Am J Neurodegener Dis. 2016 Mar 01;5(1):29-51. eCollection 2016.
Repurposing psychiatric medicines to target activated microglia in anxious mild cognitive impairment and early Parkinson's disease.
American journal of neurodegenerative disease
Edward C Lauterbach
Affiliations
Affiliations
- Department of Psychiatry and Behavioral Sciences, Mercer University School of Medicine 655 First Street, Macon, Georgia, 31201, USA.
PMID: 27073741
PMCID: PMC4788730
Abstract
Anxiety is common in the Mild Cognitive Impairment (MCI) stage of Alzheimer's disease (AD) and the pre-motor stages of Parkinson's disease (PD). A concomitant and possible cause of this anxiety is microglial activation, also considered a key promoter of neurodegeneration in MCI and early PD via inflammatory mechanisms and the generation of degenerative proinflammatory cytokines. Psychiatric disorders, prevalent in AD and PD, are often treated with psychiatric drugs (psychotropics), raising the question of whether psychotropics might therapeutically affect microglial activation, MCI, and PD. The literature of common psychotropics used in treating psychiatric disorders was reviewed for preclinical and clinical findings regarding microglial activation. Findings potentially compatible with reduced microglial activation or reduced microglial inflammogen release were evident for: antipsychotics including neuroleptics (chlorpromazine, thioridazine, loxapine) and atypicals (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone); mood stabilizers (carbamazepine, valproate, lithium); antidepressants including tricyclics (amitriptyline, clomipramine, imipramine, nortriptyline), SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), venlafaxine, and bupropion; benzodiazepine anxiolytics (clonazepam, diazepam); cognitive enhancers (donepezil, galantamine, memantine); and other drugs (dextromethorphan, quinidine, amantadine). In contrast, pramipexole and methylphenidate might promote microglial activation. The most promising replicated findings of reduced microglial activation are for quetiapine, valproate, lithium, fluoxetine, donepezil, and memantine but further study is needed and translation of their microglial effects to human disease still requires investigation. In AD-relevant models, risperidone, valproate, lithium, fluoxetine, bupropion, donepezil, and memantine have therapeutic microglial effects in need of replication. Limited clinical data suggest some support for lithium and donepezil in reducing MCI progression, but other drugs have not been studied. In PD-relevant models, lamotrigine, valproate, fluoxetine, dextromethorphan, and amantadine have therapeutic microglial effects whereas methylphenidate induced microglial activation and pramipexole promoted NO release. Clinical data limited to pramipexole do not as of yet indicate faster progression of early PD while the other drugs remain to be investigated. These tantalizing psychotropic neuroprotective findings now invite replication and evidence in AD-and PD-specific models under chronic administration, followed by consideration for clinical trials in MCI and early stage PD. Psychiatric features in early disease may provide opportunities for clinical studies that also employ microglial PET biomarkers.
