Tianeptine

Abstract

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. 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. Maximum plasma concentration (Cmax) was 0.3 mg/L, time to C_max (t_max) 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; 5 (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. 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. 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. 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.