Characteristics of tianeptine effects reported to a poison control center: a growing threat to public health.

BACKGROUND: Tianeptine is an antidepressant structurally similar to tricyclic antidepressants which is approved abroad but is currently a drug of abuse in the United States since at least 2000. In 2019, our poison center experienced an increase in calls relating to this xenobiotic. The goal of this report is to describe the characteristics of acute tianeptine intoxication and withdrawal. METHODS: All calls to a statewide poison center regarding tianeptine were reviewed from January 1, 2015 to March 15, 2020. Cases were identified using the American Association of Poison Control Centers' substance code for "other types of tricyclic antidepressants." Cases were excluded if they did not involve tianeptine. Date of call, patient demographics, symptoms, cardiac intervals if available, and disposition were recorded. RESULTS: Eighty-four cases of atypical tricyclic antidepressants were identified in the study period. Forty-eight cases involving tianeptine met inclusion criteria and were reviewed. Of these, 37 (77%) occurred from May 2019 to March 2020. Twenty-seven (56%) required medical admission including 17 cases (35%) that were managed in an intensive care unit. Seventeen of the 48 cases resulted from acute tianeptine intoxication. Lethargy was the most common presentation, but some patients also presented with agitation. Thirty-one (65%) of the cases resulted from tianeptine withdrawal, which usually exhibited agitation, anxiety, gastrointestinal distress. Naloxone was used in 4 cases (24%) of the acute intoxication cohort and benzodiazepines were frequently used both in acutely intoxicated patients and in patients experiencing tianeptine withdrawal. No patients in either cohort had cardiac conduction disturbances. CONCLUSION: Our center observed a dramatic rise in tianeptine toxicity, particularly in patients experiencing withdrawal symptoms, beginning in May 2019. More than half of the cases required medical admission including a third who were treated in the intensive care unit. Health care practitioners should be increasingly aware of this xenobiotic as usage may be on the rise.

Characteristics of Tianeptine Exposures Reported to the National Poison Data System - United States, 2000-2017.

Tianeptine (marketed as Coaxil or Stablon) is an atypical tricyclic drug used as an antidepressant in Europe, Asia, and Latin America. In the United States, tianeptine is not approved by the Food and Drug Administration (FDA) for medical use and is an unscheduled pharmaceutical agent* (1). Animal and human studies show that tianeptine is an opioid receptor agonist (2). Several case studies have reported severe adverse effects and even death from recreational abuse of tianeptine (3-5). To characterize tianeptine exposures in the United States, CDC analyzed all exposure calls related to tianeptine reported by poison control centers to the National Poison Data System (NPDS)† during 2000-2017. Tianeptine exposure calls, including those for intentional abuse or misuse, increased across the United States during 2014-2017, suggesting a possible emerging public health risk. Most tianeptine exposures occurred among persons aged 21-40 years and resulted in moderate outcomes. Neurologic, cardiovascular, and gastrointestinal signs and symptoms were the most commonly reported health effects, with some effects mimicking opioid toxicity. A substantial number of tianeptine exposure calls also reported clinical effects of withdrawal. Among 83 tianeptine exposures with noted coexposures, the most commonly reported coexposures were to phenibut, ethanol, benzodiazepines, and opioids.

Poison control center experience with tianeptine: an unregulated pharmaceutical product with potential for abuse.

Background: Interest in tianeptine as a potential drug of abuse is increasing in the United States. We performed a retrospective study of calls to the New York State Poison Control Centers (PCCs) designed to characterize one state's experience with tianeptine. Methods: Data were gathered from existing records utilizing the poison center data collection system, Toxicall® entered between 1 January 2000 through 1 April 2017. Information regarding patient demographics, reported dose and formulation of tianeptine, reported coingestants, brief narrative description of the case, disposition, and case outcome was collected. Results: There were nine reported cases of tianeptine exposure. Seven were male with a mean age of 27. Three reported therapeutic use of tianeptine and five reported intentional abuse. One case was an unintentional pediatric exposure. Doses were reported in three cases; 12.5 mg in a pediatric unintentional exposure, and 5 and 10 g daily in the two reports of intentional abuse. Of note, five patients complained of symptoms consistent with opioid withdrawal. In one of two cases in which naloxone was administered, an improvement in mental status and the respiratory drive was noted. Outcomes reported in Toxicall® were minor in two cases, moderate in five cases, major in one case, and not reported in one case. Conclusions: These cases, reported to the New York State PCCs should alert readers to the potential for tianeptine abuse, dependence, and withdrawal.