Keywords: Alzheimer’s disease; Microglia; Parkinson’s disease; antidepressant; antipsychotic; anxiety; anxiolytic; cytokine; mild cognitive impairment; mood stabilizer
References
- J Neurosci Res. 2013 May;91(5):694-705 - PubMed
- J Neurosci. 2005 Mar 9;25(10):2566-75 - PubMed
- Neuroscience. 2014 Sep 5;275:296-304 - PubMed
- Brain Behav Immun. 2010 Oct;24(7):1074-7 - PubMed
- Front Aging Neurosci. 2010 May 21;2:null - PubMed
- Neurology. 2007 May 8;68(19):1596-602 - PubMed
- Neurochem Res. 2010 Apr;35(4):651-9 - PubMed
- J Geriatr Psychiatry Neurol. 2012 Dec;25(4):233-9 - PubMed
- Neuropharmacology. 2011 Sep;61(4):574-82 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2013 Aug 1;45:207-14 - PubMed
- Mol Neurobiol. 2015 Feb;51(1):300-12 - PubMed
- Neurology. 2003 Sep 9;61(5):686-9 - PubMed
- Neuropathol Appl Neurobiol. 2016 Aug;42(5):423-35 - PubMed
- Toxicol In Vitro. 1994 Oct;8(5):1015-20 - PubMed
- J Pharmacol Sci. 2012;120(2):63-9 - PubMed
- J Neurosci. 2014 Feb 12;34(7):2583-91 - PubMed
- Mov Disord. 2015 Oct;30(12):1600-11 - PubMed
- Alzheimer Dis Assoc Disord. 2012 Jan-Mar;26(1):1-7 - PubMed
- Neurology. 2009 Jun 16;72(24):2115-21 - PubMed
- Brain Behav Immun. 2014 May;38:237-48 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):42-8 - PubMed
- Neurobiol Dis. 2003 Dec;14 (3):417-24 - PubMed
- Behav Brain Res. 2016 Jan 15;297:112-5 - PubMed
- J Geriatr Psychiatry Neurol. 2013 Mar;26(1):34-40 - PubMed
- J Neurol. 2013 Nov;260(11):2849-55 - PubMed
- Mini Rev Med Chem. 2011 Jun;11(7):575-81 - PubMed
- Dement Geriatr Cogn Dis Extra. 2013 May 18;3(1):168-78 - PubMed
- Neurosci Lett. 2006 Apr 24;397(3):185-9 - PubMed
- Mov Disord. 2014 Mar;29(3):351-9 - PubMed
- Brain Res. 2010 Dec 2;1363:143-50 - PubMed
- J Parkinsons Dis. 2015;5(4):681-97 - PubMed
- Expert Rev Clin Pharmacol. 2014 Mar;7(2):161-5 - PubMed
- JAMA. 2000 Oct 18;284(15):1931-8 - PubMed
- Mov Disord. 2011 Feb 15;26(3):484-92 - PubMed
- Exp Eye Res. 2015 Jun;135:47-58 - PubMed
- Neurobiol Aging. 2013 Jan;34(1):128-36 - PubMed
- Alzheimers Dement. 2015 Jun;11(6):608-21.e7 - PubMed
- Exp Neurol. 2013 Mar;241:148-55 - PubMed
- Evid Based Med. 2013 Oct;18(5):e50 - PubMed
- J Neuropathol Exp Neurol. 2001 Jun;60(6):647-57 - PubMed
- Brain Res Bull. 2004 Aug 30;64(2):165-70 - PubMed
- Parkinsons Dis. 2012;2012:753548 - PubMed
- Epilepsia. 2014 Jan;55(1):184-92 - PubMed
- PLoS One. 2012;7(8):e42746 - PubMed
- Neurobiol Dis. 2011 Oct;44(1):63-72 - PubMed
- Neurotoxicology. 2014 Jan;40:23-32 - PubMed
- JAMA. 2002 Apr 3;287(13):1653-61 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:236-9 - PubMed
- J Neurol. 2012 Jan;259(1):124-31 - PubMed
- Mol Cell Neurosci. 2013 Sep;56:365-74 - PubMed
- Iran Biomed J. 2012;16(2):90-100 - PubMed
