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Abuse of tianeptine. A case report
Abstract
The authors report a case of tianeptine abuse in a 30 year-old woman. After a medical prescription of the recommended dosage of 12.5 mg 3 times daily of oral tianeptine for a depressive illness, the patient spontaneously increased the dosage which after two months reached 150 tablets per day. No severe toxic effects were observed. As adverse effects, the patient, in the beginning of this high treatment period suffered from nausea, vomiting, abdominal pain, anorexia with weight loss, constipation. These side effects progressively disappeared. The biological tolerance was excellent, and hepatic parameters were not affected. The patient experienced and seek a psychostimulant effect. After seven months of such a therapy, she was hospitalized to undergo a withdrawal. The discontinuation of the tianeptine treatment occurs in four days. A withdrawal syndrome marked by myalgia, and cold feeling was transient, and alleviated by sedative phenothiazine (cyamemazine) and myorelaxant benzodiazepine (tetrazepam).
... The therapeutic dose of tianeptine was exceeded by a factor of 110 (i.e., up to 4125 mg/day) with a mean of about 1645 mg/day (Tuglu and Sahin 2010). In nine cases, the tianeptine use began with physician-recommended doses for registered indications and later progressed to abusing supra-therapeutic doses resulting in dependence (Anand et al. 2008;Bence et al. 2016;Guillem andLepine 2002, Hua et al. 1998;Hýža and Čechová 2015;Kisa et al. 2007;Lapsekili and Yavuz 2014;Tuglu and Sahin 2010;Vandel et al. 1998), with prominent euphoria in three of those cases (Anand et al. 2008;Guillem and Lepine 2002;Vandel et al. 1998). In 16 cases, the typical features of dependence were reported, including dose increases over time, tolerance (loss of efficacy), and severe withdrawal symptoms. ...
... The therapeutic dose of tianeptine was exceeded by a factor of 110 (i.e., up to 4125 mg/day) with a mean of about 1645 mg/day (Tuglu and Sahin 2010). In nine cases, the tianeptine use began with physician-recommended doses for registered indications and later progressed to abusing supra-therapeutic doses resulting in dependence (Anand et al. 2008;Bence et al. 2016;Guillem andLepine 2002, Hua et al. 1998;Hýža and Čechová 2015;Kisa et al. 2007;Lapsekili and Yavuz 2014;Tuglu and Sahin 2010;Vandel et al. 1998), with prominent euphoria in three of those cases (Anand et al. 2008;Guillem and Lepine 2002;Vandel et al. 1998). In 16 cases, the typical features of dependence were reported, including dose increases over time, tolerance (loss of efficacy), and severe withdrawal symptoms. ...
... Of particular interest is the euphoric effect of tianeptine, described in four cases (Anand et al. 2008;Guillem and Lepine 2002;Lapsekili and Yavuz 2014;Vandel et al. 1998) and yet seldom discussed in the literature. One controlled trial asserts that tianeptine lacks psychostimulant action; however, it is significantly limited by measuring the effect of a single 75 mg dose of tianeptine on a small group of healthy volunteers with no history of substance abuse (Bernard et al. 2011). ...
Tianeptine is an atypical antidepressant approved in 25 countries for the treatment of depressive syndromes. Tianeptine abuse among psychiatric patients in the community and at inpatient wards has been increasingly reported in recent years. The purpose of this article is to alert clinicians to tianeptine abuse potential and identify any patterns in the literature. We searched the Academic Search Complete, Google Scholar, MEDLINE, Science Citation Index, Scopus, and the Social Sciences Citation Index for articles published between 1960–2017 in any language containing the keywords: “tianeptine abuse,” “tianeptine misuse,” “tianeptine dependence.” The search retrieved 18 cases. Higher frequency of tianeptine abuse/dependence was observed in women and 30- to 45-year-olds. Most cases (n = 13) reported a previous history of substance abuse. The therapeutic dose of tianeptine was exceeded 110-fold (i.e., up to 4125 mg/day) with a mean of about 1469 mg/day. The most prominent phenomena associated with tianeptine abuse and dependence were marked euphoria and withdrawal symptoms perpetuating further drug misuse. Tianeptine is a drug with potential for abuse and addiction. Caution should be taken when considering the prescription of tianeptine to patients with prior history of substance abuse, and close monitoring for drug misuse is needed during the treatment period.
... Powszechnie uwa¿a siê, ¿e lek ten nie posiada w³aciwoci uzale¿niaj¹cych i w zwi¹zku z tym zaleca siê jego stosowanie w niektórych stanach psychopatologicznych zwi¹zanych z uzale¿nieniem od alkoholu i innych substancji psycho- aktywnych [11,20,21,23]. W pimiennictwie medycznym opisano zaledwie osiem przypadków uzale¿nienia od tego leku [8, 9,12,15,19,32,39]. W naszym doniesieniu przedstawiono pacjentkê z uprzednio stwierdzanym uzale¿nieniem od alkoholu i benzodiazepin, której z powodu objawów depresyjnych zlecono tianeptynê w dawce 37,5 mg/d (3 tabl./dz.) ...
... W przewa¿aj¹cej wiêkszoci, zachowania tego typu mieszcz¹ siê w pojêciu nadu¿ywania substancji (ang.: substance misuse ) czyli u¿ywania jej w sposób potencjalnie zagra¿aj¹cy zdrowiu, a tak¿e w innej dawce i innych celach ni¿ zalecane przez producenta [1,3,5,6,9,10,15,16,17,19,24-26, 29,31-36,38-40]. Choae jedynie u pacjentki u¿ywaj¹cej wysokich dawek tianeptyny stwierdzono faktyczne objawy uzale¿nienia, w wiêkszoci pozosta³ych przypadków wystêpowa³o potencjalne zagro¿enie dla zdrowia, a nawet ¿ycia chorych [15,19,25,32,34353639,40]. Przedstawione powy¿ej przyk³ady nietypowego stosowania leków wskazuj¹ na koniecznoae zwiêkszenia czujnoci lekarzy wszystkich specjalnoci na mo¿liwoae nadu¿ywania substancji teoretycznie bez potencja³u psychoaktywnego i uzale¿niaj¹cego [34]. ...
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.
... Case reports in the literature describe drug dependence [3,4,35], abuse and misuse [14,36,37,38] and even tianeptine psychosis [39]. The medical use of tianeptine under clinical supervision has been reported to result in a patient abusing the drug by escalating doses [40]. An interesting case study emerged in the United States when a chronic pain patient was denied effective analgesic prescription by his physician and sought relief in over-the-counter tianeptine only to develop tianeptine use disorder [18]. ...
Tianeptine is often incorrectly described as a selective serotonin reuptake inhibitor, but it actually is a µ-opioid receptor agonist with anxiolytic effects. It has been approved since the last 1980s in about 24 countries as a treatment for depression, but it was never cleared to market in the United States for this purpose. Nevertheless, tianeptine joined the billion-dollar US market of nootropics as ZaZa or Tianna Red and is widely available online and in small shops without a prescription, to the point that it has been nicknamed "gas station heroin." While the therapeutic dose range is about 25 to 50 mg/day, tianeptine abusers may take 100 times that amount. Tolerance occurs rapidly and users who seek to recapture the short-lived euphoric effects of the drug have to take more and more. Social media has peer-support sites for those trying to discontinue tianeptine. Tianeptine is associated with multiple side effects at high doses along with dependence, withdrawal symptoms, toxicity, respiratory depression, and even mortality. Agitation is more often a presenting symptom of withdrawal than toxicity. Tianeptine is often used by polysubstance drug abusers who may be unaware of the drug's dangers. Few clinicians are aware of tianeptine and most urine assays do not screen for it. Greater awareness is needed for this drug and steps must be taken as tianeptine or "gas station heroin" is emerging as a new public health threat.
... Back then, tianeptine was thought to have no abuse potential, as mentioned in the French summary of product characteristics before 2005, because there was no evidence of such a risk on the data available before approval (71). Nevertheless, the first reports of abuse with tianeptine emerged in the literature (72)(73)(74)(75). ...
Opioid analgesics and maintenance treatments, benzodiazepines and z-drugs, and other sedatives and stimulants are increasingly being abused to induce psychoactive effects or alter the effects of other drugs, eventually leading to dependence. Awareness of prescription drug abuse has been increasing in the last two decades, and organizations such as the International Narcotics Control Board has predicted that, worldwide, prescription drug abuse may exceed the use of illicit drugs. Assessment of prescription drug abuse tackles an issue that is hidden by nature, which therefore requires a specific monitoring. The current best practice is to use multiple detection systems to assess prescription drug abuse by various populations in a timely, sensitive, and specific manner. In the early 2000's, we designed a method to detect and quantify doctor shopping for prescription drugs from the French National Health Data System, which is one of the world's largest claims database, and a first-class data source for pharmacoepidemiological studies. Doctor shopping is a well-known behavior that involves overlapping prescriptions from multiple prescribers for the same drug, to obtain higher doses than those prescribed by each prescriber on an individual basis. In addition, doctor shopping may play an important role in supplying the black market. The paper aims to review how doctor shopping monitoring can improve the early detection of prescription drug abuse within a multidimensional monitoring. The paper provides an in-depth overview of two decades of development and validation of the method as a complementary component of the multidimensional monitoring conducted by the French Addictovigilance Network. The process accounted for the relevant determinants of prescription drug abuse, such as pharmacological data (e.g., formulations and doses), chronological and geographical data (e.g., impact of measures and comparison between regions), and epidemiological and outcome data (e.g., profiles of patients and trajectories of care) for several pharmacological classes (e.g., opioids, benzodiazepines, antidepressants, and methylphenidate).
