The effects of antidepressants on limbic structures, important in the context of the treatment of Parkinson's disease (PD)-associated depression, are relatively poorly explored in animal models. The present study investigated the impact of the tricyclic antidepressant amitriptyline (AMI), administered chronically alone or in combination with L-DOPA, on anhedonia, monoamine levels, and the binding of radioligands to their transporters in the limbic structures of unilaterally 6-OHDA-lesioned rats. Anhedonia, as a core symptom of depression, was evaluated using the sucrose preference test. Tissue concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus (HIP) were assayed by HPLC method. Bindings of [[3]H]nisoxetine to noradrenaline transporter (NET), [[3]H]GBR 12,935 to dopamine transporter (DAT), and [[3]H]citalopram to serotonin transporter (SERT) in the nucleus accumbens (NAcc), PFC, and HIP were analyzed by autoradiography. Three weeks of treatment of unilaterally 6-OHDA-lesioned rats with AMI alone significantly reduced the intake of sucrose solution compared to the sham-operated control, but the combined administration of AMI+L-DOPA enhanced sucrose consumption. Administration of AMI+L-DOPA increased tissue DA concentrations in the lesioned and intact PFC and HIP more distinctly than L-DOPA alone. L-DOPA alone significantly decreased tissue 5-HT content in the lesioned PFC and HIP, while the addition of AMI reversed this effect. 6-OHDA administered unilaterally into the MFB drastically decreased DAT binding in the lesioned NAcc while increasing it on the intact side. Neither AMI nor L-DOPA, given alone or jointly, affected DAT binding in the lesioned NAcc. SERT binding was significantly reduced in the PFC, NAcc and HIP on both sides of the brain in the AMI- or AMI+L-DOPA-treated groups. NET binding decreased in the PFC and NAcc in the AMI-treated group, but no such effect was observed in the AMI+L-DOPA-treated group. The obtained results are discussed in relation to the impaired psychiatric functions in PD.

A robust and comprehensive gas chromatographic method was developed to identify and quantify the 57 residual solvents listed in the ICH guidelines, all in a single, 30-minute chromatogram. The proposed approach, featuring dual orthogonal column chemistry and a mass spectrometry (MS) detector, significantly improved the resolution and enabled the quantification of low-response and co-eluting solvents such as benzene, chloroform, formamide, pyridine, and 1,2-dichloroethene in a complex matrix of 57 solvents. The VF-624 and HP-5 dual-column was configured in series with an MS detector. Method parameters, such as carrier gas flow rate, oven temperature program, and selection of optimal mass spectrometry acquisition parameters, scan and selected ion monitoring (SIM), were tuned to achieve uncompromised sensitivity, resolution, and reproducibility. The method was validated according to ICH Q2(R1) guidelines and demonstrated acceptable specificity, linearity (R[2] > 0.99), accuracy, precision, LOD, and LOQ. The real sample applicability was confirmed through analysis of a spiked fenoterol hydrobromide sample, establishing the method's robustness and suitability for testing the 57 residual solvents in pharmaceutical matrices. Additional evaluation with verapamil hydrochloride, amitriptyline hydrochloride, and their commercial formulations (tablets) further validated its broad applicability.

Hansen's disease is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae and Mycobacterium lepromatosis. Recently, only a few new cases have been reported in Japan. Diagnosis is based on the demonstration of the bacillus through skin smears, histopathology, or polymerase chain reaction, as well as other clinical and laboratory findings. Nerve conduction studies can detect subclinical neuropathy. Clinical classification is determined by variations in the host's cell-mediated immunity. The World Health Organization divides leprosy into paucibacillary (PB) and multibacillary (MB) forms. Ridley and Jopling classified the disease along a continuous spectrum from tuberculoid to lepromatous. Leprosy reactions, both type 1 and type 2, can lead to rapid nerve deterioration, necessitating immediate anti-inflammatory treatment and the continuation of multidrug therapy. The standard multidrug therapy regimen includes dapsone, rifampicin, and clofazimine, with typical durations of 6 months for PB and 12 months for MB. Peripheral nerve damage is irreversible once it occurs, making prevention the most effective strategy. Neuropathic pain is treated with agents such as pregabalin and amitriptyline. Rehabilitation is provided for muscle atrophy, and orthoses and prostheses are used to address deformities of the fingers and toes as well as limb deficiencies. Collaboration between dermatologists and physiatrists is essential.

In this bicenter, randomized, double-blind, placebo-controlled trial, we evaluated the effectiveness and safety of amitriptyline as an add-on therapy for leprosy-related neuropathic pain. A total of 117 participants were randomly assigned to receive amitriptyline or placebo for 9 weeks. The primary outcome was the change in pain intensity on a 100-mm visual analogue scale. Secondary outcomes included pain interference, responder rates, neuropathic pain symptoms, mood, sleep, catastrophizing, quality of life, and the Patient Global Impression of Change. No significant differences were observed between treatment arms for the primary end point. Patient Global Impression of Change scores were higher with amitriptyline, and no differences were detected between the other secondary outcomes. Amitriptyline was well-tolerated, and compliance was high in both arms. Treatment-emergent adverse events occurred in 81% of participants analysed in the amitriptyline arm and 94% in the placebo arm, were mostly mild or moderate, and no serious events were reported. A preplanned exploratory analysis examined the effects of therapy on pain phenotypes based on the intensity of spontaneous pain scores (burning, squeezing, and pressure pain). Participants with lower spontaneous pain scores at baseline showed lower pain severity, reduced emotional burden, and better quality-of-life outcomes compared with those with higher scores, regardless of treatment allocation. No significant differences between amitriptyline and placebo were observed within either symptom-defined phenotype. Amitriptyline did not provide superior analgesia compared with placebo when used as add-on therapy for neuropathic pain in people with leprosy. The clinical phenotypic heterogeneity of leprosy-related neuropathic pain may be relevant in future trial designs.

