title: Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants.
abstract: Evidence suggesting that central nervous system γ-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD's underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD. This review includes an evaluation of magnetic resonance spectroscopy data, as well as data on the expression and function of the GABA-synthesizing enzyme glutamic acid decarboxylase, GABA neuron-specific cell markers, such as parvalbumin, calretinin and calbindin, and the GABAA and GABAB receptors in clinical MDD populations. We explore a potential role for glial pathology in MDD-related reductions in GABA concentrations, and evidence of a connection between neurosteroids, GABA neurotransmission, and hormone-related mood disorders. Additionally, we investigate the effects of GABAergic pharmacological agents on mood, and demonstrate that these compounds have complex effects that do not universally support the idea that reduced GABA neurotransmission is at the root of MDD. Finally, we discuss the connections between serotonergic and GABAergic neurotransmission, and show that two serotonin-focused antidepressants - the selective serotonin-reuptake inhibitor fluoxetine and the multimodal antidepressant vortioxetine - modulate GABA neurotransmission in opposing ways, despite both being effective MDD treatments. Altogether, this review demonstrates that there are large gaps in our understanding of the relationship between GABA physiology and MDD, which must be remedied with more data from well-controlled empirical studies. In conclusion, this review suggests that the simplistic notion that MDD is caused by reduced GABA neurotransmission must be discarded in favor of a more nuanced and complex model of the role of inhibitory neurotransmission in MDD.
authors: External Sourcing and Scientific Excellence, Lundbeck Research USA, Paramus, NJ, USA.
authors: Alan L
authors: AL
authors: Pehrson
authors: External Sourcing and Scientific Excellence, Lundbeck Research USA, Paramus, NJ, USA.
authors: Connie
authors: C
authors: Sanchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D019317:Evidence-Based Medicine; D005473:Fluoxetine / Q000627:therapeutic use; D018682:GABA Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D009433:Neural Inhibition / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013440:Sulfides / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects*; D000078784:Vortioxetine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine; D018682:GABA Agents; D018698:Glutamic Acid; D010879:Piperazines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine; D005680:gamma-Aminobutyric Acid
keywords: 5-HT; GABA; major depressive disorder; serotonin
references: Biol Psychiatry. 2010 Mar 1;67(5):465-70
references: 20004363
references: Brain Res. 2001 Aug 10;910(1-2):55-66
references: 11489254
references: J Clin Psychiatry. 2004;65 Suppl 5:7-12
references: 15078112
references: Brain Res. 1998 Jan 1;779(1-2):309-13
references: 9473706
references: Brain Res. 1988 Sep 13;460(1):114-23
references: 2851368
references: Neurology. 1999 Oct 22;53(7):1503-11
references: 10534259
references: Neuropsychopharmacology. 2005 Aug;30(8):1576-83
references: 15886723
references: J Chem Neuroanat. 2002 Jun;24(1):65-74
references: 12084412
references: Biochem Biophys Res Commun. 1993 May 28;193(1):268-76
references: 8389146
references: Eur Neuropsychopharmacol. 2012 Oct;22(10):751-60
references: 22406239
references: Neuron. 1997 Sep;19(3):687-95
references: 9331358
