title: Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors.
abstract: Notwithstanding the considerable advances in the treatment options for schizophrenia, the cognitive symptoms in particular are not receptive to antipsychotic treatment and considered one of the main predictors for poor social and functional outcome of the disease. Recent findings in preclinical model systems indicate that epigenetic modulation might emerge as a promising target for the treatment of cognitive disorders. The aim of this review is to introduce some of the principles of chromatin biology to the reader and to discuss a possible role in the neurobiology and pathophysiology of schizophrenia. We will discuss potential epigenetic targets for drug therapy, including histone deacetylase inhibitors (HDACi). In a second part, conceptual and practical challenges associated with clinical trials of chromatin-modifying drugs in psychiatric patient populations are discussed, including safety profiles, the potential for adverse effects and general issues revolving around pharmacokinetics and pharmacodynamics. Additional investigations are required in order to fully evaluate the potential of HDACi and similar "epigenetic therapies" as novel treatment options for schizophrenia and other psychotic disease.
authors: Deparment of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Nussbaumstr. 7, 80336 Munich, Germany. ahasan@gwdg.de
authors: Alkomiet
authors: A
authors: Hasan
authors: Amanda
authors: A
authors: Mitchell
authors: Anja
authors: A
authors: Schneider
authors: Tobias
authors: T
authors: Halene
authors: Schahram
authors: S
authors: Akbarian
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D044127:Epigenesis, Genetic / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D003024:Clozapine
references: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13614-9
references: 18757738
references: Neuron. 2004 Jun 24;42(6):961-72
references: 15207240
references: Neuropsychology. 2009 May;23(3):315-36
references: 19413446
references: Expert Rev Neurother. 2009 Jan;9(1):87-98
references: 19102671
references: World J Biol Psychiatry. 2012 Jul;13(5):318-78
references: 22834451
references: J Neurosci. 2005 Jun 1;25(22):5376-81
references: 15930386
references: Cell. 2007 Feb 23;128(4):693-705
references: 17320507
references: Biol Psychiatry. 2011 Jul 1;70(1):88-96
references: 21457946
references: Neuropsychology. 1998 Jul;12(3):426-45
references: 9673998
references: N Engl J Med. 2005 Sep 22;353(12):1209-23
references: 16172203
references: Arch Gen Psychiatry. 1999 Aug;56(8):749-54
references: 10435610
references: J Biomed Biotechnol. 2011;2011:148046
references: 21318168
references: Am J Psychiatry. 2008 Apr;165(4):479-89
references: 18281411
references: J Neurosci Methods. 2010 Oct 30;193(1):54-61
references: 20817035
references: Schizophr Res. 2008 Jul;102(1-3):1-18
references: 18514488
references: PLoS One. 2011;6(5):e19958
references: 21625500
references: Oncol Rep. 2006 Feb;15(2):489-94
references: 16391874
references: Neuroreport. 2011 Sep 14;22(13):637-41
references: 21753741
references: Am J Psychiatry. 2006 Feb;163(2):272-5
references: 16449481
references: Curr Med Chem. 2008;15(13):1263-73
references: 18537606
references: PLoS One. 2011 Apr 29;6(4):e19229
references: 21559427
references: Mol Pharmacol. 2010 Feb;77(2):126-35
references: 19917878
references: Am J Hum Genet. 2008 Mar;82(3):696-711
references: 18319075
references: Drug Discov Today. 2007 Oct;12(19-20):870-8
references: 17933689
references: Mol Pharmacol. 2009 Feb;75(2):342-54
references: 19029285
references: Annu Rev Pharmacol Toxicol. 2011;51:189-209
references: 20868275
references: Neuron. 2004 Jun 24;42(6):947-59
references: 15207239
references: Clin Cancer Res. 2009 Oct 1;15(19):6148-57
references: 19789319
references: EMBO Mol Med. 2013 Jan;5(1):52-63