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).

Cardiac toxicity from QT-prolonging drugs can precipitate malignant ventricular arrhythmias in susceptible individuals, and family screening may clarify inherited risk. We report a 33-year-old woman with a history of postpartum cardiac arrest treated with a secondary-prevention implantable cardioverter-defibrillator (ICD) who developed an electrical storm after self-administration of a single low dose of amitriptyline (12.5 mg). ICD interrogation documented 176 episodes of ventricular fibrillation requiring repeated shocks, followed by complete battery depletion, hemodynamic collapse, and the need for venoarterial extracorporeal membrane oxygenation and continuous renal replacement therapy. The admission electrocardiogram showed marked QT prolongation (QTc 651 ms), with previously documented prolonged baseline QTc values. Targeted next-generation sequencing identified a novel SCN5A missense variant (NM_000335.5:c.5738G > A) and a rare pathogenic KCNQ1 splice variant (NM_000218.3:c.1032G > C), cascade testing across the family demonstrated variable expressivity among carriers. Given a suspected contribution of late sodium current, a mechanism-based strategy was implemented with mexiletine added to propranolol and overdrive pacing (90 bpm). This case underscores the risk of malignant ventricular arrhythmias after exposure to QT-prolonging agents even at low doses, and supports genotype-informed, mechanism-based therapy to mitigate arrhythmic risk in patients with marked QT prolongation.

This work describes the fate of amitriptyline, bupropion, carbamazepine, citalopram, clozapine, duloxetine, fluoxetine, lamotrigine, and venlafaxine using outdoor aquatic mesocosms. Water-sediment and water-gravel tanks were treated with a single amendment of the nine psychoactive pharmaceuticals and tracked in water and sediment over 272 days. Behaviour of the target chemicals followed three general fate profiles: 1) amitriptyline, bupropion, clozapine, and duloxetine dissipated rapidly with t1/2 < 2 day, and with minimal sorption); 2) carbamazepine and lamotrigine exhibited slower dissipation, with t1/2 > 10 day and minimal sorption; and 3) citalopram, fluoxetine, and venlafaxine exhibited rapid dissipation in the water column (t1/2 < 4 day) but significant sorption to sediments. Transformation products for clozapine (m/z 343.1315), duloxetine (m/z 312.1053), and venlafaxine (m/z 264.1955) were tentatively identified, semi-quantified, and included in the mass balance calculations. Duloxetine TP312 was the only product that contributed significantly to the overall mass balance, accounting for nearly 100% of the duloxetine inventory between 8 and 24 hr, before starting to dissipate. These results show that while fate mechanisms are broadly consistent among lab, mesocosm, and field studies, half-lives can vary markedly as a function of study design, and simplified systems, such as single-compartment beaker studies, can influence conclusions regarding chemical fate. This study adds to the growing body of literature describing the environmental behaviour of this important pharmaceutical class and highlights the value of outdoor mesocosm systems for generating chemical fate data.

Bladder pain syndrome is a chronic condition characterized by bladder pain associated with other urologic symptoms. It is a diagnosis of exclusion. Initial evaluation of suspected bladder pain syndrome includes a thorough history, physical examination, urinalysis, and urine culture, with cystoscopy reserved for further assessment. Symptom diaries help clarify the diagnosis, identify common triggers for flare-ups, and guide behavioral management strategies. Treatment begins with behavior and lifestyle modification and pelvic floor physical therapy. If this is inadequate, oral medications (eg, gabapentinoids, amitriptyline, antihistamines), intravesical instillation therapies, or procedural therapies (eg, neuromodulation) can be offered. Pain should be assessed at baseline and throughout the treatment course. Optimal treatment is multimodal, individualized, and multidisciplinary, frequently involving referral to urology or urogynecology specialists.

Ionizable organic compounds (IOCs) represent an important class of environmental chemicals. Though zebrafish embryos are increasingly utilized as alternative vertebrate models in chemical hazard and risk assessment related to human health and the environment, it remains unclear whether life-stage-specific physiology alters toxicokinetics and bioconcentration potential of IOCs. Here, we examined toxicokinetics and bioconcentration factors (BCFs) of eight ionizable pharmaceuticals with diverse physicochemical properties using a mixture exposure design across embryonic and larval stages of zebrafish. Coexposure did not markedly alter toxicokinetic parameters for the IOCs relative to single exposure at similar concentrations. We observed development-dependent and ionization-state-specific toxicokinetic processes and accumulation in zebrafish. Larvae exhibited an enhanced uptake and reduced elimination for cationic compounds. Importantly, the BCF values of cationic amitriptyline and cisapride exceeded the regulatory bioaccumulation threshold in larvae. Conversely, most anionic compounds displayed lower uptake and elimination in larvae, yielding similar BCFs across the stages. Further, we identified higher bioaccumulation for cations than anions in larvae, and IOC bioconcentration was generally elevated in larvae compared with embryos, which is increasingly employed in basic and translational environmental and biomedical studies. These findings highlight the importance of considering life stage and ionization state when using zebrafish as alternative models in risk assessment.