references: Neuropharmacology. 2007 Feb;52(2):497-505
references: 17045313
references: Pharmacol Ther. 2007 Oct;116(1):58-76
references: 17512983
references: Neuropsychobiology. 1992;26(1-2):33-6
references: 1335560
references: Biol Psychiatry. 2003 Oct 1;54(7):757-62
references: 14512217
references: J Neurosci. 2012 Feb 29;32(9):3022-31
references: 22378875
references: Am J Psychiatry. 1998 Jul;155(7):910-3
references: 9659856
references: Ann N Y Acad Sci. 2013 Jul;1292:21-31
references: 23876043
references: Nat Neurosci. 2005 Jun;8(6):797-804
references: 15895085
references: Am J Psychiatry. 2003 Mar;160(3):577-9
references: 12611844
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15653-8
references: 16230605
references: Trends Pharmacol Sci. 1998 Dec;19(12):500-5
references: 9871412
references: Am J Psychiatry. 1980 Mar;137(3):362-4
references: 7356067
references: J Affect Disord. 2009 Feb;113(1-2):45-55
references: 18538859
references: J Neurosci. 1995 Mar;15(3 Pt 2):2445-52
references: 7891179
references: J Psychopharmacol. 2014 Oct;28(10):891-902
references: 25122043
references: J Clin Psychiatry. 1998;59 Suppl 14:11-4
references: 9818625
references: Brain Res. 2003 Jan 3;959(1):58-67
references: 12480158
references: J Neurosci. 1998 Jul 15;18(14):5275-84
references: 9651210
references: J Neurosci. 2012 Nov 21;32(47):16616-28
references: 23175817
references: Alcohol Clin Exp Res. 1995 Apr;19(2):350-5
references: 7625568
references: Neuroscience. 2011 Sep 8;190:328-38
references: 21684321
references: Exp Brain Res. 2013 Oct;230(4):427-39
references: 23591691
references: Neuroreport. 2002 Dec 3;13(17):2177-80
references: 12488792
references: Am J Psychiatry. 2004 May;161(5):826-35
references: 15121647
references: Neurosci Lett. 2008 Sep 5;442(1):24-9
references: 18606211
references: Psychopharmacology (Berl). 2012 May;221(2):261-72
references: 22147258
references: Science. 1986 May 23;232(4753):1004-7
references: 2422758
references: Brain Res. 2000 Jun 9;867(1-2):131-42
references: 10837806
references: Neurosci Lett. 2012 Nov 14;530(1):97-102
references: 23022470
references: Eur J Pharmacol. 2015 Apr 15;753:19-31
references: 25107284
references: N Engl J Med. 1998 Jan 22;338(4):209-16
references: 9435325
references: Trends Pharmacol Sci. 2004 Sep;25(9):481-6
references: 15559250
references: Arch Gen Psychiatry. 2002 Sep;59(9):851-8
references: 12215085
references: Ann N Y Acad Sci. 2007 Jan;1096:157-69
references: 17405927
references: Perspect Dev Neurobiol. 1998;5(2-3):119-29
references: 9777630
references: Biol Psychiatry. 1999 May 1;45(9):1085-98
references: 10331101
references: Perspect Dev Neurobiol. 1998;5(2-3):109-18
references: 9777629
references: Drug Metab Dispos. 2006 Sep;34(9):1443-7
references: 16760229
references: Eur Arch Psychiatry Clin Neurosci. 2012 Dec;262(8):647-55
references: 22526728
references: J Neurochem. 1993 Feb;60(2):395-407
references: 8419527
references: Cereb Cortex. 2004 Dec;14(12):1365-75
references: 15166106
references: J Chem Neuroanat. 2001 Jan;21(1):63-73
references: 11173221
references: Neurosci Lett. 2002 May 10;324(1):1-4
references: 11983280
references: J Neurosci. 1997 Jul 15;17(14):5591-8
references: 9204940
references: Transl Psychiatry. 2013;3:e303
references: 24022508
references: Neurochem Res. 2012 May;37(5):920-7
references: 22278721
references: Neuropsychiatr Dis Treat. 2014 Jul 15;10:1297-307
references: 25075188
references: Pediatrics. 1987 Dec;80(6):909-17
references: 3684404
references: Brain Stimul. 2008 Jul;1(3):151-63
references: 20633382
references: Br J Pharmacol. 2014 Sep;171(18):4255-72
references: 24846338
references: J Neurophysiol. 1997 Jan;77(1):517-21
references: 9120594
references: Biol Psychiatry. 2002 Oct 1;52(7):708-15
references: 12372661
references: Biol Psychiatry. 2003 Oct 15;54(8):792-9
references: 14550678
references: Biol Psychiatry. 2009 May 1;65(9):792-800
references: 19058788
references: J Clin Psychiatry. 2011 Apr;72(4):473-9
references: 21208574
references: Neurochem Int. 2012 Sep;61(4):546-58
references: 22365921
references: J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22
references: 9400006
references: Epilepsia. 1999;40 Suppl 10:S21-47
references: 10609603
references: Nat Neurosci. 2007 Apr;10(4):469-77
references: 17351635
references: Neurochem Int. 2013 Jan;62(2):182-8
references: 23219521
references: Depress Anxiety. 2013 Jun;30(6):515-27
references: 23468126
references: Biol Psychiatry. 2006 Feb 1;59(3):284-6
references: 16139814
references: Mol Psychiatry. 2012 Nov;17(11):1130-42
references: 21912391
references: Arch Gen Psychiatry. 2000 Nov;57(11):1061-9
references: 11074872
references: Psychopharmacology (Berl). 2006 Jun;186(3):323-33
references: 16193334
references: Biol Psychiatry. 2005 Dec 15;58(12):969-73
references: 16043137
references: Neurobiol Dis. 2011 Apr;42(1):116-24
references: 21232602
references: Neuropsychopharmacology. 2008 May;33(6):1323-35
references: 17625499
references: Arch Gen Psychiatry. 2004 Jul;61(7):705-13
references: 15237082
references: Prog Neurobiol. 2009 Oct;89(2):193-219
references: 19654034
references: Brain Res. 1991 Jun 7;550(2):181-91
references: 1679370
references: Arch Gen Psychiatry. 2007 Feb;64(2):193-200
references: 17283286
references: Br J Clin Pharmacol. 1989;27 Suppl 1:101S-107S
references: 2667602
references: Cereb Cortex. 2003 Aug;13(8):870-82
references: 12853374
references: Neuroscience. 2009 Dec 1;164(2):692-701
references: 19660530
references: J Neurosci. 1992 Mar;12(3):1040-62
references: 1312131
references: Schizophr Res. 2011 May;128(1-3):37-43
references: 21303731
references: CNS Spectr. 2014 Apr;19(2):121-33
references: 23903233
references: Adv Pharmacol. 2010;58:427-51
references: 20655491
references: Depress Anxiety. 2010;27(1):78-89
references: 19569060
references: Pharmacol Biochem Behav. 2000 Sep;67(1):137-43
references: 11113493
references: Biol Psychiatry. 2006 Jun 1;59(11):1052-60
references: 16581036
references: Eur J Pharmacol. 1998 Nov 20;361(2-3):299-309
references: 9865521
references: Libyan J Med. 2014;9:23480
references: 24560379
references: Neuropharmacology. 1994 Mar-Apr;33(3-4):527-41
references: 7984292
references: Int J Neuropsychopharmacol. 2012 Jul;15(6):715-25
references: 22008735
references: Eur J Nucl Med Mol Imaging. 2010 Mar;37(3):565-74
references: 19890631
references: Neuropsychiatr Dis Treat. 2012;8:369-73
references: 22977304
references: J Neurochem. 2003 Apr;85(2):503-14
references: 12675927
references: J Neurosci. 2006 Aug 16;26(33):8537-48
references: 16914680
references: Neurochem Res. 1998 May;23(5):653-9
references: 9566603
references: J Affect Disord. 1990 Jan;18(1):11-5
references: 2153156
references: J Psychiatr Res. 2009 Jun;43(9):855-63
references: 19128810
references: Nat Neurosci. 2002 Aug;5(8):721-2
references: 12118257
references: J Pharmacol Exp Ther. 1990 Jan;252(1):171-8
references: 2137174
references: J Physiol. 2005 Apr 15;564(Pt 2):421-36
references: 15705652
references: Psychiatry Res. 2006 Nov 29;145(1):39-48
references: 17045658
references: World J Biol Psychiatry. 2007;8(2):112-22