references: 23184605
references: Schizophr Res. 2004 Aug 1;69(2-3):125-32
references: 15469185
references: World J Biol Psychiatry. 2013 Feb;14(1):2-44
references: 23216388
references: Nat Rev Drug Discov. 2008 Oct;7(10):854-68
references: 18827828
references: Schizophr Bull. 2006 Jan;32(1):179-94
references: 16166612
references: Transl Psychiatry. 2011 Dec 20;1:e64
references: 22832356
references: BMC Med. 2012 Oct 30;10:129
references: 23106849
references: Am Fam Physician. 2000 Sep 15;62(6):1343-53, 1357-8
references: 11011863
references: Learn Mem. 2006 Sep-Oct;13(5):609-17
references: 16980541
references: J Neurosci Res. 2004 Sep 15;77(6):858-66
references: 15334603
references: Am J Psychiatry. 1996 Mar;153(3):321-30
references: 8610818
references: Psychiatr Q. 1998 Fall;69(3):169-91
references: 9682284
references: Nat Rev Genet. 2012 Jan 31;13(3):153-62
references: 22290458
references: Neuropsychopharmacology. 2007 Sep;32(9):1888-902
references: 17299517
references: Psychiatry Res. 2007 Jun 30;151(3):179-88
references: 17433451
references: J Neurochem. 2004 Sep;90(5):1117-31
references: 15312167
references: J Neurosci Res. 2004 May 15;76(4):581-92
references: 15114630
references: Curr Pharm Des. 2007;13(25):2584-620
references: 17897003
references: Psychol Med. 2012 Nov;42(11):2287-99
references: 22475159
references: Neuropsychopharmacology. 2011 Jul;36(8):1545-56
references: 21508930
references: J Psychiatr Res. 2010 Jul;44(10):673-81
references: 20100621
references: Behav Brain Res. 2011 Oct 10;224(1):15-22
references: 21645555
references: Schizophr Res. 2004 Dec 15;72(1):21-8
references: 15531404
references: Neuron. 2012 Aug 23;75(4):714-24
references: 22920261
references: Neurobiol Dis. 2013 May;53:61-74
references: 23142533
references: Cardiol J. 2012;19(4):434-8
references: 22825908
references: Mol Psychiatry. 2012 Dec;17(12):1206-27
references: 22584864
references: Neurobiol Learn Mem. 2011 Jul;96(1):27-34
references: 21521655
references: Arch Gen Psychiatry. 2002 Jul;59(7):631-40
references: 12090816
references: Curr Opin Genet Dev. 2011 Apr;21(2):175-86
references: 21342762
references: Biol Chem. 2009 Nov;390(11):1145-53
references: 19747081
references: Neuropharmacology. 2009 Oct-Nov;57(5-6):481-95
references: 19631671
references: Ann Hematol. 2004;83 Suppl 1:S91-2
references: 15124690
references: FASEB J. 2008 Mar;22(3):659-61
references: 17942826
references: J Neurosci. 2008 Mar 5;28(10):2576-88
references: 18322101
references: Nat Med. 2011 Mar;17(3):330-9
references: 21386836
references: Biochem J. 2008 Jan 15;409(2):581-9
references: 17868033
references: Drugs R D. 2011 Sep 1;11(3):227-49
references: 21902286
references: Nature. 2006 Nov 16;444(7117):337-42
references: 17086191
references: Nature. 2009 Jul 23;460(7254):473-8
references: 19525931
references: EMBO J. 2001 Dec 17;20(24):6969-78
references: 11742974
references: Mol Cancer Res. 2007 Oct;5(10):981-9
references: 17951399
references: Curr Opin Chem Biol. 2009 Jun;13(3):263-71
references: 19541531
references: Behav Neurosci. 2007 Oct;121(5):1125-31
references: 17907845
references: Int J Neuropsychopharmacol. 2010 Jul;13(6):813-32
references: 20128953
references: J Biol Chem. 2001 Sep 28;276(39):36734-41
references: 11473107
references: Science. 2010 May 7;328(5979):753-6
references: 20448184
references: Schizophr Res. 2008 Jan;98(1-3):111-7
references: 17961987
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1587-92
references: 16432198
references: Curr Drug Saf. 2010 Jan;5(1):93-6
references: 20210725
references: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10164-9
references: 17553960
references: J Neurosci. 2007 Oct 17;27(42):11254-62
references: 17942719
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4746-51
references: 11296301
references: Eur Arch Psychiatry Clin Neurosci. 2011 Nov;261 Suppl 2:S150-4
