Pharmacokinetic/pharmacodynamic considerations for epilepsy – depression comorbidities

ABSTRACT

Introduction: Epilepsy may be frequently associated with psychiatric disorders and its co-existence with depression usually results in the reduced quality of life of patients with epilepsy. Also, the efficacy of antiepileptic treatment in depressed patients with epilepsy may be significantly reduced.

Areas covered: Results of experimental studies indicate that antidepressants co-administered with antiepileptic drugs may either increase their anticonvulsant activity, remain neutral or decrease the protective action of antiepileptic drugs in models of seizures. Apart from purely pharmacodynamic interactions, pharmacokinetic mechanisms have been proven to contribute to the final outcome. We report on clinical data regarding the pharmacokinetic interactions of enzyme-inducing antiepileptic drugs with various antidepressants, whose plasma concentration may be significantly reduced. On the other hand, antidepressants (especially selective serotonin reuptake inhibitors) may influence the metabolism of antiepileptics, in many cases resulting in the elevation of plasma concentration of antiepileptic drugs.

Expert opinion: The preclinical data may provide valuable clues on how to combine these two groups of drugs – antidepressant drugs neutral or potentiating the anticonvulsant action of antiepileptics are recommended in this regard. Avoidance of antidepressants clearly decreasing the convulsive threshold or decreasing the anticonvulsant efficacy of antiepileptic drugs (f.e. bupropion or mianserin) in patients with epilepsy is recommended.

KEYWORDS:

• Antiepileptic drugs
• antidepressant drugs
• epilepsy
• depression
• pharmacodynamics
• pharmacokinetics

Article highlights

• Epilepsy may frequently co-exist with depression which may lead to the poor quality of life in patients with epilepsy, increased seizure frequency and reduced efficacy of antiepileptic treatment.

• Antidepressant drugs may affect seizure susceptibility via a number of mechanisms, including their effects of monoaminergic neurotransmission, as well as their influence on ionic channels and other neurotransmitter systems.

• Polytherapy with antiepileptic and antidepressant drugs may induce pharmacokinetic interactions resulting from the competition for the same metabolic pathway or induction of the microsomal P-450 enzymes.

• Results of experimental studies with the use of maximal electroshock test in mice indicate that the final outcome of the combinations of antiepileptic and antidepressant drugs (given chronically) is variable. Mianserin reduced the anticonvulsant action of valproate and phenytoin (pharmacodynamic effect) and trazodone diminished that of carbamazepine and phenytoin (pharmacokinetic effect). In contrast, reboxetine potentiated pharmacodynamically the anticonvulsant activity of carbamazepine and fluoxetine that of conventional antiepileptic drugs due to a pharmacokinetic mechanism. Milnacipran remained neutral upon the action of antiepileptic drugs.

• In clinical conditions, enzyme inducing antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) may lower the plasma concentration of antidepressants. Valproate, as an enzyme inhibitor, may produce an opposite effect. Some antidepressants (fluoxetine, fluvoxamine) have been documented to elevate the plasma concentrations of valproate, phenytoin, phenobarbital, clobazam or lacosamide. Due to the possibility of pharmacokinetic and/or pharmacodynamic interactions between antiepileptic and antidepressant drugs, their therapeutic efficacy and adverse activity must be carefully monitored.

This box summarizes key points contained in the article

Declaration of interest

This paper has been supported by a grant (DS. 475/16) from Medical University of Lublin. B Błaszczyk, SJ Czuczwar decalre financial support from UCB, GlaxoSmithKline, Bayer, Novartis, Sanofi-Aventis, Janssem for lecturing, SJ Czuczwar has also received an unrestrictive grant from GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.