Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder.
For a number of patients with bipolar disorder, current pharmacotherapy is generally insufficient. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Drug development for bipolar disorder may occur through one of two approaches: the first is by understanding the therapeutically relevant biochemical targets of currently effective medications. Two promising direct targets of lithium and valproate are glycogen synthase kinase-3 and histone deacetylase. The second path results from our understanding that severe mood disorders, although not classical neurodegenerative disorders, are associated with regional impairments of structural plasticity and cellular resilience. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, Maryland, USA. zaratec@mail.nih.gov
Carlos A
CA
Zarate
Jaskaran
J
Singh
Husseini K
HK
Manji
D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D006655:Histone Deacetylases / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use*; D009473:Neuronal Plasticity / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D018692:Antimanic Agents; D014635:Valproic Acid; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases