Effect of tianeptine on seizure threshold and anticonvulsant activity of valproate, phenobarbitone and phenytoin in mice

Background: Depression is a common psychiatric comorbidity in patients with epilepsy and often remains untreated due to concern of antidepressant induced seizures. Tricyclic antidepressants, norepinephrine reuptake inhibitors and bupropion have been shown to increase the risk of seizures. Selective serotonin reuptake inhibitors and venlafaxine have shown both anticonvulsant and proconvulsant activity. The information on anticonvulsant effects of tianeptine, a newer antidepressant, is limited to few animal studies. In view of this, the present study was undertaken to investigate the anticonvulsant activity of tianeptine and its interaction with conventional antiepileptic drugs (AEDs) viz. valproate, phenobarbitone and phenytoin in mice.Methods: The study was carried out in 3 phases using healthy adult male mice. In phase I, effect of oral administration of tianeptine on seizure threshold was studied using electroconvulsive threshold method. In phase II and phase III, effect of tianeptine on median effective dose (ED50) of valproate, phenobarbitone and phenytoin was studied using maximal electroshock seizure (MES) test after administering tianeptine with these AEDs in various combinations. In phase II, drugs were administered orally once while in phase III, these were daily administered orally for 28 days.Results: In phase I, tianeptine increased electroconvulsive threshold in dose dependent manner but effect was significant only at 20 and 40 mg/kg (P<0.05 and 0.001 respectively). In phase II and III, tianeptine exhibited dose dependent reduction in ED50 of all the studied AEDs, however, significant reduction of ED50 of valproate and phenobarbitone (P<0.05 for both) was observed only when tianeptine was administered at 40 mg/kg, while significant reductions in ED50 of phenytoin were observed when tianeptine was administered as 20 and 40 mg/kg (P<0.05 and 0.01 respectively) and in phase III, significant reduction of ED50 value of valproate (P<0.01) and phenobarbitone (P<0.05) was observed with tianeptine at 40 mg/kg while reduction in ED50 of phenytoin was significant at all the studied doses of tianeptine with P<0.05 at 10 and 20 mg/kg and P<0.01 at 40mg/kg..Conclusions: Tianeptine exhibits anticonvulsant action which is synergistic with anticonvulsant effects of valproate, phenobarbitone and phenytoin suggesting that tianeptine may be a safe option in patients of epilepsy concurrently suffering from depression