... Tianeptine's safety credentials are furthermore enhanced by the fact that it has a very low overdose risk, therefore, has been classed as a drug with a low abuse potential. Surprisingly in a single case study, a patient abused tianeptine by consuming 50 times the recommended dose on a daily basis and no severe toxicity was observed [32]. ...
Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late 1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to have the apparently paradoxical mechanism of action of enhancing serotonin reuptake. However, recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AM-PA receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective: We have reviewed clinical and preclinical data for tianeptine to provide a compre-hensive study of its pharmacology. Results: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality. Tianeptine appears more efficacious in males than females, although these gender-specific differences may be accounted for by pharmacokinetics. Pre-clinical data suggest that the ability to stabilise glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive function and anxiety-related symptoms. Alternative-ly, μ-receptor activation of the mTOR signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions at μ-receptors could also explain the potential abuse li-ability and dependence issues seen with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much promise as an experimental tool yielding valuable insights into the molecular mechanisms underlying depression.
... Although an effective antidepressant and anxiolytic, tianeptine carries with it a potential for hazardous use, especially in patients with a history of alcohol or drug dependence, as it activates mu-opioid receptors at higher doses (Wilde and Benfield, 1995). Numerous case reports and series from countries across Europe and Asia have demonstrated its abuse potential (Vandel et al., 1998;Durmus et al., 2013;Leterme et al., 2003). Tianeptine also carries a risk of hepatotoxicity that is higher than many traditional antidepressants (Voican et al., 2014). ...
: Tianeptine is a tricyclic antidepressant that stimulates mu-opioid receptors at high doses. It is marketed and used across Europe and Latin America as an antidepressant, but is not approved by the Food and Drug Administration for use in the United States. In the United States, tianeptine is sold through online health stores as a cognition enhancer, dietary supplement, or as research chemical. We report the case of a 36-year-old man with a history of major depressive disorder, responsive to sertraline, who turned to the unmonitored use of tianeptine purchased online to treat residual feelings of apathy and boredom. His use of tianeptine was marked by rapidly escalating doses and a significant withdrawal syndrome that made discontinuation of this substance difficult. This case serves as a reminder that unscheduled pharmaceutical agents are available for misuse by the general population and have the potential to cause significant harm. Therefore, medical providers must be aware of and screen for the use of such products amongst their patients.
... Approximately 12.5 million Americans abused prescription opioids in 2012 (Brady et al, 2016). However, there have only been a few isolated case reports of addiction or withdrawal symptoms associated with tianeptine in the literature (Guillem and Lepine, 2003;Leterme et al, 2003;Saatcioglu et al, 2006;Vadachkoria et al, 2009;Vandel et al, 1999). While tianeptine did support a conditioned place preference, it did not lead to tolerance or withdrawal symptoms. ...
Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu-opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR. Interestingly, while tianeptine also produces many opiate-like behavioral effects such as analgesia and reward, it does not lead to tolerance or withdrawal. Furthermore, the primary metabolite of tianeptine (MC5), which has a longer half-life, mimics the behavioral effects of tianeptine in a MOR-dependent fashion. These results point to the possibility that MOR and its downstream signaling cascades may be novel targets for antidepressant drug development.
... Tianeptine is a tricyclic antidepressant with a unique mechanism of action as a glutamatergic modulator. However, tianeptine is also known for its abuse and dependence potential (3)(4)(5). ...
... 1-5 M tianeptine is expected to be reached in the plasma with a single 75-mg oral dose per day on the basis of bioavailability, distribution volume, etc. (Ginestet, 1997;Wagstaff et al., 2001). One case report about tianeptine abuse showed that a woman who took 150 tablets of 12.5 mg per day for 1-2 months did not exhibit severe toxic effects and hepatic damage but some minor side-effects such as nausea, vomiting, constipation, etc (Vandel et al., 1999). After four-day treatment for discontinuation of tianeptine, she returned to normal with minor symptoms like myalgia and cold feeling. ...
Pheochromocytoma originates from chromaffin cells in the adrenal medulla and sympathetic paraganglia. 36-53% of pheochromocytoma becomes malignant and, thereafter, resistant to conventional treatments. Pheochromocytoma also causes hyper-secretion of catecholamines that cause severe hypertension. We found that an antidepressant, tianeptine, interfered with normal life cycle of pheochromocytoma cells at its clinical doses. Treatment with tianeptine caused microtubule bundling and specific degradation of cytoplasmic dynein, a retrograde microtubule motor that mediates various microtubule-dependent processes during interphase and mitosis, in the rat pheochromocytoma PC12 cells. Tianeptine also increased the levels of pro-apoptotic proteins, slowed cell cycle progression, and increased apoptosis in PC12 cells. Importantly, tianeptine treatment decreased high K(+)-stimulated secretion of norepinephrine and chromogranin A in PC12 cells and of epinephrine in the mouse pheochromocytoma MPC cells. Our study demonstrates, for the first time, that tianeptine interferes with normal life cycle of pheochromocytoma cells.
... Tianeptine does not undergo cytochrome P450dependent biotransformation to a significant extent; 45 and increased tianeptine concentration caused by co-use of these drugs is unlikely to be a problem because tianeptine has a wide therapeutic margin. 46 Because tolerability and drug interactions are a concern in combination treatment, the favorable tolerability profile and low risk of drug interactions associated with tianeptine could be of benefit in combination strategies for TRD patients. ...
Aims:
The goal of this study was to assess the efficacy and tolerability of tianeptine in combination with selective serotonin re-uptake inhibitor (SSRI) in partial responders or non-responders to SSRI monotherapy.
Methods:
In this prospective, open-label, 6-week study, 150 patients with major depressive disorder who had previously not responded or partially responded to SSRI monotherapy were recruited. Tianeptine was given in combination with an SSRI for 6 weeks.
Results:
Significant improvements were observed in the mean scores of the Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), and Clinical Global Impression-Severity (CGI-S). The change in the mean HDRS, MADRS, and CGI-S scores was significant from week 1. The response rates were 64.7% (HDRS) and 68.7% (MADRS), and the remission rates were 34.0% (HDRS) and 42.0% (MADRS) at week 6. Thirty-six patients (24.0%) reported adverse events that were determined by the investigator to be related to one of the study drugs. The tianeptine and SSRI combination was generally well-tolerated.
Conclusions:
A combination strategy with tianeptine may be an effective and well-tolerated tool for patients who have failed to adequately respond to SSRI monotherapy.
... However, in our case, even assuming the possibility of a decrease in tianeptine's absorption by the presence of alcohol, the concentration found is still high and thus, this absorption decrease percentage would not be relevant. To our knowledge, only a few cases of tianeptine abuse have been reported15161718. However, there are no published reports of fatal cases due to this antidepressant. ...
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 (1) is an unusual antidepressant in that its mechanism of action appears to be independent from any activity at serotonin receptors or monoamine transporters. In fact, tianeptine has been shown to be a moderately potent agonist for the mu opioid receptor (MOR) and to a lesser extent the delta opioid receptor (DOR). Additionally, tianeptine’s efficacy may be related to its action on glutamate-mediated pathways of neuroplasticity. Regardless of which neurotransmitter system is primarily responsible for the observed efficacy, the MOR agonist activity is problematic with respect to abuse liability. Increasing numbers of case reports have demonstrated that tianeptine is indeed being used recreationally at doses far beyond what are considered therapeutically relevant or safe, and scheduling reclassifications or outright bans on tianeptine products are ongoing around the world. It is the aim of this review to discuss the medicinal chemistry and pharmacology of tianeptine and to summarize this intriguing discrepancy between tianeptine’s historical use as a safe and effective antidepressant and its emerging potential for abuse.
Tianeptine, an antidepressant and full μ-opioid receptor agonist, has increased in popularity and has been used as an over-the-counter supplement over the past decade. Due to its well-documented euphoric effects, there exists elevated risk for potential abuse. Buprenorphine–naloxone has been successfully utilized to treat opioid use disorder (OUD) in patients concurrently using tianeptine, limiting withdrawal symptoms and abstinence. However, there is limited evidence on the management of tianeptine use disorder, specifically methadone or naltrexone. The current opioid epidemic, the emerging use of tianeptine, and the lack of physician awareness have emphasized the need for further research on the role of tianeptine in medication-assisted treatment for OUD. This case report aims to demonstrate how medication-assisted therapy can be successfully utilized in a patient with opioid and severe other (tianeptine) drug use disorder.
