Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers
Open Access
- 11 May 2004
- journal article
- review article
- Published by Springer Nature in Molecular Psychiatry
- Vol. 9 (8), 734-755
- https://doi.org/10.1038/sj.mp.4001518
Abstract
Bipolar disorder afflicts approximately 1–3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.Keywords
This publication has 225 references indexed in Scilit:
- Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3′-phosphoadenosine-5′-phosphate phosphatase activities: a novel target of lithium therapyJournal of Molecular Biology, 2002
- Lithium Inhibits Glycogen Synthase Kinase-3 by Competition for MagnesiumBiochemical and Biophysical Research Communications, 2001
- A novel target of lithium therapyFEBS Letters, 2000
- Inhibition of the High Affinity Myo-Inositol Transport System A Common Mechanism of Action of Antibipolar Drugs?Neuropsychopharmacology, 1999
- Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomesSynapse, 1997
- Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cellsCurrent Biology, 1996
- Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brainNeurochemical Research, 1993
- Dibutyryl cyclic AMP has epileptogenic potential in the hippocampus of freely behaving rats: a combined EEG-intracerebral microdialysis studyNeuroscience Letters, 1992
- Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responsesEuropean Journal of Pharmacology: Molecular Pharmacology, 1991
- Carbamazepine and electroconvulsive shock attenuate β-adrenoceptor and muscarinic cholinoceptor coupling to G protein in rat cortexEuropean Journal of Pharmacology: Molecular Pharmacology, 1990