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Background Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. Methods We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout ( Nlrp3 −/− ) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3 −/− mice. Results We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. Conclusion Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. DBhggTBWtuReWsEtfqqAGm Video Abstract

Tricyclic antidepressants are used to treat a variety of mental disorders, and are considered a common cause of fatal drug poisoning. This study reports a young woman with no history of cardiac diseases who presented to the emergency department with heart palpitation, weakness, and lethargy. After a short period of time, she became unconscious and experienced hypotension and refractory arrhythmia, finally being diagnosed with imipramine poisoning. Accurate history taking and the possible causes of these complications including cardio-toxic drug poisoning should be considered in such patients.

Background: While the potential anti-cancer effects of antidepressants have been investigated, limited research has been conducted incorporating age-specific analyses for individual tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). This study aims to elucidate the associations between TCAs and SSRIs with gynecologic cancers and to identify specific age groups and cancer types that may benefit from the chemopreventive effects of these medications. Methods: A case-control study comprised 97,736 female patients diagnosed with gynecologic cancers between 2002 and 2016. Each newly diagnosed case of cervical, ovarian, or uterine cancer was matched with four controls. Both cases and controls were then stratified by age to perform subgroup analyses. Associations between antidepressant use and cancer risk were evaluated using multivariable conditional logistic regression models. Results: The TCA class was significantly associated with reduced risks of cervical, ovarian, and uterine cancers, displaying adjusted odds ratios (aORs) of 0.799, 0.775, and 0.813, respectively. The SSRI class also indicated reduced risks, with aORs of 0.736, 0.638, and 0.567 for the same cancer types. Particularly noteworthy were females aged 40–64, who demonstrated the most significant associations between gynecologic cancers and using TCAs or SSRIs. Conclusions: TCAs and SSRIs are associated with reduced risks of developing cervical, ovarian, and uterine cancers. The middle-aged population may have the most significant potential for future research on drug repurposing against gynecologic cancers, and both cervical and uterine cancers are potential targets for drug repurposing involving TCAs or SSRIs.

Major depression or deterioration of previous mood disorders is a common adverse consequence of coronary heart disease, heart failure, and cardiac revascularization procedures. Therefore, treatment of depression is expected to result in improvement of mood condition in these patients. Despite demonstrated effects of anti-depressive treatment in heart disease patients, the use of some antidepressants have shown to be associated with some adverse cardiac and non-cardiac events. In this narrative review, the authors aimed to first assess the findings of published studies on beneficial and also harmful effects of different types of antidepressants used in patients with heart diseases. Finally, a new categorization for selecting antidepressants according to their cardiovascular effects was described. Using PubMed, Web of Science, SCOPUS, Index Copernicus, CINAHL, and Cochrane Database, we identified studies designed to evaluate the effects of depression and also using antidepressants on cardiovascular outcome. A 40 studies were finally assessed systematically. Among those eligible studies, 14 were cohort or historical cohort studies, 15 were randomized clinical trial, 4 were retrospective were case-control studies, 3 were meta-analyses and 2 animal studies, and 2 case studies. According to the current review, we recommend to divide antidepressants into three categories based on the severity of cardiovascular adverse consequences including (1) the safest drugs including those drugs with cardio-protective effects on ventricular function, as well as cardiac conductive system including selective serotonin reuptake inhibitors, (2) neutralized drugs with no evidenced effects on cardiovascular system including serotonin-norepinephrine reuptake inhibitors, and (3) harmful drugs with adverse effects on cardiac function, hemodynamic stability, and heart rate variability including tricyclic antidepressants, serotonin antagonist and reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants. The presented categorization of antidepressants can be clinically helpful to have the best selection for antidepressants to minimizing their cardiovascular harmful effects.

We are presenting the case of a 28-year-old female patient who presented with refractory shock secondary to overdose of tricyclic antidepressants, calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors. After initial resuscitation, bicarbonate infusion for TCA toxicity was used; and CCB toxicity was managed with high-dose insulin euglycemia therapy (HIET) with simultaneous dextrose infusion and vasopressors in the intensive care unit.