Psychiatry Trainees’ Attitudes, Knowledge, and Training in Addiction
Psychiatry—A European Survey
Resumen
Objetivo
Señalar, mediante la exposición de un caso clínico, la necesidad de tener en cuenta el riesgo de abuso o dependencia de un antidepresivo de reciente aparición en nuestro país: la tianeptina.
Caso clínico
Se presenta el caso de un varón de 47 años con diagnósticos de trastorno bipolar tipo ii, trastorno límite de personalidad y trastorno por uso sustancias, que presentaba una dependencia a tianeptina, de la que llegó a consumir 1.125 mg al día.
Resultados
Durante la búsqueda bibliográfica apenas se encontraron revisiones de casos centrados en el potencial abuso o dependencia de tianeptina. Se halló que, por la modulación de los sistemas de neurotransmisión opioidérgico (activación de los receptores μ), su uso a dosis altas se relaciona con un mayor riesgo.
Conclusiones
Ciertas características personales y enfermedades, como pueden ser los trastornos de personalidad o un abuso de sustancias previo, implican una mayor probabilidad de abuso o dependencia de tianeptina.
This nationwide study aimed to compare use of oxycodone and doctor shopping for oxycodone in 2010 and 2016, and to quantify doctor shopping for oxycodone by sex, age, formulation, and dosage in 2010 and 2016. This study is a cross-sectional comparative analysis of doctor shopping based on all dispensings of oxycodone in France, in 2010 and 2016. Dispensings of oxycodone were extracted from the Système national des données de santé, which covers the 67 million inhabitants in France. Quantification of doctor shopping relies on an algorithm accounting for overlapping prescriptions, which is a proxy for potential misuse or abuse. The number of subjects that received oxycodone increased by 214% from 67838 subjects in 2010 to 212753 subjects in 2016, and the number of subjects with doctor-shopping behavior increased by 197%, from 1066 subjects in 2010 to 3163 subjects in 2016. For 30-44 year-old men, the total quantity of oxycodone obtained by doctor shopping increased by 391%, from 4582 defined daily doses in 2010 to 22517 defined daily doses in 2016. By formulation and dosage, the total quantity of oxycodone obtained by doctor shopping increased with the dosage for both immediate-release and extended-release tablets in 2010 and 2016. The widespread extent of doctor shopping and its threefold increase in line with population exposure is a strong signal in the French context. These results are another argument to avoid trivializing oxycodone to prevent misuse, potential abuse, and potential oxycodone-related deaths, but it requires caution to prevent compromising effective treatment of pain.
: Tianeptine is an atypical antidepressant which exerts an opioid-like effect on the μ-opioid receptor. There is well documented intentional misuse and addiction to tianeptine in Europe, and this is increasingly being seen in the United States. We presented a case of buprenorphine/naloxone successfully being used to aid in cessation and subsequent abstinence from tianeptine after years of use. An additional consideration with tianeptine use is the potential for the development or re-emergence of depression and anxiety on cessation. Chronic daily use of tianeptine may represent tianeptine use disorder, which can have a clinical course consistent with opioid use disorder, including the development of impaired control, functional impairment, tolerance, and withdrawal. It is appropriate to consider medications for opioid use disorder for the management of tianeptine use disorder.
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.
Tianeptine is a dibenzothiazepine type an atypical, tricyclic antidepressant. Biochemically it has been shown that after single or repeated administration, tianeptine increases the presinaptic reuptake of serotonine at the brain and trombocytes. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress and antogonizes the behavoiral problems induced by stress. Its pharmacotherapotic effects are neither stimulant nor sedative. Addiction to antidepressant therapy is controversial and rarely defined at the literature. Here we represent the tolerance, withdrawal symptoms and treatment issues of the case whom misused tianeptine at extremly high doses.
Antidepressant drugs are relatively efficient psychopharmacologic agents that are widely used in the treatment of anxiety and affective disorders although controversies are attached to their adverse reactions' profile. In particular, the possibility of this family of drugs to withhold addictive potentials has not been profoundly studied in the literature although it might be encountered in daily clinical practice. In fact, many case reports described antidepressant drug abuse or dependence such as in the case of misuse of antidepressant drugs having amphetamine-like properties. Misuse of antidepressants concern mainly patients with a diagnosis of personality disorder and a previous history of drug or alcohol abuse and who are treated for a depressive disorder. Methadone treated patients are often prone to antidepressant drugs misuse. The latter may enhance the rewarding effect of other psychoactive drugs. From a neurobiological perspective, antidepressant drugs act on the same monoamines involved in addiction. Conversely, the pharmacodynamic profiles of most antidepressants and the absence of acute "desirable" effects in therapeutic dosages make addiction theoretically unlikely. However, rare cases of antidepressant drugs misuse exist in the literature. Discontinuation syndrome and tachyphylaxis/ tolerance are both frequently encountered aspects of antidepressant drugs usage. They correspond to the physical component of the dependence on this class of drugs and are in no means sufficient or indicative of a predisposition or a presence of a dependence on antidepressant drugs. Accordingly, their occurrence should never be confounded with the very rare typical dependence on antidepressant drugs. In this chapter, a review of the literature intends to cover all aspects of this controversial issue regarding antidepressant drugs safety.
Tianeptine is an antidepressant compound approved for several years in France and in some other countries. It shows an interesting mechanism of action, different from all known antidepressants. On the one side the compound leads to a decrease of extracellular serotonin which was associated with an enhanced serotonin uptake, on the other side tianeptine showed in preclinical models a positive influence on neuroplasticity, synaptic function, glutamatergic and cognitive processes. In a considerable number of clinical trials tianeptine showed a superior efficacy compared to placebo and an at least comparable efficacy to standard antidepressants, namely SSRIs and tricyclics. Also positive long-term trials are published. The side effect profile is similar to SSRIs, however, gastrointestinal disturbances, tremor and palpitations are comparatively lower, dryness of mouth higher. Insofar, a new, interesting pharmacological treatment option for depression will also be available in Germany.
Das Antidepressivum Tianeptin wurde 1988 in Frankreich zugelassen, dann in einer Reihe europäischer Länder, vor allem in Mittel- und Osteuropa. Somit liegen zahlreiche Erfahrungen aus der klinischen Anwendung vor. Seit etwa eineinhalb Jahren ist die Substanz nun auch in Deutschland erhältlich. Diese Arbeit gibt einen kurzen Überblick über die präklinischen und klinischen Daten.
Background
Rates of prescription drug abuse have reached epidemic proportions. Large-scale epidemiologic surveys of this under-recognized clinical problem have not included antidepressants despite their contribution to morbidity and mortality. The purpose of this review is to look specifically at the misuse of antidepressants and how this behavior may fit into the growing crisis of nonmedical use of prescription drugs.
Methods
We conducted a comprehensive search on PubMed, Medline, and PsycINFO using the search terms “antidepressant”, “abuse”, “misuse”, “nonmedical use”, “dependence”, and “addiction”, as well as individual antidepressant classes (eg, “SSRI”) and individual antidepressants (eg, “fluoxetine”) in various combinations, to identify articles of antidepressant misuse and abuse.
Results
A small but growing literature on the misuse and abuse of antidepressants consists largely of case reports. Most cases of antidepressant abuse have occurred in individuals with comorbid substance use and mood disorders. The most commonly reported motivation for abuse is to achieve a psychostimulant-like effect. Antidepressants are abused at high doses and via a variety of routes of administration (eg, intranasal, intravenous). Negative consequences vary based upon antidepressant class and pharmacology, but these have included seizures, confusion, and psychotic-like symptoms.
Conclusion
The majority of individuals prescribed antidepressants do not misuse the medication. However, certain classes of antidepressants do carry abuse potential. Vulnerable patient populations include those with a history of substance abuse and those in controlled environments. Warning signs include the presence of aberrant behaviors. Physicians should include antidepressants when screening for risky prescription medication use. When antidepressant misuse is detected, a thoughtful treatment plan, including referral to an addiction specialist, should be developed and implemented.
Use of some medication, such as tranquilizers or hypnotics may carry important risks for patients including the
emergence of abuse and/or dependence. The problem we tackle consists of identifying and discriminating the group most “at risk” of abuse and/or dependence for a given drug, in order to provide an estimation of its prevalence and to develop preventive measures targeted toward the corresponding drug prescription. A criterion, currently employed to characterize patients’consumption of a drug, is the ratio between their daily average consumption and the maximum recommended daily dose as specified in the drug monograph, called the F factor. In theory, any patient having an F factor greater than 1 should be classified as an over-consumer for the corresponding drug, but in practice this threshold might not be very relevant for all drugs. The proposed approach, combining different statistical methods (extreme value theory with the Peaks Over Threshold Model, logistic
regression, ROC curve), is an innovative way to study consumption behaviors of psychotropic drugs. Two drugs are studied: an antidepressant, tianeptine and a hypnotic, zolpidem. From one drug to another, different thresholds for the F factor and patient’s characteristics associated with the risk of extreme consumption are found, revealing different consumption behaviors.
