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.

Imipramine is a tricyclic antidepressant used in the treatment of several psychiatric disorders including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment in the management of panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting) (1). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, α1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, also a tricyclic antidepressant. Further metabolism is catalyzed by CYP2D6. Individuals who are “CYP2D6 ultrarapid metabolizers” carry more than two normal function alleles (i.e., multiple copies) (Table 1, 2), whereas individuals who are “CYP2C19 ultrarapid metabolizers” carry two increased function alleles (Table 3, 4). Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for imipramine states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. Their recommendations include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6 (1). In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes. Amitriptyline and nortriptyline were used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, it may be reasonable to apply the recommendations to other tricyclics, including imipramine (2). For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., imipramine) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects (2).

This case report presents the successful use of high-dose insulin euglycemic therapy (HIET) and venous arterial extracorporeal membrane oxygenation (VA-ECMO) in managing severe toxic cardiogenic shock following poly-intoxication in an elderly patient. A 67-year-old woman, with a history of depression, previous suicide attempts and chronic renal failure, overdosed on multiple cardiovascular active agents including metoprolol (β-blocker), nifedipine (calcium channel blocker), nortriptyline (tricyclic antidepressant), venlafaxine (serotonin-noradrenaline reuptake inhibitor), and temazepam (benzodiazepine) were reported. Initial treatment with vasopressors, HIET and supportive measures stabilized her condition temporarily. Despite these interventions, the patient developed catecholamine-refractory shock with progressive multiorgan failure, requiring escalation to VA-ECMO as a bridge to recovery. VA-ECMO resulted in hemodynamic stabilization, enabling vasopressor withdrawal and decannulation after three days. The patient survived the acute toxic phase without irreversible neurological injury. However, the course was complicated by vascular complications, prolonged mechanical ventilation, renal replacement therapy, severe functional decline and eventually death eight months later. This case illustrates that VA-ECMO may provide effective temporary circulatory support in severe reversible toxic cardiogenic shock, even in elderly patients with significant comorbidity. However, the substantial burden of long-term morbidity and prolonged recovery should be carefully weighed during multidisciplinary decision-making.

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.

Many drugs that block voltage-gated K[+] channels encoded by the human Ether-à-go-go-Related Gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically-approved hERG blockers including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism undergirds facilitation. We focus on nifekalant, a Class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblock of these open-yet-blocked channels results in supranormal hERG current. We develop rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generate atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements reveal that agonism-while-blocking undergirds nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

The Enhanced Ames Test (EAT) is currently recommended by regulatory authorities for evaluating the mutagenicity of N-nitrosamine drug impurities, including nitrosamine drug substance-related impurities (NDSRIs). In previous studies, we developed protocols to evaluate the genotoxicity and mutagenicity of NDSRIs in both two-dimensional (2D) and three-dimensional (3D) HepaRG cell cultures as a follow-up to verify EAT findings. In this study, we investigated the genotoxicity and mutagenicity of six EAT-positive NDSRIs, N-nitroso-desmethyl-diphenhydramine, N-nitroso-duloxetine, N-nitroso-lorcaserin, N-nitroso-nortriptyline, N-nitroso-propranolol, and N-nitroso-sertraline, in 3D HepaRG spheroids using a 14-day treatment protocol. Genotoxicity was evaluated using the CometChip DNA damage assay and the micronucleus (MN) assay, while mutagenesis was measured with an error-corrected sequencing (ECS) method, High-Fidelity sequencing (HiFi-seq). The six EAT-positive NDSRIs induced time- and concentration-dependent cytotoxicity in HepaRG spheroids. All except N-nitroso-lorcaserin caused DNA damage, while only N-nitroso-propranolol induced MN formation at acceptable levels of cytotoxicity. Notably, all six EAT-positive NDSRIs significantly increased mutation frequency in HepaRG spheroids, each exhibiting distinct mutational spectra. Quantitative analysis revealed varying levels of DNA damage and mutagenic potency among the six NDSRIs and two previously reported NDSRIs (N-nitroso-varenicline and N-nitroso-fluoxetine). These findings represent an important first step towards supporting the use of 3D HepaRG spheroids as a human-relevant in vitro new approach methodology (NAM) for mutagenicity assessment as a follow-up to the EAT. The results also provide evidence for genotoxic potency ranking of NDSRIs and offer mechanistic insights through mutational spectrum analysis.

Renal fibrosis represents a significant pathological hallmark of chronic kidney disease (CKD), yet therapeutic strategies for its management remain notably inadequate. RNA-binding motif single-stranded interacting protein 1 (RBMS1), an RNA-binding protein (RBP) previously implicated in cancer progression and fibrosis, remains poorly understood within the context of renal fibrosis. The current investigation demonstrates elevated RBMS1 expression in kidney tissues from CKD patients, fibrotic mouse models, and transforming growth factor-β1 (TGF-β1)-induced rat renal fibroblasts. Fibroblast-specific conditional knockout of RBMS1 in mice markedly ameliorated renal injury and fibrosis, accompanied by reduced fibrotic marker expression. Similarly, siRNA-mediated knockdown of RBMS1 in renal fibroblasts suppressed TGF-β1-induced fibroblast activation, proliferation, and migration. RNA-seq and RIP assays revealed Annexin A8 (ANXA8) as a key downstream target of RBMS1. RBMS1 directly bound the coding region of ANXA8 mRNA via its RRM2 domain, thereby enhancing transcript stability. ANXA8 overexpression activated fibroblasts and promoted PI3K/AKT signaling, whereas ANXA8 knockdown abolished the pro-fibrotic effects of RBMS1. Pharmacological inhibition of RBMS1 with nortriptyline (NTP) significantly attenuated renal fibrosis in unilateral ureteral obstruction (UUO) mice. These results reveal an RBMS1/ANXA8/PI3K/AKT regulatory axis in renal fibrosis, highlighting RBMS1 as a potential therapeutic target.

Amitriptyline is a tricyclic antidepressant used in the treatment of several psychiatric disorders, including major depression, obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Amitriptyline also has different off-label uses, including migraine prevention, neuropathic pain management, fibromyalgia, and enuresis (bedwetting) (1). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (H1 histamine, alpha 1 α1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Amitriptyline is metabolized mainly via CYP2C19 and CYP2D6 pathways. Metabolism by CYP2C19 results in active metabolites, including nortriptyline, which is also a tricyclic antidepressant. Metabolism catalyzed by CYP2D6 results in the formation of the less active 10-hydroxy metabolite. Individuals who are “CYP2D6 ultrarapid metabolizers” carry more than two normal function alleles (i.e., multiple copies) (Table 1, 2), whereas “CYP2C19 ultrarapid metabolizers” carry two increased function alleles (Table 3, 4). Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for amitriptyline states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. The FDA recommendations also include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6 (1). In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes (2). For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., amitriptyline) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations while monitoring plasma concentrations to avoid side effects (2).