This study aimed to select a high-performance cation-exchange resin (CER) and estimate its uptake of positively ionized tricyclic antidepressants (TCAs), i.e., amitriptyline (AMI), imipramine (IMI), clomipramine (CLO), and desipramine (DES), which are frequently used, and detected in wastewater treatment systems. For the selection of the resin, the one-point check test of AMI in distilled water was examined using several CERs. As a result, the strong-acid polystyrene CER, Dowex 50WX4-200, was selected on the basis of its outstanding uptake of AMI. The maximum adsorption capacities of Dowex 50WX4-200 for removal of the TCAs ranged from 2.53 ± 0.20 mmol/g to 3.76 ± 0.12 mmol/g, which are significantly higher when compared with those of previously reported adsorbents. This is likely because the combination of electrostatic and π-π interactions between the TCAs and Dowex 50WX4-200 may lead to high uptakes of the TCAs. Additionally, the removal efficiency of DES as a representative of the TCAs was tested in actual wastewater system containing activated sludge and miscellaneous cations. Consequently, the removal efficiencies of the DES in distilled water, aerobic wastewater, and filtered wastewater were 95.68%, 77.99%, and 56.66%, respectively. It is interesting to note that the activated sludge could also contribute to adsorption of the DES, leading to increased removability, while the cations present in the wastewater acted as competing ions, decreasing the removal efficiency.

Active pharmaceutical ingredients such as tricyclic antidepressants (TCAs) are contaminants of emerging concern which are commonly detected in wastewater effluent and which can disrupt the behavior of non-target organisms. In aquatic snails, the righting response is a critical behavior that has been shown to be inhibited by exposure to SSRI-type antidepressants. We exposed marine and freshwater snails to three tricyclic antidepressants (clomipramine, amitriptyline, and imipramine) for 1 h and measured righting response time. In the marine mud snail ( Ilyanassa obsoleta ), all three TCAs significantly increased righting time at concentrations as low as 156 μg/L. Similarly, in the freshwater snail Leptoxis carinata , all three TCAs increased righting time at concentrations as low as 263 μg/L. However, exposure to imipramine from 15.8 to 316 μg/L resulted in significantly faster righting time. Such low-dose stimulation and high-dose inhibition are characteristics of a hormetic response. We discuss the possible physiological mechanism of action of TCAs and other antidepressants on snail behavior, and the occurrence of non-monotonic, hormetic dose responses to human pharmaceuticals in the aquatic environment.

Tricyclic antidepressants are known as potentially inappropriate medications in the elderly. A notification issued in July 2015 in South Korea recommended caution while prescribing tricyclic antidepressants to the elderly. Further, since October 2015, the nationwide computerized drug utilization review monitoring system provides a pop-up window, on a real-time basis, whenever tricyclic antidepressants are prescribed to elderly outpatients. Therefore, we evaluated whether providing drug utilization review information was effective in reducing tricyclic antidepressant prescription to elderly outpatients. We used the Health Insurance Review and Assessment Service-Adult Patient Sample data from 2014 to 2016. Data related to the prescription of tricyclic antidepressants to outpatients aged 65 years or more were extracted. We determined the number of prescriptions per day per 100,000 elderly patients in each month, compared the average number of prescriptions before and after the drug utilization review information was provided, and evaluated the changes in the number of prescriptions by using an interrupted time series analysis. The average number of tricyclic antidepressant prescriptions per day per 100,000 elderly patients decreased from 76.6 (75.5 to 77.6) to 65.7 (64.5 to 66.9), a 14.2% reduction after the provision of drug utilization review information started. Following initiation of provision of drug utilization review information, there was an immediate drop of 9.2 tricyclic antidepressant prescriptions per day per 100,000 elderly patients, whereas there was no statistically significant change in trends. Providing the drug utilization review information on tricyclic antidepressant prescription for the elderly contributed to the reduction in tricyclic antidepressant prescriptions.