Tianeptine is an antidepressant agent with a novel neurochemical profile. It increases serotonin (5-hydroxytryptamine; 5-HT) uptake in the brain (in contrast with most antidepressant agents) and reduces stress-induced atrophy of neuronal dendrites. Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with most tricyclic antidepressant agents, tianeptine does not appear to be associated with adverse cognitive, psychomotor, sleep, cardiovascular or bodyweight effects and has a low propensity for abuse.
Tianeptine has a comparatively favourable pharmacokinetic profile. It is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. While this offers advantages for tianeptine over the tricyclic antidepressant agents in terms of dose titration, treatment changes and potential drug interactions, its rapid elimination makes adherence to dosage schedules more important. Tianeptine differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system, indicating less likelihood of drug-drug interactions; this is of particular interest for elderly patients.
Tianeptine, in dosages of 25 to 50 mg/day, has been investigated in patients with major depression, depressed bipolar disorder, dysthymia or adjustment disorder. It has equivalent antidepressant efficacy to several classical antidepressant agents (amitriptyline, clomipramine, imipramine, mianserin) and the SSRIs fluoxetine (in most patients), paroxetine and sertraline. Comparison with maprotiline indicated superior efficacy for tianeptine but dothiepin appeared superior in another study. Extended treatment with tianeptine decreases the incidence of relapse/ recurrence of depression.
Tianeptine appears to be as effective as fluoxetine, sertraline, amitriptyline, clomipramine and mianserin and more effective than maprotiline in improving associated anxiety in patients with depressive disorders. Depression and anxiety symptoms in alcohol dependant patients also respond well to tianeptine.
The adverse effects associated with tianeptine are similar in many respects to those of the SSRIs and minimal in comparison with the tricyclic antidepressants. The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis.
Conclusions: The antidepressant efficacy and favourable tolerability and pharmacokinetic profiles of tianeptine in patients with depression, including those with associated anxiety, have been proven; the data indicate that it may have additional potential in specific subgroups of depressed patients such as the elderly and those with chronic alcoholism.
Pharmacodynamic Profile
Tianeptine is an antidepressant drug with structural similarities to the tricyclic antidepressant agents but a novel neurochemical profile. The main difference between this and other antidepressant agents is its action on serotonin (5-hydroxytryptamine; 5-HT): tianeptine increases serotonin uptake in the brain and platelets. The behavioural (in animal models) and physical (atrophy of neuronal dendrites) effects of stress on the hypothalamic-pituitary-adrenal axis are reduced by tianeptine, and levels of noradrenaline (norepinephrine) and dopamine are indirectly increased in several regions of the brain. The main metabolite (MC5; pentanoic acid) has some minor antidepressant activity.
Clinical studies indicate that, unlike tricyclic antidepressant agents, tianeptine is not associated with adverse effects on driving skills or cognitive function (such as sedation or impaired memory) and may have slight activating properties, particularly in aspects of attention. Similarly, there appear to be few effects on sleep in healthy volunteers or patients with concurrent depression and alcoholism after withdrawal of alcohol.
Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with the tricyclic antidepressants, tianeptine has a favourable cardiovascular profile in healthy volunteers and patients with depression, with and without concurrent alcoholism.
Pharmacokinetic Profile
The maximum plasma concentration (Cmax) of tianeptine was 0.3 mg/L, time to Cmax (tmax) was 0.94 hours and bioavailability was 99% after a single oral dose of tianeptine 12.5mg in healthy volunteers. The drug is not subject to first-pass hepatic metabolism. Food decreases Cmax and prolongs tmax but does not affect the extent of absorption. Although the distribution of tianeptine is rapid (distribution half-life 0.7 hours) protein binding is high (95%), resulting in alow volume of distribution (0.5 to 0.8 L/kg) in healthy volunteers.
Tianeptine undergoes extensive extrarenal metabolism and has a short elimination half-life (t1/2β; 2.5 hours in healthy volunteers). The major metabolic pathway of tianeptine is a 2-step β-oxidation process of the aliphatic chain, leading to the formation of 2 main metabolites MC5 and MC3 (propionic acid). MC3 is the main metabolite of tianeptine in urine and MC5 is the main metabolite in plasma. Tianeptine does not undergo cytochrome P450—dependent biotransformation to any significant extent, thus reducing the risk of drug interactions.
The pharmacokinetic profile of a single dose of tianeptine in adults with depression appears similar to that in healthy adult volunteers, although the tmax and t12β were prolonged. Steady-state pharmacokinetics were achieved after 1 month of treatment with tianeptine 37.5 mg/day and were maintained over 3 months. Most values were similar to those seen in depressed patients after a single dose, but the area under the concentration-time curve (AUC) was significantly greater after extended treatment (1.3 vs 1 mg/L · h; p < 0.03).
The pharmacokinetic profile of oral tianeptine was not significantly altered in patients with compromised renal function. However, the t1/2β and AUC of the MC5 metabolite were increased compared with controls, suggesting a decreased clearance of this metabolite in patients with renal failure. Although bioavailability of tianeptine remained high (85%) in elderly individuals, clearance was lower than that reported in younger individuals. The pharmacokinetic profile of tianeptine is not altered in patients with alcoholic cirrhosis and depression.
Therapeutic Efficacy
The clinical antidepressant efficacy of tianeptine 25 to 50 mg/day has been proven against placebo in patients aged 18 to 60 years with major depression (single episode or recurrent) or bipolar disorder (depressed) in 2 double-blind trials. Initial improvements were seen after 7 days, and improvement continued throughout the 6 weeks of study. Improvements from baseline on the Montgomery-Åsberg Depression Rating Scale (MÅDRS) were 44 and 54% with tianeptine and 28 and 38% in placebo recipients (p < 0.05 and p < 0.01, respectively).
Tianeptine 25 to 37.5 mg/day for 1.5 to 3 months had equivalent antidepressant efficacy to fluoxetine 20 mg/day in patients with major depression (single episode or recurrent), bipolar disorder (depressed) or dysthymic disorder in several studies. However, although equivalence was noted in several parameters in elderly patients receiving tianeptine or fluoxetine in one study, reductions from baseline in the MÅDRS scores were statistically significantly greater in those receiving fluoxetine (62 vs 51% in fluoxetine and tianeptine recipients, respectively, compared with 50 vs 51%, respectively, in a study in patients aged 18 to 65 years which used this assessment tool). The antidepressant efficacy of tianeptine 37.5 mg/day (reduction in MÅDRS score of 56%) was equivalent to that of sertraline 50 mg/day (reduction of 54%) after 1.5 months in patients with major depression or bipolar disorder. A study published only in abstract form indicates that tianeptine 37.5 mg/day has similar efficacy to paroxetine 20 mg/day for 3 months (reductions in MÅDRS scores of 62 and 61%, respectively).
In comparative studies with tricyclic or tetracyclic antidepressant agents, the antidepressant efficacy of tianeptine 25 to 50 mg/day (44 to 64% reduction in MÅDRS scores) was equivalent to that of amitriptyline 50 to 100 mg/day for 1 or 1.5 months (53 and 69%), clomipramine 100 to 200 mg/day for 6 months (55%), imipramine 100 to 200 mg/day for 1.5 months (41%) and mianserin 30 to 80 mg/day for 1.5 or 6 months (48 and 50%) in patients with major depression (single episode or recurrent), bipolar disorder (depressed), dysthymic disorder or adjustment disorder. Tianeptine 37.5 mg/day (56% reduction in MÅDRS score) was more effective than maprotiline 75 mg/day for 2 months (47%) in a study of perimenopausal women with anxio-depressive symptoms and less effective than dothiepin 150 to 225 mg/day for 1 month in a small study of patients with depressive disorders.
The anxiolytic efficacy of tianeptine was assessed in several comparative trials of patients with concurrent depression and anxiety. Tianeptine 25 to 50 mg/day appears to have equivalent anxiolytic efficacy to fluoxetine 20 mg/day for 1.5 to 3 months, sertraline 50 mg/day for 1.5 months, amitriptyline 50 to 100 mg/day for 1 to 1.5 months, clomipramine 100 to 200 mg/day for 6 months and mianserin 30 to 80 mg/day for 1.5 or 6 months. Superior anxiolytic efficacy was attributed to tianeptine over maprotiline 75 mg/day for 2 months in a study of perimenopausal women with anxio-depressive symptoms.
