Antidepressant drugs, a treatment option for limbic epilepsy?

Introduction
The neurobiological relationships between epilepsy and affective disorders are receiving increased attention. Refractory epilepsy has an enormous impact on daily, social and psychosocial life of the patients. Co-morbid depression correlates with the poorest quality of life among epileptic patients (1) and suicide is one of their leading causes of death (2). Key roles for monoamines in depression have been established for decades since monoamine oxidase inhibitors and reuptake blockers have clinical efficacy. Nevertheless, many controversies around the treatment of depression in epileptic patients arise in clinical practice. Antidepressant drugs are classified as enhancing seizure risk. Is this really the case? Data obtained from preclinical studies have shed a new light on these issues. Indeed, elevated levels of limbic noradrenalin, serotonin (5-HT) and dopamine (DA) are associated with both antidepressant and anticonvulsant actions (3,4). We also demonstrated anticonvulsant effects of intrahippocampally perfused DA or 5-HT (5) and defined an extracellular DA and 5-HT concentration range in which rats were protected from pilocarpine-induced seizures. Glutamate is known to regulate the brain's excitability via ionotropic (iGluR i.e. NMDA, AMPA, kainate) and metabotropic (mGluR) receptors and as a key player in epilepsy. Glutamate hyperexcitability is also increasingly recognised to be involved in depression (6). Potential beneficial treatments of depression with ligands targeting glutamate receptors are currently under investigation.

Method
We used behavioural assessment of seizure severity in the focal pilocarpine rat model, antidepressant-like activity within the rat forced swim and the mouse tail suspension tests, and locomotor activity in an open field. In vivo microdialysis in rats was used to investigate possible facilitatory effects on hippocampal DA or 5-HT release of the clinically used antidepressants imipramine and citalopram, the selective DA reuptake blocker GBR-12909, and several anticonvulsant iGluR antagonists (MK-801, LY303070) and mGluR ligands (AIDA, MPEP, LY379268). More methodological details are described by Smolders et al. (7).

Results
Imipramine, citalopram and GBR12909 exerted both antidepressant-like and anticonvulsant effects in our animal models and also directly enhanced extracellular hippocampal monoamine levels as measured with microdialysis. Combined anticonvulsant-antidepressant activities of the NMDA antagonist MK-801 and the mGluR group I antagonists (AIDA, MPEP) were again associated with locally elicited increases in hippocampal DA and/or 5-HT levels. We are the first to report that GBR-12909 possessed antidepressant activity in the rat forced swim and the mouse tail suspension tests, and that AIDA was antidepressant in the mouse tail suspension test. The AMPA receptor antagonist LY303070 and the mGlu2/3 agonist LY379268 were anticonvulsant but they both failed to show antidepressant activity and did not directly modulate hippocampal monoamines. The mGlu2/3 antagonist with antidepressant properties had no anticonvulsant effects and did neither alter DA or 5-HT in the hippocampus.

Conclusion
A direct facilitation of hippocampal DA or 5-HT release was consistently found for the various compounds with combined anticonvulsant-antidepressant actions suggesting that the hippocampus is an important site of action. This work does not claim that the monoamine facilitation is a hippocampal specific event. We focussed on the hippocampal mechanisms but we do not exclude that similar effects can appear in other limbic brain areas. We suggest that direct facilitation of hippocampal DA and/or 5-HT levels might have predictive value for possible combined anticonvulsant-antidepressant-like effects of test compounds potentially useful for drug treatment of depression in refractory epileptic patients. Since clinically there is a clear relationship between epilepsy and depression, we think that the presented effects on hippocampal monoamines might unravel one of the possible neurobiological mechanisms of action behind this relationship. Moreover, we claim that, in view of these data, antidepressants are an interesting treatment option for epileptic patients with major depression.