- Exp Neurol. 2007 Jul;206(1):33-42 - PubMed
- Neuroscience. 2015 May 21;294:60-8 - PubMed
- Neuropsychiatr Dis Treat. 2015 Jan 30;11:243-56 - PubMed
- Neuroreport. 1998 Sep 14;9(13):3029-32 - PubMed
- J Neuroimmunol. 2009 Feb 15;207(1-2):24-31 - PubMed
- Eur J Pharmacol. 2015 Oct 15;765:249-57 - PubMed
- Eur J Pain. 2015 Jan;19(1):111-22 - PubMed
- Neurodegener Dis. 2010;7(1-3):38-41 - PubMed
- Neuroscience. 2006 Jul 21;140(4):1149-56 - PubMed
- J Pharmacol Exp Ther. 2007 Jun;321(3):892-901 - PubMed
- Eur Neuropsychopharmacol. 2005 Jan;15(1):23-30 - PubMed
- Anesthesiology. 2009 Jun;110(6):1379-89 - PubMed
- J Neuropsychiatry Clin Neurosci. 2011 Summer;23(3):242-60 - PubMed
- J Neurochem. 2008 Jul;106(2):815-25 - PubMed
- Neuropsychopharmacology. 2011 Mar;36(4):857-70 - PubMed
- J Pharmacol Sci. 2015 Jan;127(1):145-9 - PubMed
- Ann Clin Transl Neurol. 2014 Jul;1(7):512-8 - PubMed
- J Neurochem. 2008 Sep;106(6):2449-62 - PubMed
- J Pharmacol Exp Ther. 2003 Apr;305(1):212-8 - PubMed
- Eur J Pharmacol. 2015 May 15;755:74-9 - PubMed
- J Neuroinflammation. 2015 May 29;12 :108 - PubMed
- Dement Geriatr Cogn Disord. 2013;35(1-2):1-22 - PubMed
- Eur J Pharmacol. 2014 Sep 5;738:256-62 - PubMed
- Int J Mol Sci. 2013 Nov 15;14(11):22558-603 - PubMed
- Neurology. 2009 Jan 6;72 (1):56-62 - PubMed
- PLoS One. 2012;7(3):e33693 - PubMed
- Brain Behav Immun. 2012 Feb;26(2):277-83 - PubMed
- Neurobiol Aging. 2012 Jul;33(7):1329-42 - PubMed
- JAMA Psychiatry. 2015 Mar;72(3):284-91 - PubMed
- Mov Disord. 2011 Feb 15;26(3):436-41 - PubMed
- Neuropharmacology. 2011 Sep;61(4):592-9 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 30;30(8):1523-8 - PubMed
- Schizophr Res. 2013 Dec;151(1-3):20-8 - PubMed
- Curr Neurol Neurosci Rep. 2013 Dec;13(12 ):405 - PubMed
- Psychiatr Genet. 2015 Apr;25(2):71-8 - PubMed
- Int J Neuropsychopharmacol. 2008 Feb;11(1):111-7 - PubMed
- Neurology. 2015 Jun 16;84(24):2422-9 - PubMed
- Mol Psychiatry. 2010 Mar;15(3):272-85, 228 - PubMed
- Am J Geriatr Psychiatry. 2014 Dec;22(12):1418-26 - PubMed
- Stroke. 2003 May;34(5):1287-92 - PubMed
- Neurology. 2009 May 5;72(18):1555-61 - PubMed
- Neurosci Lett. 2010 Sep 20;482(1):51-6 - PubMed
- J Pharm Pharmacol. 2011 Aug;63(8):1063-9 - PubMed
- Int J Geriatr Psychiatry. 2009 Dec;24(12):1335-42 - PubMed
- Neurologist. 2007 Sep;13(5):272-93 - PubMed
- Intern Med. 2013;52(5):539-45 - PubMed
- J Neuropathol Exp Neurol. 2004 Jan;63(1):43-52 - PubMed
- Neurochem Int. 2012 Oct;61(5):666-71 - PubMed
- Int J Neuropsychopharmacol. 2006 Feb;9(1):27-35 - PubMed
- Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2013 Dec;29(12):1251-3 - PubMed
- Int J Geriatr Psychiatry. 2011 Feb;26(2):166-72 - PubMed