Tianeptine 25 to 50 mg/day is effective as long term treatment to prevent relapse or recurrence in patients with depression. It also appears to have potential for use in specific subgroups. The efficacy of tianeptine 25 or 37.5 mg/day was equivalent to that of mianserin 30 mg/day and similar in some but not all parameters to that of fluoxetine 20 mg/day in elderly patients. Patients with chronic alcoholism often develop depression, especially on withdrawal of alcohol. Assessments of antidepressant and anxiolytic efficacy for tianeptine 37.5 mg/day were equivalent to those for amitriptyline 75 mg/day over 1 to 2 months in this patient population.
Improvements in quality-of-life scales with depressed tianeptine recipients were similar to those in patients receiving mianserin or fluoxetine.
Tolerability
The adverse effect profile of tianeptine appears to be similar in many respects to that of the SSRIs, in that cognitive, cardiovascular and bodyweight effects are minimal in comparison with the classical tricyclic antidepressant agents. In fact, in comparisons with placebo, the only symptom appearing significantly more often with tianeptine was headache. In clinical trials, the most common adverse effects seen in patients with depressive disorders receiving tianeptine were gastrointestinal (nausea, constipation, abdominal pain) or CNS (headache, dizziness, change in dreaming) disturbances, which decreased in frequency with continued treatment.
Effects such as dry mouth, hot flushes, somnolence, vertigo, gastrointestinal disturbances, increased bodyweight, increased heart rate and tremor occurred significantly more often in patients receiving tri- or tetracyclic antidepressant agents than in those receiving tianeptine. In studies comparing tianeptine with fluoxetine, paroxetine or sertraline, in contrast, the incidence of most adverse effects was similar; nausea, tremor and palpitations tended to occur more often in fluoxetine recipients, and the incidence of dry mouth tended to be higher in tianeptine recipients. Tianeptine has only rarely been associated with hepatoxicity.
The favourable tolerability profile of tianeptine has been confirmed in long term trials, and in elderly patients (including those with cardiovascular pathology before treatment initiation) and patients with alcoholism. The low incidence of anticholinergic and neurological effects associated with tianeptine is of particular importance in these subgroups, who have increased sensitivity to the adverse effects of psychotropic drugs.
Tianeptine has a wide therapeutic margin; overdosage has been associated with only minor transient adverse effects.
Dosage and Administration
The recommended dosage of tianeptine in patients with depression is 37.5 mg/day orally in 3 divided doses, with meals. The dosage should be reduced in elderly patients and patients with severe renal failure, but dosage reduction is not required in patients with chronic alcoholism or hepatic impairment or those undergoing haemodialysis.
The dosage of tianeptine should be reduced over 1 to 2 weeks when discontinuing treatment, although there is little evidence of psychological or physical dependence on the drug. As with other antidepressants, tianeptine is contraindicated in patients taking monoamine oxidase inhibitors.
The authors present a pharmaco-epidemiological method for the characterization of drug overconsumption. Using the database of a French regional health insurance office, a comparison was made between patients receiving doses higher than recommended and all patients receiving normal doses of two antidepressant drugs (tianeptine and milnacipran). Logistic regression models were used to identify the variables related to overconsumption. The selected variables were different for each antidepressant and provided a good characterization of overconsumption features: insufficient effectiveness and severity of the condition for milnacipran and abuse/misuse for tianeptine. Characterization of overconsumption of antidepressants can be performed using logistic regression models. This method of analysis, which is seldom used in the context of pharmacodependence, makes it possible to explain posology increase.
The primary objective of the present study was to assess the potential psychostimulant effect of a single oral supratherapeutic dose of tianeptine (75 mg in 1 shot) in young healthy volunteers compared with methylphenidate (40 mg) and placebo.
Eighteen healthy young male and female volunteers with no history of psychostimulant abuse completed this balanced, crossover, placebo-controlled study. Subjective and behavioral effects were assessed before treatment and 1, 2, 3, 4, and 8 hours after drug intake. Subjective effects of the drugs were recorded using self-questionnaire Addiction Research Center Inventory (ARCI 49). In addition, the Profile of Mood Scale, Visual Analog Scale, and attention/vigilance tests (choice reaction time and critical flicker fusion test) were used to evaluate mood state, subjective feeling, and sustained attention, respectively.
Analysis on changes from baseline, from 1 to 8 hours, showed statistically significant differences between treatment groups for 2 of the 5 ARCI subscales: amphetamine and morphine benzedrine scales. A trend to significance was observed for Lysergic Acid Diethylamide scale. Indeed, although tianeptine did not significantly change any ARCI scores, methylphenidate significantly increased amphetamine and morphine benzedrine scores of the ARCI compared with placebo. No significant treatment effect was observed on the Profile of Mood Scale and the visual analog scale. Analyses of attention and vigilance tests showed a psychostimulant effect for methylphenidate on choice reaction time (decrease of recognition time) and critical flicker fusion test (higher frequency).
A single administration of a supratherapeutic dose of tianeptine does not induce psychostimulant effect in young healthy volunteers in contrast to methylphenidate at a therapeutic dose. These findings suggest an absence of psychostimulant liability of tianeptine in a therapeutic situation.
Doctor-shopping is a patient behaviour characterized by simultaneous consultations of several physicians during the same period. Some case reports have described an abuse of tianeptine, an atypical antidepressant. Our objective was to assess the extent of abuse of this drug with a method quantifying doctor-shopping in comparison with other antidepressants and benzodiazepines (BZD). All dispensations of antidepressants and BZD during the year 2005 in a French area of 4.5 million inhabitants were extracted from a reimbursement database. For each patient, two quantities were computed: quantity dispensed and obtained by doctor-shopping. Tianeptine and other drugs were compared using their doctor-shopping indicator (DSI), defined as the percentage of drug obtained by doctor-shopping among dispensed quantity; 410 525 patients received at least one antidepressant dispensation during the year 2005. Tianeptine was the sixth most dispensed antidepressant. The DSI of tianeptine was 2.0%, ranking it first among antidepressant (the second being mianserine with a DSI of 1%). Flunitrazepam has the highest DSI (30.2%), the DSI of the five following BZD (clonazepam, zolpidem, oxazepam, diazepam, bromazepam) range from 3.0% to 2.0%. Tianeptine is associated with higher DSI, compared with other antidepressants, suggesting that it may be subject to abuse in the population. Moreover, its DSI as a measure of diversion is similar to the DSI of diazepam or bromazepam.
Tianeptine, an atypical tricyclic antidepressant, is one of the first chemical agents, like tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs), which are employed for the treatment of anxiety and depressive disorders. It is believed that tianeptine, unlike the SSRIs, is enhancing serotonin re-uptake the velocity of the cortical neurons in the lymbic system and hippocampal neurons. In literature, there are more examples of dependence cases of antidepressants, which have amphetaminergic effects, such as amineptine and tranylcipromine, than amitriptyline, fluoxetine and tianeptine. Contrary to the reports about using high dosages of tianeptine, case reports about misuse and dependence have revealed that the most common reason of dependence is the psychostimulant effect. In these cases, tolerance to tianeptine and the symptoms of depreviation in absence of the drug have been seen, and the history of dependence or abuse of any drug or alcohol, treatment for mood and/or personality disorders are mentioned as possible risks for the dependence to tianeptine. This report discusses the diagnosis and treatment of a tianeptine dependence case. The 34 year-old patient, who is in conflict with her own family members, does not have the history of dependence or abuse of any substances, except for smoking, had been using excessive doses of 750 mg/day of tianeptine for a year.
Tianeptine, an atypical antidepressant patented and developed by Servier, enhances the synaptic reuptake of serotonin, without affecting norepinephrine and dopamine uptake, while it lacks affinity for neurotransmitter receptors. This mechanism for an antidepressant is apparently paradoxical, since the currently employed antidepressants enhance serotonin by inhibiting its breakdown or by inhibiting monoaminergic reuptake. Although tianeptine has been shown to reduce central 5HT availability and to indirecty modulate central adrenergic and dopaminergic systems and to indirectly inhibit cholinergic hyperactivity, its antidepressant action is believed to be more directly related to central neuronal remodeling and restoration of neuronal plasticity. In reliable animal models of depression tianeptine has been shown to prevent neurodegeneration and decreases in hippocampal volume in response to chronic stress. These effects on neuroplasticity are suspected to involve the normalization of the hypothalamic-pituitary-adrenal axis and modulatory effects on excitatory amino acids and N-methyl-D-aspartate receptors. Together with a body of related studies, these data provide further support for the hypothesis that depression may involve dysregulation of pathways controlling cellular resilience and that treatment should be directed towards the reversal thereof. Importantly, tianeptine is not anxiogenic and has also been shown to be effective in treatment-resistant depression, which may lead the way to a major breakthrough in the treatment of depression.
Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-13%), creatine and phosphocreatine (-15%), and choline-containing compounds (-13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.
