Neurodevelopment and mood stabilizers.
Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.
Harwood
A J
AJ
MRC Laboratory for Molecular Cell Biology & Dept of Biology, University College London, London, UK. a.harwood@ucl.ac.uk
D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D006801:Humans; D007294:Inositol / Q000378:metabolism; D019964:Mood Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*
D011619:Psychotropic Drugs; D007294:Inositol; D038362:Glycogen Synthase Kinase 3