- Brain Res Mol Brain Res. 2005 Mar 24;134(1):162-9 - PubMed
- Support Care Cancer. 2015 Apr;23(4):953-65 - PubMed
- Arch Neurol. 2004 Jul;61(7):1044-53 - PubMed
- Neuroscience. 2015 Apr 2;290:530-42 - PubMed
- Neuroscience. 2006 Nov 3;142(4):1303-15 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2010 Oct 1;34(7):1306-16 - PubMed
- Eur Neuropsychopharmacol. 2015 Nov;25(11):2098-107 - PubMed
- Curr Top Med Chem. 2013;13(18):2306-27 - PubMed
- FASEB J. 2005 Apr;19(6):533-42 - PubMed
- Brain Res. 2011 Jul 27;1403:1-11 - PubMed
- J Neurosci. 2011 Apr 27;31(17):6277-88 - PubMed
- Exp Gerontol. 2015 Aug;68:51-8 - PubMed
- Alzheimers Dement. 2015 Sep;11(9):1041-9 - PubMed
- Behav Brain Res. 2012 Jan 1;226(1):351-6 - PubMed
- Neuroreport. 2008 Jul 2;19(10 ):997-1002 - PubMed
- J Alzheimers Dis. 2010;19(1):355-61 - PubMed
- Pharm Biol. 2014 Nov;52(11):1451-9 - PubMed
- Brain Behav Immun. 2016 Jul;55:225-35 - PubMed
- Neurology. 2004 Aug 24;63(4):651-7 - PubMed
- Alzheimers Dement. 2011 May;7(3):270-9 - PubMed
- Prog Neuropsychopharmacol Biol Psychiatry. 2012 Aug 7;38(2):107-15 - PubMed
- Glia. 2016 Jan;64(1):76-89 - PubMed
- Ann Neurol. 2005 Feb;57(2):168-75 - PubMed
- Am J Geriatr Psychiatry. 2015 May;23 (5):466-76 - PubMed
- Neurosci Res. 2013 Sep-Oct;77(1-2):87-96 - PubMed
- Schizophr Res. 2008 Dec;106(2-3):182-91 - PubMed
- Mov Disord. 2006 Jan;21(1):89-93 - PubMed
- Br J Psychiatry. 2011 May;198(5):351-6 - PubMed
- J Neuroinflammation. 2014 Mar 12;11:47 - PubMed
- J Neurotrauma. 2015 May 1;32(9):633-44 - PubMed
- Biochem Soc Trans. 2011 Aug;39(4):886-90 - PubMed
- PLoS One. 2014 Apr 04;9(4):e93966 - PubMed
- Schizophr Res. 2007 May;92(1-3):108-15 - PubMed
- BMC Neurol. 2012 Jun 21;12:44 - PubMed
- Acta Neurol Scand Suppl. 2006;185:107-14 - PubMed
- N Engl J Med. 2005 Jun 9;352(23):2379-88 - PubMed
- Neuropharmacology. 2008 Oct;55(5):826-34 - PubMed
- Exp Neurol. 1996 Feb;137(2):234-41 - PubMed
- Lancet Neurol. 2013 Aug;12 (8):747-55 - PubMed
- J Neuroimmune Pharmacol. 2014 Sep;9(4):582-90 - PubMed
- Psychol Med. 2013 May;43(5):911-20 - PubMed
- J Cereb Blood Flow Metab. 2015 Nov;35(11):1804-11 - PubMed
- Brain Behav Immun. 2016 Jul;55:151-65 - PubMed
- J Neuropsychiatry Clin Neurosci. 2010 Winter;22(1):8-18 - PubMed
- Alzheimers Dement. 2011 May;7(3):280-92 - PubMed
- Ann Transl Med. 2015 Jun;3(10):136 - PubMed
- Neuropharmacology. 2015 Aug;95:332-42 - PubMed
- Neurobiol Dis. 2006 Feb;21(2):404-12 - PubMed
- PLoS One. 2015 Mar 23;10(3):e0119768 - PubMed
- Int J Geriatr Psychiatry. 2011 Oct;26(10):1080-8 - PubMed
- Neurobiol Aging. 2011 Dec;32(12 ):2318.e31-41 - PubMed
- J Neuropsychiatry Clin Neurosci. 2010 Spring;22(2):130-54 - PubMed
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