Lithium and valproic acid: parallels and contrasts in diverse signaling contexts.
The introduction of lithium salts to treat bipolar disorder (BPD) revolutionized the therapy of psychiatric illnesses, but the pathogenesis of the disease and the mechanism of lithium action remain unknown. While several direct molecular targets of lithium have been identified, it is unknown which, if any, of these targets plays a role in the therapeutic response to lithium. Exposure to lithium evokes a wide spectrum of behavioral, physiological, and developmental responses in diverse organisms, and these effects have been exploited to explore the mechanisms of lithium action. Valproic acid (VPA), a widely used anticonvulsant, is also an effective therapy for BPD, and again its mechanism of action is not known, although new in vitro targets have been identified recently. In this review, the clinical, physiological, and developmental effects of lithium and VPA are summarized and recent work on direct targets for lithium and VPA is discussed in the context of these effects. We then describe some of the physiological effects common to the two drugs, in addition to treatment of BPD, and address signaling pathways that could be regulated by both lithium and VPA.
Gurvich
Nadia
N
Graduate Group in Pharmacological Sciences, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Klein
Peter S
PS
D000818:Animals; D018692:Antimanic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000009:adverse effects / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology*
D018692:Antimanic Agents; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D015222:Sodium Channels; D014635:Valproic Acid; D008094:Lithium; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D006655:Histone Deacetylases