Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: preliminary results from a clinical population.
Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To examine this effect in a clinical setting, 14 schizophrenic and bipolar patients were treated with valproic acid (Depakote ER), either as monotherapy or in combination with antipsychotics, over a period of 4 weeks. AcH3 and acH4 levels from lymphocyte nuclear protein extracts were measured by Western Blot. Treatment with Depakote ER resulted in a significant increase of acH3 and a trend-level increase of acH4. Levels of valproic acid were positively and significantly correlated with percent increase in acH3 but not acH4. Schizophrenia patients were significantly less likely to increase their acH3 and acH4 levels after 4 weeks on Depakote ER. The authors consider these results in the context of future application of HDAC inhibitors to the treatment of psychiatric disorders.
Sharma
Rajiv P
RP
The Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. rsharma@psych.uic.edu
Rosen
Cherise
C
Kartan
Saritha
S
Guidotti
Alessandro
A
Costa
Erminio
E
Grayson
Dennis R
DR
Chase
Kayla
K
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D011159:Population Surveillance / Q000379:methods; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*; D014635:Valproic Acid / Q000627:therapeutic use*
D014150:Antipsychotic Agents; D014635:Valproic Acid; D051548:Histone Acetyltransferases