Kindling reflects a cumulative and progressive unfolding of physiological and behavioral changes in response to repeated stimulation over time that eventuates in seizures, initially triggered then occurring spontaneously.80 Although epileptic seizures may have some mechanisms in
common with affective disorders, eg, increased transmembranous calcium fluxes,81 we are aware that they clearly are two different conditions. However, the rough anatomical substrate is similar, as the amygdaloid complex plays a key role in both diseases. Repeated electrical stimulation of the basolateral amygdala decreases the threshold for epileptic seizures, often leading to spontaneous Inhibitors,research,lifescience,medical epileptic activity. The correlate on the buy SGC-CBP30 synaptic level is an increase in both NMD A- and non-NMDA-receptor-mediated glutamatergic transmission with a parallel decrease in inhibitory GABAergic transmission.82 Inhibitors,research,lifescience,medical At the level of expression of early genes and neuropeptides, an increase in c-fos and thyrotropin-releasing hormone (TRH) mRNA was
observed.83 With full manifestation Inhibitors,research,lifescience,medical of seizures, these changes at the synaptic level and of substrate expression also involve the contralateral, nonstiinulated amygdala complex. It is assumed that, like electrical kindling, recurrent affective episodes cause analogous long-term changes in neuronal networks, such as lowering the threshold for any consecutive episode. This hypothesis Inhibitors,research,lifescience,medical is backed up by a clinical study by Goldberg and Harrow.84 Although having a comparable total number of episodes before, patients who had a pattern of close periodicity of episodes
showed an increased relapse risk during follow-up, interpreted as an indicator of a previous kindling process. Different drugs useful in BD exert anlikindling potencies, such as lithium, nimodipine, and different anticonvulsants, eg, CBZ, VPA, and LTG. However, they can all induce tolerance, leading to insufficient suppression of seizures Inhibitors,research,lifescience,medical in the kindling model.85 At the clinical level, this may correspond to tolerance or drug resistance observed with longterm treatment and/or discontinuation of lithium, CBZ, and VPA, as seen in some bipolar patients.86, 87 The clinical issue: spectrum of efficacy of anticonvulsants in bipolar disorder Carbamazepine and oxcarbazepine ln the 60s and early 70s, antiaggressive and emotionally stabilizing features Endonuclease had been observed with phenytoin and CBZ, both in epileptic patients and otherwise emotionally disturbed populations.88-90 These reports, together with observed antikindling potencies in the animal model, initiated independent trials of the effects of CBZ in bipolar patients both in Japan and the US.91-92 Since then, 19 controlled studies (Table II) have been conducted on the antimanic efficacy of CBZ and its derivative, oxcarbazepine. Comparison was made with lithium (6 studies), neuroleptics (6 studies), and placebo (2 as a parallel ann study, 2 in an A-B-A substituting design of the active drug).