title: Neural network dysfunction in bipolar depression: clues from the efficacy of lamotrigine.
abstract: One strategy to understand bipolar disorder is to study the mechanism of action of mood-stabilizing drugs, such as valproic acid and lithium. This approach has implicated a number of intracellular signalling elements, such as GSK3beta (glycogen synthase kinase 3beta), ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However, lamotrigine does not seem to modulate any of these targets, which is intriguing given that its profile in the clinic differs from that of valproic acid or lithium, with greater efficacy to prevent episodes of depression than mania. The primary target of lamotrigine is the voltage-gated sodium channel, but it is unclear why inhibition of these channels might confer antidepressant efficacy. In healthy volunteers, we found that lamotrigine had a facilitatory effect on the BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic stimulation) of the prefrontal cortex. This effect was in contrast with an inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a follow-up study, a similar prefrontal specific facilitatory effect was observed in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and prefrontal cortical TMS-induced BOLD response. In vitro, we found that lamotrigine (3-10 microM) enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid (100 microM). These data suggest that lamotrigine has a positive effect on corticolimbic network function that may differentiate it from other mood stabilizers. The results are also consistent with the notion of corticolimbic network dysfunction in bipolar disorder.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, Medicines Research Centre, GlaxoSmithKline S.p.A., Via Fleming 4, 37135, Verona, Italy. charles.h.large@gsk.com
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
authors.forename: Elena
authors.initials: E
authors.lastname: Di Daniel
authors.forename: Xingbao
authors.initials: X
authors.lastname: Li
authors.forename: Mark S
authors.initials: MS
authors.lastname: George
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D000077213:Lamotrigine; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine