Antidepressant drugs and seizure susceptibility: From in vitro data to clinical practice

The use of antidepressant drugs (ADs) in patients with epilepsy still raise s uncertainties because of the widespread conviction that this class of dru gs facilitates seizures. A detailed knowledge of this issue in its various aspects may help in optimal management of patients suffering concurrently f rom epilepsy and depression. This article reviews the available data in vit ro in animals and humans concerning the known potential of various ADs to i nduce epileptic seizures. Emphasis has been placed on those variables that may generate confusion in interpreting the results of the various studies. Most ADs at therapeutic dosages exhibit in nonepileptic patients a seizure risk close to that reported for the first spontaneous seizure in the genera l population (i.e., <0.1%). in patients taking high AD doses, seizure incid ence rises markedly and may reach values up to 40%. With a patient history of epilepsy and/or concomitant drugs that act on neuronal excitability, low or therapeutic AD doses may be sufficient to trigger seizures. Experimenta l data are in partial conflict with human data on the relative potential se izure risk of the various ADs. Therefore, a reliable scale for assigning a relative value to an individual AD or to single AD classes cannot be made. It appears fair to say that maprotiline and amoxapine exhibit the greatest seizure risk, whereas trazodone, fluoxetine, and fluvoxamine exhibit the le ast. Some ADs may also display antiepileptic effects, especially in low dos es, in experimental models of epilepsy and in humans, but the mechanism of this action is largely unknown. The available data suggest that ADs may dis play both convulsant and anticonvulsant effects and that the most important factor in determining the direction of a given compound in terms of excita tion/inhibition is drug dosage. It is probable that drugs that increase ser otonergic transmission are less convulsant or, even, more anticonvulsant th an others. Because of mutual pharmacokinetic interactions between antiepile ptic drugs and ADs, with consequent marked changes in plasma concentrations , it remains to be established Whether or not plasma AD levels that are eff ective against depression also facilitate seizures. Finally, exploring the mechanisms through which ADs modulate neuronal excitability might open new possibilities in antiepileptic drug development.