Successful treatment of epilepsy with serotonin reuptake inhibitors: proposed mechanism

The widely used antidepressants Specific Serotonin Reuptake Inhibitors (SSRI) have been tried with success as anticonvulsants in cases of nonsymptomatic epilepsy. This attempt was performed on the basis of experimental data suggesting the involvement of impairments of the serotonin system in the genesis of epilepsy. This overview summarizes the clinical data and presents biochemical and neurochemical evidences suggesting the mechanism of the therapeutic effects of SSRI in nonsymptomatic epilepsy. In particular, studies on blood-borne neutral amino acids and platelet serotonin transporter (SERT) in epileptics suggest: (a) That a decreased brain availability of tryptophan may be related to some types of epilepsy. (b) That reduction of the density of SERT may be a homeostatic reaction in the brain following epileptic seizures. The possibility that derangements in the brain serotonin system may be involved in the generation of epileptic seizures has been discussed since long time ago [1]. Over the years, this possibility has been tested in animal models, among which the GEPR (genetically prone rat) model [2, 3]. Even more importantly, links between noradrenaline and serotonin deficiencies and the epileptic human brain have been found [3]. This theory is at odds with the initial suggestions that monoamine uptake blocking antidepressants are convulsants [4–6]. The lack of contradiction of this circumstance and the noradrenaline/serotonin theory in epilepsy has been discussed at length by Jobe and Browning [3]. The main point discussed is that doses much above the antidepressant therapeutic range are those leading to convulsions, thus eliminating the possibility that potentiation of the amine function may be the basis for the proconvulsant effect. The core of the theory discussed by Jobe and Browning [3] is that epilepsy and affective illnesses have a common background. In their view, the two illnesses have different intrinsic fabricators, i.e. neuronal circuits which actually initiate and sustain dysfunctional episodes. However, they share common exterior defensive shields which are made up of circuits using noradrenaline and serotonin and protect the system from a deranged function of the intrinsic fabricators. This may lead to either the epileptic pathology or affective disorders, such as depression, according to the particular fabricator involved. These ideas have been tested by those authors in the genetically epilepsy prone rat model GEPR. The idea that serotonin could be involved in epileptogenesis was already present in the early 1990s [7–10]. Even much earlier works had shown in animal models that 5-hydroxytryptophan, a serotonin precursor, has an antiepileptic effect [e.g. 11, 12]. Our group thus set out at that time to test in a clinical trial whether potentiation of the brain serotoninergic system could be helpful in patients with drug refractory epilepsy. Fluoxetine was initially added to ongoing treatments with carbamazepine or carbamazepine/phenobarbital and later this was repeated with cytalopram in another group of patients. Later over the years, we tested in epileptic patients and in controls the blood levels of the serotonin precursor tryptophan and of the neutral amino acids able to compete for the same carrier for the passage of the blood–brain barrier (BBB). In addition, we studied the status of the serotonin transporter (SERT) of the venous blood platelets in epileptic patients vs. controls. In the present overview we try and discuss the overall picture emerging from these approaches. The results do not contradict the theoretical framework proposed by Jobe and Browning [3].