Neurobiological basis of the use of antiepileptics in bipolar disorder

Abstract

Currently, antiepileptic drugs are a therapeutic alternative to lithium when treating bipolar disorder. Among these, carbamazepine, valproate and lamotrigine have been authorized both for the treatment of manic phases and for the prevention of depressive episodes. In this paper, we will review the mechanisms of action of these drugs as euthymic agents, despite they have not been completely elucidated yet. At a synaptic level, the anticonvulsivant agents might act blocking the sodium voltage-depending channel with the subsequent stabilization of the neuronal membrane and the inhibtion of the release of excitatory neurotransmitters, modulating the glutamatergic mechanisms of neurotransmission. This is due to the action exerted on the NMDA, kainate or AMPA receptors or potentiating the gabergic mechanisms (increase of action of DAG enzyme, inhibition of GABA transaminase, selective GABA recaptation or potentiation of GABA receptor’s agonist actions). With regard to the complicated molecular mechanisms associated to the signal transduction in postsynaptic neurones and their effect on antiepileptics, there are only significant data on carbamazepine and valproate. The most studied signal transduction systems of secondary messengers are those referring to adenylate ciyclase and to the phosphoinositol ways, which include A and C proteincinases, respectively. Regarding the euthymics, the most discussed hypothesis is the mioinositol depletion. It holds back a whole sequence of transduction events, where the phospolipase C, secondary messengers such as the diacylglycerol and the inositol triphosphate, the proteincinase C, the protein MARCKS and the immediate early response genes c-jun, c-fos or Egr-1 are involved. Lastly, we will discuss the euthymics effects on the glycogen synthase kinase 3’s way and other intracellular transduction ways related to the neuroplasticity phenomena which are gradually acquiring a higher significance in the bipolar disorder physiopathology. Among the neurotrophic factors associated to the mechanism of action of the mood regulators we should mention the BDNF, ERK or CREB, as well as the protein bcl-2 which presents neuroprotective and antiapoptotic properties.