The authors relate eight cases of amineptine dependency collected between 1980 and 1988 in 7 women and 1 man treated in the CHU of Besancon (France). The pharmacodependency appeared to be limited mainly to an abuse and a psychic dependence, i.e. a compulsive need to use the drug on a periodic (two cases) or continuing (six cases) basis in order to experience its psychomotor stimulant like effect. The used dosages ranged between 1000 and 2500 mg per day. The daily dose was divided into little doses, every hour for example. The induction modality was progressive during weeks or months and a stable dose period was then encountered. In one patient only, we observed a progressive increase of the dose without stabilisation of the dose. The withdrawal of amineptine was obtained without problem except in 2 cases where we observed clinical manifestations of anxiety, psychomotor agitation or bulimia during one day. Four years after the beginning, amineptine dependence was still present in 2 patients. In 4 patients we obtained an interruption of the amineptine pharmacodependency for one to three years. We did not see again the two remaining patients. In two cases, the main diagnosis, according to DSM III, was a major personality disorder (borderline). In the six other cases the diagnosis was a bipolar affective disorder (including four cases with only hypomanic episodes only). In these six patients the main characteristic of their affective illness was the association with other psychiatric disorders, especially personality disorders, such as borderline personality in one case and atypical personality with uncontrolled behavior as the main feature, in the 5 other patients. The two patients with borderline personality and four of the six bipolar ones had antecedents of bulimia, alcohol or psychotropic drugs (including amphetamines) abuse. In six patients impulsive traits were noted. In conclusion the prescription of amineptine might be a risk in patients with affective illness associated with impulsive personality traits, or bulimia, alcohol and psychotropic drug abuse.
Synopsis
Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile.
Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology.
The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, Imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups.
Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, Imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted.
Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence o f dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs. Discontinuation of tianeptine has not been associated with a withdrawal syndrome, and no deaths from overdosage have been reported.
Thus, tianeptine is a unique antidepressant agent that increases the reuptake of serotonin while paradoxically having well documented therapeutic activity compared with other antidepressant agents. Tianeptine also has anxiolytic properties in patients with coexisting depression and anxiety, and appears to have a more favourable tolerability profile than amitriptyline in terms of anticholinergic, sedative and cardiovascular adverse effects. These properties may be particularly useful in patients with coexisting anxiety and depression, and in the elderly and patients withdrawing from the effects of alcohol.
Pharmacodynamic Properties
Tianeptine is a novel antidepressant agent that, in contrast with classical tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), stimulates presynaptic serotonin (5-hydroxytryptamine; 5-HT) uptake in rat brain (cortex and hippocampus) and rat and human platelets following both short and long term administration. Tianeptine and its metabolites have no effect on serotonin uptake in vitro. The activity of tianeptine appears to be selective for serotonergic mechanisms although most reports show that the drug does not bind to serotonin receptor subtypes.
Tianeptine does not directly affect the uptake or release of dopamine or interfere with monoamine oxidase activity or monoamine uptake. However, the drug increases levels of the dopamine metabolite dihydroxyphenylacetic acid and increases extracellular concentrations of dopamine.
In contrast to other tricyclic antidepressants and paroxetine, tianeptine reduced most 5-hydroxytryptophan (5-HTP; a serotonin precursor)-induced behaviours in rats while the drug had no effect on behaviour elicited by postsynaptic serotonin receptor stimulation. However, after 4 weeks’ tianeptine administration, behavioural responses to tryptophan or 5-HTP were unaffected or intensified and were similar to those with paroxetine. The antidepressant properties of tianeptine have been demonstrated in animal models of depression. Tianeptine also reduced anxiety in the rat (social interaction test) and counteracted benzodiazepine and ethanol withdrawal-induced anxiety.
Tianeptine reduces stimulation of the hypothalamic-pituitary-adrenal axis in response to stress, antagonises stress-induced behavioural deficits in animal models of depression, and prevents stress- or corticosterone-induced changes in cerebral morphology. Although the exact mechanism of these effects is unknown, evidence suggests that the effects of tianeptine on serotonin reuptake account for these observations.
Tianeptine had no significant effects on memory or vigilance in healthy volunteers; single doses had activating effects followed by sedation according to electroencephalographic (EEG) mapping. Tianeptine does not significantly affect sleep EEG parameters in healthy volunteers.
Pharmacokinetic Properties
Maximum plasma concentration (Cmax) was 0.3 mg/L, time to Cmax (tmax) was 0.94h and bioavailability was 99% following a single oral dose of tianeptine 12.5mg in young healthy volunteers. The drug is not subject to first-pass hepatic metabolism. Food delays, but does not affect the extent of, absorption. The apparent volume of distribution of tianeptine is low (0.5 to 0.8 L/kg) and protein binding is high (95%). The pharmacokinetics of tianeptine are linearly related to dose.
Tianeptine is extensively metabolised by extrarenal routes; <3% of the dose is excreted unchanged in the urine. β-Oxidation is the major metabolic pathway. MC5 (pentanoic acid) and MC3 (propionic acid) are the major metabolites in plasma and urine, respectively; MC5 possesses antidepressant activity.
The overall pharmacokinetic profile of single doses of tianeptine in adults with depression is similar to that in healthy volunteers although the terminal elimination half-life (t½β) is longer (6.3 vs 2.5h). Furthermore, the overall pharmacokinetics of tianeptine at steady-state are similar to those after single dose administration although area under the concentration-time curve (AUC) was significantly higher after 1 month than after a single dose (1.3 vs 1 mg/L ∙ h).
The t½β and AUC of MC5 following a single oral dose of tianeptine 12.5mg were increased in patients with chronic renal failure. Similarly, t½β of tianeptine (after oral and intravenous administration) was increased, clearance of tianeptine (after intravenous administration) was decreased, and the Cmax and tmax of MC5 (after oral administration) were increased in the elderly compared with younger counterparts. Thus, dosage adjustments are recommended in patients with chronic renal failure and in the elderly. Dosage adjustments do not appear to be necessary in patients undergoing haemodialysis or those with chronic alcoholism, and are not likely to be necessary in patients with compensated hepatic impairment.
Therapeutic Efficacy
The efficacy of tianeptine in the treatment of depression was greater than that of placebo in 2 trials of patients with major depression or depressed bipolar disorder, with or without melancholia. Furthermore, the antidepressant efficacy of tianeptine 25 to 50 mg/day administered for 4 weeks to 3 months appeared to be similar to that of amitriptyline 50 to 100 mg/day, imipramine 100 to 200 mg/day and fluoxetine 20 mg/day in patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymia. However, it must be noted that submaximal dosages of amitriptyline were used in these studies. Response rates of 58 to 78%, according to Montgomery-Åsberg Depression Rating Scale (MÅDRS), Hamilton Depression Rating Scale (HDRS) or Clinical Global Impression (CGI) scores, have been reported with tianeptine. Evidence from a noncomparative trial suggests that tianeptine may also be effective in patients with endogenous depression.
Therapeutic benefits observed after short term therapy appear to progressively improve with long term (up to 1 year) tianeptine therapy. Furthermore, prolonged tianeptine treatment may also reduce the incidence of relapse and recurrence of depression. A placebo-controlled trial of long term therapy with this drug is currently under way.
The anxiolytic properties of tianeptine appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline in patients with depression and coexisting anxiety; however, submaximal dosages of amitriptyline and maprotiline were used and studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine reduced Hamilton Anxiety Rating Scale (HARS) scores by 36 to 66%. Furthermore, tianeptine appeared to reduce the need for concomitant anxiolytics compared with fluoxetine.
Short term tianeptine therapy effectively reduced depression and anxiety in elderly patients with major depression without melancholia or psychotic features or dysthymic disorder. Therapeutic benefits were at least sustained in the long term. Tianeptine was also effective in the treatment of patients with major depression or dysthymic disorder following alcohol withdrawal.
Tolerability
Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. In a general practice study involving 1858 patients with depression treated with tianeptine for 3 months, the most common adverse events were dry mouth (12%), constipation (4%), bitter taste (4%), ‘change in dreaming’ (4%), drowsiness (4%), weight gain (3%), agitation/tension (3%) and nausea (3%). In more than 3300 patients treated with tianeptine for up to 1 year, no significant changes in heart rate, blood pressure, cardiac conduction or ventricular function were observed. Less than 5% of patients withdrew from short or long term tianeptine treatment because of an adverse event.
Tianeptine appears to have a lower propensity to cause sedative, anticholinergic and cardiovascular effects than classical tricyclic antidepressant agents. In a review of double-blind trials, dry mouth (38 vs 20%) occurred in significantly more amitriptyline than tianeptine recipients; heart rate increased with amitrip-tyline and decreased with tianeptine. There was also a trend towards more dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%), postural hypotension (8 vs 3%) and constipation (19 vs 15%) with amitriptyline. Insomnia and nightmares occurred in significantly more tianeptine than amitriptyline recipients (20 vs 7%). No significant electrocardiographic (ECG) changes were observed with tianeptine. The tolerability profile of tianeptine was similar to that of fluoxetine in a clinical trial.
