MECHANISMS OF ACTION OF THE ANTICONVULSANTS IN THE AFFECTIVE DISORDERS

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Mechanisms of action of the anticonvulsant and psychotropic drug carbama- zepine (CBZ) are explored in patients with affective disorder and seizure models. Based on biochemical, pharmacological, and cross-tolerance data CBZ has been found to exert its anticonvulsant action in part through peripheral-type benzodiazepine receptors. These regulate mitochondrial Ca++ flux and neurosteroid biosynthesis and thus could indirectly modulate GABAergic and NMDA receptors. CBZ has been discovered to increase TRH and decrease NPY in the spinal fluid of affectively ill patients. As TRH has been shown to exert antidepressant effects in our refractory patients, it is possible that the elevation in TRH (in the context of a reduction in T3, T4, and free T4) could contribute to CBZ's anticonvulsant or psychotropic profile. New studies also indicate important actions of CBZ on calcium mediated through NMDA receptors; CBZ blocks a new type of NMDA receptor induced by kindling better than traditional NMDA receptors. These data propel further exploration of agents with activities at this type of channel, such as ADCI, and at other types of calcium channels such as the L-type affected by the antagonist nimodipine. CBZ potentiates the clinical effects of the L- type calcium channel blocker nimodipine suggesting that multiple targets of calcium channel blockade may contribute to its efficacy in ultradian cycling. A variety of biological alterations at the level of immediate early genes, neurotransmitters, receptors, and neuropeptides have been found in association with the phenomenon of contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. These data suggest that loss of normal endogenous compensatory mechanisms may play a role in loss of efficacy in this model. Since tolerance development to carbamazepine is also a problem clinically for its anticonvulsant, antinociceptive, and psychotropic uses, this model of contingent tolerance promises to yield important targets for preventing or reversing loss of efficacy when it develops in the clinical arena. New approaches to the therapeutics of affective disorder involve attempts to enhance endogenous peptide mechanisms with TRH, inhibit GABAergic mechanisms with GABApentin, and block excitatory amino acid mechanisms with lamotrigine.