Case Reports of Fatalities Involving Tianeptine in the United States.

Tianeptine is a tricyclic anti-depressant that is also known to have opioid receptor activity. We present two fatal cases of tianeptine intoxication in Texas in which tianeptine was used recreationally. The first case involved a 28-year-old white male found alone on the floor of his locked residence. He had a history of drug abuse but no other toxicological findings. The second case involved a 30-year-old white male found on the floor of the bathroom in his home. Drug paraphernalia and bags labeled as tianeptine powder were found at both scenes. In response to the first case, our laboratory developed a method for quantitation of tianeptine by LC-MS-MS. This method was then validated according to SWGTOX guidelines for specificity, calibration model, limit of detection, limit of quantitation, accuracy, precision, ion suppression, and carryover. This method was successfully used to determine tianeptine concentrations in postmortem blood in two cases. In these cases, tianeptine was measured at 2.0 mg/L and 8.4 mg/L. These represent the first known tianeptine fatalities in Texas and in the United States.

Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine.

Tianeptine (7-[([3-chloro-6,11]-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl) amino] heptanoic acid S, S dioxide) is a tricyclic compound prescribed as an antidepressant in European countries, but is not currently approved for use in the United States. There are few published case reports of tianeptine intoxication. Presented is the first case of acute toxicity associated with the intravenous use of tianeptine. A 36-year-old male intentionally injected tianeptine powder intravenously to "help him see into the future". He became unresponsive and a bystander called emergency medical services. Upon arrival to the Emergency Department, excessive constriction of the pupils, sedation, and a respiratory rate of 6 respirations per minute (rpm) were noted. Blood and urine were collected ~2 h post admission. The patient's serum ethanol concentration was 133 mg/dL. His toxicity was successfully reversed with two doses of naloxone 0.4 mg IV. He was started on a naloxone infusion at 0.2 mg/h and discharged 13 h after admittance awake, alert and oriented. The patient's urine sample screened negative for common drugs of abuse and total tricyclic antidepressants. A high performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify tianeptine in urine. The calibration range was 1-100 ng/mL with linear regression correlation (r2) of 0.9996 or greater. The limit of quantitation was administratively set at 1 ng/mL. The bias of the assay was determined to be within ±20% of the target value for each quality control specimen. The intra-day and inter-day precision did not exceed 15% coefficient of variation for each quality control specimen. Matrix effects, absolute recovery, carryover and specificity were also evaluated. The patient's tianeptine urine concentration was determined to be 2 ng/mL.

Amitriptyline and tianeptine poisoning treated by naloxone.

INTRODUCTION: Severe amitriptyline toxicity may cause cardiac dysrhythmias, severe hypotension, convulsions and CNS depression, including coma. Management with gastric lavage, activated charcoal, alkalinization and supportive care with mechanical ventilation, antiarrhythmics and anticonvulsants, if required, is the general approach. CASE REPORT: A 33-year-old woman who had taken overdose antidepressants (amitriptyline and tianeptine) was admitted to the emergency service. She was intubated because she had pure respiratory arrest. Besides hypotension (80/60 mmHg), she was unresponsive to verbal and painful stimuli and her Glasgow coma score was 6. Hemogram and serum biochemical parameters and electrocardiography were within normal limits. The patient was examined for substance dependence and no trace of the injector was found in the body. Patient underwent a coma cocktail (naloxone 2 mg/body, 50% dextrose 25g/body and thiamin 100 mg/body). [corrected] Activated charcoal and intravenous alkalinization by NaHCO(3) were initiated. Spontaneous respiration started again 20 min after being given the coma cocktail. She became responsive to verbal stimuli first hour after the coma cocktail, and her Glasgow coma score improved to 13. She had spent 2 days in the service and was discharged by the second day of admission, without any complications. DISCUSSION: Herein, we report successful treatment in a case of severe amitriptyline and tianeptine poisoning by naloxone in addition to the above supportive care. Naloxone treatment may have a beneficial role in lethal doses of amitriptyline ingestion because amitriptyline may affect opioid receptors.

[Misuse of substances theoretically without abuse potential--case series]. / Naduzywanie substancji teoretycznie bez znanego potencjalu uzalezniajacego--przeglad przypadków.

The aim of our study was to present cases of misuse of different substances theoretically without abuse potential. In the last few years such behavior became an increasing problem in toxicological and emergency units. Lack of typical signs of intoxication with psychoactive substances, and negative results of standard toxicological tests may be a challenge for toxicologists and emergency medicine practitioners.

Planned complex suicide: an unusual case.

We report an unusual case of planned complex suicide. The victim was a woman aged 67 years, who was found dead in her bath in a state of advanced putrefaction. A plugged-in hairdryer was submerged in the water and the electrical fuses in the room had short-circuited. A kitchen knife lay below the body of the victim, whose left forearm bore incisions suggestive of wrist-cutting. At autopsy, no sign suggesting electrocution could be observed because of the advanced state of putrefaction of the body. Toxicological analysis revealed massive ingestion of tianeptine (blood concentration 15.5 mg/L). Although the exact cause of death could not be determined because of the state of the corpse, meticulous examination of the scene and information obtained from the victim's relatives led to the conclusion of suicide.

Fatal intoxication with tianeptine (Stablon).

Tianeptine (Stablon), although structurally similar to tricyclic antidepressants, acts by enhancing the reuptake of serotonin. A fatal case is presented involving a 26-year-old man, found lying in bed with a "mushroom of foam" around his mouth. Empty blister packs of Stablon and a suicide note were found next to the body. A liquid-liquid extraction procedure with n-hexane: ethyl acetate and n-hexane: 2-propanol, followed by LC-DAD-MS analysis, using positive mode electrospray ionization was performed. The detection limit was 0.001 microg/mL. The toxicological results revealed the following tianeptine concentrations in the post-mortem samples: blood 5.1 microg/mL; urine 2.0 microg/mL; liver 23 microg/g; stomach contents 22 mg. Femoral blood analyses also revealed an ethanol concentration of 0.53 g/L. The present method was also developed and validated for the other post-mortem specimens, since no previous published data had confirmed the post-mortem distribution of tianeptine. The absence of other suitable direct causes of death (macroscopic or histological) and the positive results achieved with the toxicological analysis led the pathologist to rule that death was due to an intoxication caused by the suicidal ingestion of tianeptine in combination with alcohol.

Tianeptine--an instance of drug-induced hepatotoxicity predicted by prospective experimental studies.

We report the case of a patient who developed acute hepatitis after taking tianeptine, a new tricyclic antidepressant, for 8 weeks. Hepatitis exhibited cholangitis-like clinical features and was associated with hypersensitivity manifestations suggestive of an immuno-allergic mechanism. Histological examination showed microvesicular steatosis. The discontinuation of tianeptine administration was followed by complete recovery. Immunoallergic hepatitis and microvesicular steatosis were predicted 2 years ago from prospective experimental studies prompted by the similarity of the chemical structures of tianeptine and amineptine, another tricyclic antidepressant, well-known for its hepatotoxicity. Experimentally, tianeptine has been found to be oxidized into reactive metabolites in several rodents and human liver and to produce microvesicular steatosis probably through inhibition of mitochondrial beta-oxidation of fatty acid in mice. This case illustrates the value of prospectively assessing potential hepatotoxicity mechanisms for new compounds chemically related to drugs already known to be hepatotoxic.