Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder.
Several clinical studies have investigated the use of the anticonvulsant lamotrigine (LTG) as a treatment for bipolar affective disorder. Evidence suggests that this drug may have a broad spectrum of utility in this illness, having both mood-stabilising (antimanic) and acute antidepressant properties. This makes this molecule of particular interest in helping to understand the underlying disease processes. In this review, we describe the cellular and molecular actions of LTG that may contribute to its action in bipolar disorder. LTG preferentially inhibits neuronal hyperexcitability and modifies synaptic plasticity via use- and voltage-dependent inhibition of neuronal voltage-activated Na+ channels and possibly high-voltage-activated Ca>cf6>2+>cf1> channels. As a consequence, it reduces excessive transmitter release in the brain. Indirectly, these effects would be expected to regulate aberrant intracellular and intercellular signalling in critical regions of the limbic forebrain where hyperactivity may occur in mania, and thus may be directly relevant to its mood-stabilising properties. Whether other molecular actions of LTG, for example on monoamine disposition, could contribute to its antidepressant activity, are less clear at present but warrant further investigation.
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Neurosciences Unit, Medicines Research Centre, GlaxoWellcome, Stevenage, Herts, UK. xx44913@glaxowellcome.co.uk
Hagan
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D000085:Acetates / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000588:Amines; D000927:Anticonvulsants / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D000077213:Lamotrigine; D008032:Limbic System / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009433:Neural Inhibition / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D003509:Cyclohexanecarboxylic Acids; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D015222:Sodium Channels; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D000077206:Gabapentin; D000077213:Lamotrigine