The low incidences of anticholinergic effects, sedation and cardiotoxicity make tianeptine particularly attractive for use in the elderly and in patients with previous alcoholism who are known to have increased sensitivity to the adverse effects of psychotropic agents. A review of noncomparative trials involving 549 elderly patients, and a long term trial of tianeptine in 130 patients with depression following alcohol withdrawal support the favourable tolerability profile of tianeptine in these patient groups.
Dosage and Administration
Tianeptine 12.5mg 3 times daily is the recommended dosage in patients with depression. Some patients may benefit from a dosage of 50 mg/day whereas a reduced daily dosage of 25 mg/day is recommended in patients with severe renal failure and in the elderly. Progressive therapeutic improvements have been observed over a 1-year period and long term treatment may reduce depressive relapse or recurrence.
Salicylic acid decreases the protein binding of tianeptine. Therefore, a reduced dosage of tianeptine is recommended when high dosages of salicylic acid are concomitantly administered.
Evaluated the therapeutic efficacy and acceptability during long-term administration of the antidepressant tianeptine in 130 adult depressed patients after withdrawal from alcohol abuse or dependence. Only 1 S dropped out because of side effects, and medication was interrupted in 5% of the Ss because of alcoholic relapses. In the long term, tianeptine did not produce orthostatic hypotension, changes in body weight, or alterations in EKG. All changes found in hematological and biochemical investigations suggest an improvement in Ss' physical state. Ss also showed significant improvement in depressive symptoms while taking tianeptine. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Tianeptine is a new tricyclic compound whose principal action is to increase the reuptake of serotonin. In a multicentre trial in which 380 depressed patients were treated for one year, tianeptine produced a significant reduction in the MADRS scores from day 14, with a sustained reduction maintained for up to 12 months; other measures of efficacy (HRSA, HSCL, and CGI) also reflected the improvement. Only 11% of patients withdrew because of recurrence of depression and 2% because of side-effects, which were mainly drowsiness, irritability, and gastrointestinal disturbance. Apart from a minor reduction in heart rate, unaccompanied by any conduction changes, no clinically relevant changes in vital signs or laboratory tests were seen. Seven subjects who attempted suicide by tianeptine overdose had favourable outcomes, in spite of also taking other psychotropic drugs or alcohol. No evidence of tolerance or withdrawal symptoms was seen after treatment was stopped. These results suggest that tianeptine has the potential to provide safe antidepressant activity in both the acute and chronic phases of treatment.
Tianeptine is a tricyclic antidepressant with an unusual chemical structure (a long lateral chain grafted on to a substituted dibenzothiazepin nucleus), and with biochemical and animal-behavioural properties which are strikingly different from those of classical tricyclics. Unlike the latter, which decrease serotonin (5-HT) uptake, acute and chronic tianeptine treatment enhances 5-HT uptake in rat brain and in rat and human platelets ex vivo. In vivo, tianeptine potentiates the depletion of rat brain 5-HT by 4-methyl-alpha-ethyl metatyramine and increases rat hippocampal 5-HIAA; 5-HT uptake inhibitors (e.g. fluoxetine) have opposite effects. On iontophoretic injection into CA1 pyramidal cells, tianeptine shortens the period of neuronal hypoactivity caused by GABA or 5-HT, whereas other tricyclics prolong it, and it enhances attention, learning, and memory in laboratory animals, while classical tricyclics have opposite effects. However, the relationships between these effects of tianeptine in animal experiments and their relevance to clinical findings remain to be determined.
1,927 outpatients were included by 392 general practitioners in an open study in order to evaluate the safety of tianeptine in the ambulatory treatment of depression. The results of 1,858 depressed patients without melancholia and psychotic features, fulfilling DSM III criteria of Major Depressive Episode or Dysthymic Disorder, could be analysed. 1,458 patients completed the 3-month treatment period. The group treated with 37.5 mg/day of tianeptine showed improvement on the Montgomery-Asberg Depression Rating Scale. With regard to the clinical tolerance of tianeptine, somatic complaints were rarely reported and adverse events necessitating premature termination of treatment (4.8% of included patients) were without clinical severity. Cardiovascular, haematologic, hepatic and biochemical safety were verified. No signs of dependence and no specific withdrawal symptoms were found after discontinuation of treatment.
The effect of various doses of tianeptine on the extracellular concentrations of dopamine was studied in the striatum and nucleus accumbens of the rat. At 5 (but not 2.5) mg/kg intraperitoneally, tianeptine increased the extracellular dopamine only in the nucleus accumbens. At 10 mg/kg, the effect was also seen in the striatum but it was less marked and shorter-lasting. At 10 mg/kg (i.p.), tianeptine significantly raised the extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in both regions. The effect of 10 mg/kg tianeptine on dopamine and its metabolites was not significantly changed in animals which had received this dose twice daily for 15 days. Intracerebroventricular administration of 150 micrograms/20 microliters 5,7-dihydroxytryptamine, which markedly depleted serotonin in the brain, did not modify the effect of 10 mg/kg tianeptine on the extracellular concentrations of dopamine and HVA in the nucleus accumbens but reduced the effect on DOPAC. Various doses of tianeptine (1, 3 and 10 mg/kg i.p.) did not change the synthesis of serotonin and dopamine in the striatum and nucleus accumbens. The results show that tianeptine increased the extracellular concentrations of dopamine more in the nucleus accumbens than in striatum. The effect on the output of DA in the nucleus accumbens could be involved in the antidepressant activity of tianeptine.
The effects of the new tricyclic antidepressant tianeptine were investigated on dopaminergic (DAergic) metabolism in the anteromedian prefrontal cortex and the nucleus accumbens of the rat. DAergic metabolism was assessed by the measurement of DOPAC, the main presynaptic metabolite of dopamine, using in vivo voltammetry in rats ventilated with halothane (0.5-0.75% in air). Acute treatment with tianeptine (10 mg/kg, 20 mg/kg) only increased significantly DOPAC levels in the anteromedian prefrontal cortex. After chronic treatment with tianeptine (15 days, 2 times/day) the increases in DOPAC levels in this structure were altered and less pronounced with the 20 mg/kg dose. Previous studies led to suggest that both acute and chronic effects on DAergic terminals in the anteromedian prefrontal cortex may be involved in the therapeutic action of this new antidepressant.
129 chronic alcoholic patients, withdrawn from alcohol and presenting major depression or dysthymic disorder, were treated for 4-8 weeks under double-blind conditions either with a new antidepressant, tianeptine (37.5 mg per day), or with amitriptyline (75 mg per day). Both groups presented steady improvement of the symptoms of depression during treatment, as scored on the Montgomery and Asberg Depression Rating Scale and the Hopkins Symptom Checklist self-evaluation; for the latter scale, the improvement was significantly greater in the tianeptine group. In addition to the improvement of mood, tianeptine also produced significant reduction of the somatic complaints of the depressed patients. Furthermore, tianeptine possesses anxiolytic activity, as shown by the change of the Hamilton Anxiety Rating Scale global score, similar to that produced by amitriptyline. The anxiolytic activity of tianeptine was not accompanied by any impairment of vigilance, unlike that of amitriptyline. Tianeptine produced rare, mild anticholinergic effects. The results obtained show that tianeptine is an effective anxiolytic antidepressant, with better safety than amitriptyline, suitable for use in the treatment of mood disorders following alcohol withdrawal.
The evaluation of clinical and paraclinical safety of tianeptine was performed in (a) clinical pharmacology studies assessing night sleep EEG organization; electrocardiographic stability by continuous 24-h recordings (Holter's method); ocular tonus in patients with stabilized glaucoma; salivary flow; prolactin secretion; photodynamic dermatologic reactions; cerebral electrical activity; hematologic, hepatic, renal and main metabolic parameters; separately, withdrawal phenomena and addictive potential were searched for in drug addicts; (b) double-blind controlled studies versus reference compounds. The results confirm that the therapeutic safety of tianeptine is satisfactory with respect to clinical side effects and paraclinical parameters. Tianeptine does not induce sedation and thus does not disturb the recovery of active life. It does not induce anticholinergic effects (dry mouth, constipation, etc.), even in elderly subjects. It is devoid of heart and blood pressure side effects including postural hypotension tachycardia, ECG abnormalities, and especially atrioventricular or intraventricular conduction disorders. Moreover, tianeptine does not disturb the hematologic, renal, hepatic parameters, even in alcoholic patients in the detoxification period. It does not induce physical or psychological signs of dependence when discontinued, even in alcoholic patients or drug addicts. No abuse of tianeptine and no tolerance were noted in detoxified opiate addicts.
