine, haloperidol, and thioridazine were the top three most prescribed antipsychotics which constituted 71.34% of antipsychotics use in public hospitals of Hadiya zone. The most commonly prescribed combinations were antipsychotics with antidepressants and antipsychotics with anti-anxiety medicines. Typical antipsychotics were prescribed more often (73.86%) than atypical antipsychotics (26.14%). Among antidepressants, amitriptyline, a tricyclic antidepressant, was most frequently prescribed (74.9%), followed by fluoxetine, selective serotonin reuptake inhibitor (21.5%). Treatment shift was undertaken in 11.5% of patients. The percentage of encounters with two or more psychotropic medicines was 36.1%, which shows a polypharmacy practice. Antipsychotics were the most commonly utilized psychotropic medicines, followed by antidepressants and anticonvulsants. Chlorpromazine, Amitriptyline, and Risperidone showed a higher proportion of utilized medicines. More than one-third of psychiatric patients were prescribed psychotropic polypharmacy. Close to 10% of psychiatric patients had a treatment switch, mostly because of poor improvement, relapse, side effects, and non-adherence. Further prospective continuous studies on both prevalence and use patterns need to be undertaken to get more information.

Early detection of neurotoxicity remains a challenge, as functional disturbances often precede overt morphological abnormalities. Zebrafish (Danio rerio) larvae provide a suitable in vivo model for integration of behavioral and biochemical endpoints. In this study, we applied a combined metabolomic and behavioral approach to identify biomarkers of neurotoxicity following exposure to pharmaceutical compounds with diverse mechanisms of action. Locomotor activity was evaluated in zebrafish larvae exposed to selected compounds at sublethal concentrations using a light-dark transition assay. In parallel, targeted metabolomic analysis was performed to quantify metabolites associated with neurotransmitter pathways. Behavioral profiling highlighted distinct pharmacological signatures across drug classes: antipsychotics led to pronounced hypolocomotion and coordination impairment, antidepressants produced moderate and phase-specific activity changes, whereas stimulants promoted increased locomotor activity. Metabolomic analysis demonstrated that the most informative changes were associated with serotonergic, catecholaminergic, and γ-aminobutyric acid (GABA)-related pathways. While pathway-specific alterations reflected pharmacological neuroactivity, coordinated perturbations across multiple neurotransmitter-related pathways were observed for selected compounds, including amitriptyline and ethanol. These changes were accompanied by behavioral alterations consistent with a neurotoxicity-like phenotype. Reduced locomotor activity alone was not a sufficient marker of neurotoxicity as pharmacologically distinct compounds provided similar locomotor effects. Instead, the integration of multidimensional behavioral endpoints with metabolomic data allowed discrimination between pathway-specific neuroactivity and broader neurotoxicity-like effects. Overall, combined metabolomic and behavioral profiling in zebrafish larvae provides a sensitive and mechanistically informative approach for early neurotoxicity assessment. The identified alterations in neurotransmitter-related pathways represent candidate biomarkers associated with neurotoxicity-like responses and support the application of integrated omics-based strategies in toxicological screening.

Poly-(vinyl alcohol) (PVA) hydrogels incorporating β-cyclodextrin (βCD) nanosponges (CDNSs) were developed as hybrid supramolecular systems for the controlled delivery of amitriptyline hydrochloride (AMT). The βCD-derived nanosponges provide host-guest cavities for drug inclusion, while the PVA network acts as a diffusion-regulating matrix. Initially, adsorption-desorption studies were performed on isolated CDNSs to evaluate their drug-loading capacity prior to incorporation into the hydrogels. The CDNSs exhibited efficient encapsulation (∼60%) and released more than 90% of the drug, confirming strong yet reversible host-guest interactions within CDs cavities. The drug-loaded CDNSs were subsequently dispersed in PVA solutions and physically cross-linked by freeze-thaw cycling, producing hydrogels containing embedded supramolecular reservoirs. Increasing the PVA concentration (from 14 to 20% w/v) generated denser polymer networks, reducing the swelling degree from ∼60 to ∼30 and slowing water uptake. CDNSs incorporation altered the hydrogel microstructure and introduced additional drug-matrix interactions, resulting in reduced burst release, measurable lag times, and more prolonged release compared with neat PVA hydrogels. Release kinetics were best described by the Weibull model, indicating diffusion-controlled transport in the pure matrices and heterogeneous diffusion behavior in the hybrid systems. Overall, AMT release is governed by coupled mechanisms involving diffusion through the polymer network and dissociation from cyclodextrin host sites, with CDNSs acting as supramolecular reservoirs within the hydrogel matrix.

Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.