references: 17455104
references: J Pharmacol Exp Ther. 2003 Mar;304(3):978-84
references: 12604672
references: J Physiol Pharmacol. 2011 Oct;62(5):535-40
references: 22204801
references: J Comp Neurol. 1993 Feb 8;328(2):282-312
references: 7678612
references: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12599-604
references: 8901628
references: Biol Psychiatry. 2007 Mar 15;61(6):806-12
references: 17210135
references: Cereb Cortex. 2012 Jul;22(7):1487-97
references: 21893679
references: Int J Neuropsychopharmacol. 2008 Mar;11(2):255-60
references: 17625025
references: Int J Neuropsychopharmacol. 2011 Jul;14(6):721-34
references: 21226980
references: Int Clin Psychopharmacol. 1995 Sep;10(3):181-95
references: 8675972
references: Neuropharmacology. 1999 Jul;38(7):955-63
references: 10428414
references: Front Integr Neurosci. 2013 Apr 19;7:25
references: 23626526
references: Biol Psychiatry. 2013 Apr 1;73(7):691-8
references: 23200528
references: Psychiatry Res. 1988 Nov;26(2):119-29
references: 2853398
references: J Neurochem. 1989 Jun;52(6):1823-9
references: 2566651
references: J Neurosci. 1997 May 1;17(9):3157-67
references: 9096150
references: Arch Gen Psychiatry. 1999 Nov;56(11):1043-7
references: 10565505
references: J Neurol Neurosurg Psychiatry. 1993 Aug;56(8):925-8
references: 8350115
references: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44
references: 9501247
references: Brain Res. 1997 Jan 23;746(1-2):207-19
references: 9037500
references: Biochem Biophys Res Commun. 2011 Jun 17;409(4):596-602
references: 21539809
references: Brain Res. 2004 Jun 4;1010(1-2):156-65
references: 15126129
references: Int J Neuropsychopharmacol. 2010 May;13(4):411-20
references: 20236554
references: J Physiol. 2002 May 1;540(Pt 3):743-59
references: 11986365
references: Schizophr Res. 2005 Jan 1;72(2-3):109-22
references: 15560956
references: Neuropsychopharmacology. 2007 Feb;32(2):471-82
references: 17063153
references: J Comp Neurol. 2001 Jan 22;429(4):571-89
references: 11135236
references: Biol Psychiatry. 1995 Nov 1;38(9):578-91
references: 8573660
references: J Pharmacol Exp Ther. 2000 Aug;294(2):672-9
references: 10900247
references: J Neurosci. 2012 Apr 25;32(17):5804-9
references: 22539842
references: Neuroscience. 2004;129(1):65-73
references: 15489029
references: J Nutr. 2001 Sep;131(9 Suppl):2498S-504S; discussion 2523S-4S
references: 11533301
references: Biol Psychiatry. 2010 Mar 1;67(5):458-64
references: 19922906
references: PLoS One. 2011;6(2):e16970
references: 21383986
references: Neurochem Res. 2007 Sep;32(9):1559-65
references: 17486443
references: Biol Psychiatry. 2010 Nov 1;68(9):785-94
references: 20728076
references: Am J Psychiatry. 2002 Apr;159(4):663-5
references: 11925309
references: PLoS One. 2009;4(8):e6585
references: 19668376
references: Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):59-79
references: 14965245
references: J Neural Transm (Vienna). 2002 May;109(5-6):881-9
references: 12111475
references: Hum Psychopharmacol. 2012 Nov;27(6):549-58
references: 23027677
references: Biol Psychiatry. 2013 Jun 15;73(12):1172-9
references: 23726152
references: Acta Psychiatr Scand. 1989 Jun;79(6):586-96
references: 2475012
references: Psychopharmacology (Berl). 1996 Jul;126(2):173-8
references: 8856837
references: Int Clin Psychopharmacol. 1991 Winter;6(4):197-207
references: 1816278
references: Curr Drug Targets. 2013 Oct;14(11):1225-36
references: 23469922
references: Brain Res. 2006 Dec 13;1125(1):138-46
references: 17118347