references: 21866371
references: Curr Pharm Biotechnol. 2007 Dec;8(6):388-400
references: 18289048
references: Trends Pharmacol Sci. 2010 Dec;31(12):605-17
references: 20980063
references: J Neurosci. 2007 Jun 6;27(23):6128-40
references: 17553985
references: Am J Psychiatry. 2004 Feb;161(2 Suppl):1-56
references: 15000267
references: Nature. 2009 May 7;459(7243):55-60
references: 19424149
references: PLoS One. 2007 Aug 29;2(8):e809
references: 17726539
references: Cell. 2006 May 5;125(3):497-508
references: 16678094
references: Neuropsychology. 1997 Jul;11(3):437-46
references: 9223148
references: Trends Genet. 2006 Apr;22(4):197-202
references: 16494964
references: Nature. 2012 Feb 29;483(7388):222-6
references: 22388814
references: Neuropharmacology. 2011 Jun;60(7-8):1007-16
references: 21074545
references: Schizophr Res. 2005 Nov 15;79(2-3):157-73
references: 16139990
references: Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12711-6
references: 21768347
references: J Pharmacol Exp Ther. 2003 Nov;307(2):720-8
references: 12975486
references: J Neurosci. 2011 Jan 12;31(2):764-74
references: 21228185
references: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17095-100
references: 12481028
references: Biol Psychiatry. 2009 Mar 15;65(6):455-63
references: 18986648
references: Nat Struct Mol Biol. 2007 Nov;14(11):1025-1040
references: 17984965
references: Hum Mol Genet. 2006 Nov 1;15(21):3132-45
references: 16984965
references: Schizophr Res. 2008 Aug;103(1-3):330-2
references: 18539439
references: Mol Psychiatry. 2011 Apr;16(4):362-4
references: 21430674
references: Cell. 2011 Sep 16;146(6):1016-28
references: 21925322
references: Pharmacol Biochem Behav. 2011 Aug;99(2):245-53
references: 21115035
references: J Neural Transm (Vienna). 2009 Mar;116(3):275-89
references: 19034380
references: Int Clin Psychopharmacol. 2012 Mar;27(2):76-90
references: 22107783
references: Lancet. 2003 Sep 6;362(9386):798-805
references: 13678875
references: Arch Gen Psychiatry. 2012 Mar;69(3):314-24
references: 22065254
references: Neurosci Lett. 2003 Jul 17;345(2):141-3
references: 12821190
references: Neuropsychopharmacology. 2010 Jan;35(1):239-57
references: 19727065
references: Br J Psychiatry. 2009 Dec;195(6):475-82
references: 19949193
references: Arch Gen Psychiatry. 2005 Aug;62(8):829-40
references: 16061760
references: J Biol Chem. 2011 Jul 15;286(28):24685-93
references: 21610077
references: J Neurosci. 2012 Apr 11;32(15):5062-73
references: 22496552
references: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references: 15803162
references: Nature. 2007 May 24;447(7143):407-12
references: 17522673
references: Brain Res. 2008 Jul 7;1218:267-77
references: 18534564
references: Brain Res Brain Res Rev. 2000 Mar;31(2-3):288-94
references: 10719155
references: Nat Neurosci. 2012 Sep;15(9):1245-54
references: 22864611
references: Brain Res Rev. 2006 Sep;52(2):293-304
references: 16759710
references: Nat Rev Genet. 2011 Jan;12(1):7-18
references: 21116306
references: Leuk Res. 2010 Jun;34(6):687-95
references: 19762081
references: Neuropsychopharmacology. 2010 Dec;35(13):2521-37
references: 20811339
references: Acta Neurol Scand Suppl. 2003;180:23-32
references: 14510817
references: Biochim Biophys Acta. 2011 Oct;1809(10):577-86
references: 21782046
references: Cancer Res. 1990 Aug 15;50(16):5049-54
references: 2379170
references: Schizophr Bull. 2010 Jan;36(1):71-93
references: 19955390
references: Am J Psychiatry. 2010 Nov;167(11):1305-20
references: 20843874
references: Psychopharmacology (Berl). 2005 Jul;180(2):191-205
references: 15864560
references: Mol Psychiatry. 2013 Jul;18(7):740-2
references: 22925834
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9341-6
references: 15961543
references: Cell. 2011 Dec 23;147(7):1459-72
references: 22169038