Background: Many individuals in the community are prescribed psychoactive drugs with sedative effects. These drugs may affect their daily functions, of which automobile driving is a major component. Objective: To examine the association of three classes of commonly used psychoactive drugs ( viz. benzodiazepines and newer non-benzodiazepine hypnotics, antidepressants and opioids) with (i) the risk of traffic accidents (as indexed by epidemiological indicators of risk); and (ii) driving performance (as indexed by experimental measures of driving performance). Methods: A literature search for material published in the English language between January 1966 and January 2010 in PubMed and EMBASE databases was combined with a search for other relevant material referenced in the retrieved articles. Retrieved articles were systematically reviewed, carrying out meta-analyses where possible. Twenty-one epidemiological studies (13 case-control and 8 cohort studies) fulfilled the inclusion criteria by estimating the accident risk associated with drug exposure (ascertained by blood/urine analysis or prescription records). Sixty-nine experimental studies fulfilled the inclusion criteria by testing actual or simulated driving performance after administering a single dose or multiple doses. Results: Two meta-analyses showed that benzodiazepines are associated with a 60% (for case-control studies: pooled odds ratio [OR] 1.59; 95% CI 1.10, 2.31) to 80% (for cohort studies: pooled incidence rate ratio 1.81; 95% CI 1.35, 2.43) increase in the risk of traffic accidents and a 40% (pooled OR 1.41; 95% CI 1.03, 1.94) increase in ‘accident responsibility’. Co-ingestion of benzodiazepines and alcohol was associated with a 7.7-fold increase in the accident risk (pooled OR 7.69; 95% CI 4.33, 13.65). Subgroup analysis of case-control studies showed a lower benzodiazepine-associated accident risk in elderly (>65 years of age) drivers (pooled OR 1.13; 95% CI 0.97,1.31) than in drivers <65 years of age (pooled OR 2.21; 95% CI 1.31, 3.73), a result consistent with age-stratified risk differences reported in cohort studies. Anxiolytics, taken in single or multiple doses during the daytime, impaired driving performance independent of their half-lives. With hypnotics, converging evidence from experimental and epidemiological studies indicates that diazepam, flurazepam, flunitrazepam, nitrazepam and the short half-life non-benzodiazepine hypnotic zopiclone significantly impair driving, at least during the first 2–4 weeks of treatment. The accident risk was higher in the elderly (>65 years of age) who use tricyclic antidepressants (TCAs); however, the evidence for an association of antidepressants with accident risk in younger drivers was equivocal. Sedative but not non-sedative antidepressants were found to cause short-term impairment of several measures of driving performance. Limited epidemiological research reported that opioids may be associated with increased accident risk in the first few weeks of treatment. Conclusions: Benzodiazepine use was associated with a significant increase in the risk of traffic accidents and responsibility of drivers for accidents. The association was more pronounced in the younger drivers. The accident risk was markedly increased by co-ingestion of alcohol. Driving impairment was generally related to plasma half-lives of hypnotics, but with notable exceptions. Anxiolytics, with daytime dosing, impaired driving independent of their half-lives. TCAs appeared to be associated with increased accident risk, at least in the elderly, and caused short-term impairment in driving performance. Opioid users may be at a higher risk of traffic accidents; however, experimental evidence is limited on their effects on driving.

We report on the direct electrochemical preparation of a nanocomposite composed of graphene, cetyl trimethylammonium bromide (CTAB), and polyaniline, and its application to headspace solid-phase microextraction (HS-SPME) of the tricyclic antidepressant drugs (TCAs) imipramine, desipramine and clomipramine. The new nanocomposite coating offers good mechanical and thermal stability and high extraction efficiency due to its large specific surface. The SPME conditions such as temperature, concentration of NaOH and extraction time were optimized with the aid of Box-Behnken design through response surface methodology. The TCAs were thermally desorbed and analyzed by GC. The limits of detections range from 0.10 to 0.35 ng mL −1 , and the calibration plots are linear within the 0.30–400 ng mL −1 concentration range. The method was successfully applied to the extraction and determination of TCAs in plasma, urine, milk and hair samples. Graphical Abstract We report on the direct electrochemical preparation of a nanocomposite composed of graphene, cetyl trimethylammonium bromide and polyaniline, and its application to headspace solid-phase microextraction of the tricyclic antidepressant drugs. The new nanocomposite coating offers good mechanical and thermal stability and high extraction efficiency due to its large specific surface.