We relate two cases of amineptine (Survector) overconsumption by patients cured for atypical depression with asthenia and activities deficit as the prevalent symptoms. Prescription of two tablets a day (0,200 g) was respected in one case during six months, and in the other case during two years, with therapeutic benefit on apragmatism. To no obvious reason, within few months both patients had gradually raised the doses to twenty tablets (2 g) and thirty tablets (3 g) respectively: we observed subexcitation, insomnia, sensorial hyperaesthesia, irritability, tachyphemia with dysarthria, anorexia with weight lost of more than 10 kg and amphetamine-like troubles without confusion or delusion, as a result of which both patients were treated for their addiction, in hospital. Treatment with clorazepate perfusions did not cause any physical dependence problems. However, psychological dependence was strong enough for one of the patients to go out, on the third day, against medical decision. As far as we know, in France, only one such case of addiction use at high doses and in single intakes is mentioned in the existing literature. However, our observations suggest that it might be necessary to re-assess the place of amineptine among new antidepressive molecules with psychostimulant abilities.
Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
The effects of various doses of tianeptine on extracellular concentrations of dopamine were studied in the frontal cortex and nucleus accumbens of the rat. At 5 and 10 mg/kg intraperitoneally, tianeptine raised extracellular dopamine in the nucleus accumbens but only the higher dose caused a significant increase in the frontal cortex. At 10 mg/kg tianeptine significantly raised the concentrations of dihydroxyphenylacetic acid and homovanillic acid in both brain regions. In another experiment, 10 and 20 mg/kg tianeptine did not modify the extracellular concentrations of noradrenaline in the frontal cortex but dose dependently blocked the increase in extracellular noradrenaline caused by restraint stress.
Several arguments are in favour of the use of antidepressant drugs in alcohol-dependent patients, especially those acting on the serotoninergic system: (1) neurochemical data indicate the interaction between alcohol and 5-HT metabolism, (2) pharmacological studies show an improvement in the behaviour of alcoholized animals treated with antidepressants, (3) depression is a frequent disease in alcoholic patients. Tianeptine has been shown to be active in the treatment of depression in patients with history of alcohol abuse or dependence. In a first double-blind study performed versus amitryptiline, depression after withdrawal was improved by tianeptine, and biological abnormalities usually related to chronic alcohol intake tended to decrease. Similar results were found in an open study carried out on 277 alcoholic patients treated for 1 year. As these patients were depressed, no definite conclusion could be drawn from these results in respect of a specific action of tianeptine on alcohol dependence. Thus, a multicentre double-blind study has been performed which compared tianeptine (12.5 mg t.i.d) and placebo in 342 non-depressed patients fulfilling DSM-III-R criteria for Psychoactive Substance Dependence (alcohol). Other inclusion criteria were: daily alcohol intake higher than 80 g, minimum score of 3 on the Short-Mast Questionnaire, mean corpuscular volume above 98 fl and/or gamma Gt more than twice the upper limit of normal. The patients were treated for 9 months. The intention-to-treat population and the per protocol population were made up of 327 patients and 111 patients, respectively. The main efficacy criterion was the absence of alcoholic relapse (abstinence) defined by the patient's statements, the investigators clinical judgement and some biological parameters: alcohol blood levels, gamma Gt levels. Secondary criteria were the evolution of the alcohol consumption in the patients who relapsed, cumulative abstinence duration, a visual analogue scale for the evaluation of the appetence for alcohol and the clinical global impressions scale. The statistical analysis showed no difference between both groups in respect of the maintenance of abstinence (intention-to-treat and per protocol populations). In spite of the methodological problems of the studies in dependence (choice of the inclusion and efficacy criteria, especially), the preliminary results obtained with the serotoninergic antidepressants were not confirmed in the different trials performed in the maintenance of alcohol abstinence. The indication of tianeptine should be restricted to the treatment of depressive syndromes, which have a high lifetime prevalence in the alcoholic patient, and which have a noticeable role on the alcoholic relapse.
Unlabelled:
Tianeptine is an antidepressant agent with a novel neurochemical profile. It increases serotonin (5-hydroxytryptamine; 5-HT) uptake in the brain (in contrast with most antidepressant agents) and reduces stress-induced atrophy of neuronal dendrites. Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with most tricyclic antidepressant agents, tianeptine does not appear to be associated with adverse cognitive, psychomotor, sleep, cardiovascular or bodyweight effects and has a low propensity for abuse. Tianeptine has a comparatively favourable pharmacokinetic profile. It is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. While this offers advantages for tianeptine over the tricyclic antidepressant agents in terms of dose titration, treatment changes and potential drug interactions, its rapid elimination makes adherence to dosage schedules more important. Tianeptine differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system, indicating less likelihood of drug-drug interactions; this is of particular interest for elderly patients. Tianeptine, in dosages of 25 to 50 mg/day, has been investigated in patients with major depression, depressed bipolar disorder, dysthymia or adjustment disorder. It has equivalent antidepressant efficacy to several classical antidepressant agents (amitriptyline, clomipramine, imipramine, mianserin) and the SSRIs fluoxetine (in most patients), paroxetine and sertraline. Comparison with maprotiline indicated superior efficacy for tianeptine but dothiepin appeared superior in another study. Extended treatment with tianeptine decreases the incidence of relapse/recurrence of depression. Tianeptine appears to be as effective as fluoxetine, sertraline, amitriptyline, clomipramine and mianserin and more effective than maprotiline in improving associated anxiety in patients with depressive disorders. Depression and anxiety symptoms in alcohol dependant patients also respond well to tianeptine. The adverse effects associated with tianeptine are similar in many respects to those of the SSRIs and minimal in comparison with the tricyclic antidepressants. The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis.
Conclusions:
The antidepressant efficacy and favourable tolerability and pharmacokinetic profiles of tianeptine in patients with depression, including those with associated anxiety, have been proven; the data indicate that it may have additional potential in specific subgroups of depressed patients such as the elderly and those with chronic alcoholism.
Five cases of excessive consumption of tianeptine suggest possible drug-abuse of this substance. This side effect is unknown in animals and humans. According to DSM IV, CIM 10 criteria and the French public health code, these five patients had pathological profiles of psychoactive drug abusers. Tianeptine dosage was always used higher than recommended and the drug was taken in association with other psychotropes. Withdrawal was difficult and induced anxiety and other disorders which led to relapse in most of the patients.
A meta-analysis was performed to compare the efficacy of tianeptine and selective serotonin reuptake inhi-bitors (SSRI) in the short-term treatment of depression. Consecutive selection and inclusion processes allowed five stu-dies to be selected: two studies on tianeptine versus fluoxetine, two studies on tianeptine versus paroxetine, and one study on tianeptine versus sertraline. A total of 1 348 patients were included in the five studies; 681 subjects received an SSRI and 667 tianeptine. A strict step-by-step methodology was applied in order to legitimize this meta-analysis and to interpret the results. Considering all the patients or those with a Montgomery-Asberg Depression Rating Scale (MADRS) inclusion score greater or equal than 28, none of the assessed parameters (MADRS total score and responder rate) revealed any significant difference between the two treatment groups. Further analysis based on clinical global impression (CGI) items found no significant difference, except for CGI item 3 (therapeutic index), where a tendency (p=0.06 or 0.07 depending on the methodology) was found in favor of tianeptine. All in all, this study confirmed that tianeptine is at least as effective as SSRI, with a trend for a better acceptability profile in the treatment of depressed patients.
We report on a tianeptine dependence lasting for eighteen months in a 42 year old patient. The patient had a previous history of addiction to opiates, amineptine, cocaïne and alcohol. He also had a family history of addiction to alcohol and opiates. Tianeptine was prescribed for a major depressive disorder. The patient alleged a "flash sensation" like with heroin since the very first doses with a physical and psychological well-being sensation, better psychomotor performances and transient mood elation. His addiction to tianeptine was immediate and heavy. The positive reinforcement faded away after one month and a total dependance took over, with physical and psychological withdrawal symptoms when doses were not renewed. After two months of treatment, the daily consumption of tianeptine was of 90 tablets. The patient was hospitalised to treat both the addiction to tianeptine and the ongoing major depressive disorder. He was taking 240 tablets daily. In the literature, reports of addictions to antidepressants are scarce and most of them involve agents with amphetamine-like properties, including amineptine and tranylcypromine. Other reports involving other antidepressant agents, including amitriptyline, fluoxetine and tianeptine remain exceptional. Addictions to antidepressants almost exclusively concern patients with a diagnosis of personality disorder and a previous history of drug or alcohol abuse and who are treated for a depressive disorder. Tianeptine, which is devoid of any psychostimulating effect in human, does not seem to have addictive properties apart from the reports of scarce cases.
Gradually increased doses of tianeptine: maximal tolerated dose and linearity of the pharmacokinetics
- M Ansseau
- J Wauthy
- Freckell
Ansseau M, Wauthy J, von Freckell R et al.. (1992) Gradually increased doses of tianeptine: maximal tolerated dose and linearity of the pharmacokinetics. Ann Psiquiatria, 8(suppl.1):56