Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants

Figures & data

Figure 1 Amino acid neurotransmitter synthesis and catabolism. The synthesis and catabolism of GABA and glutamate are tightly interconnected in the brain.

Abbreviations: αKGDH, α-ketoglutarate dehydrogenase; AAT, aspartate aminotransferase; CoA, coenzyme A; Cys, cysteine; GABA, γ-aminobutyric acid; GDH, glutamate dehydrogenase; GABA-T, GABA transaminase; GAD, glutamic acid dehydrogenase; GCL, γ-glutamyl cysteine ligase; Gln, glutamine; Glu, glutamyl; Gly, glycine; GSH, glutathione; GHB, γ-hydroxybutyric acid; GGT, γ-glutamyl transferase; GGCT, γ-glutamyl cyclotransferase; OPLAH, 5-oxoprolinase (adenosine triphosphate-hydrolyzing); SSADH, succinic semialdehyde dehydrogenase; SSAR, succinic semialdehyde reductase.

Table 1 The relationship between major depressive disorder and GABA concentration measured by magnetic resonance spectroscopy

Brain region	Comparison groups	Direction	Reference
OCC	14 medication-free depressed versus 18 healthy controls	Down	^Citation20
OCC	33 depressed subjects versus 38 healthy controls	Down	^Citation19
OCC	6 depressed subjects versus 12 healthy controls	Down	^Citation17
OCC	15 treatment-resistant depressed versus 24 healthy controls	Down	^Citation18
OCC	15 treatment-resistant depressed versus 18 non-treatment-resistant depressed	Down	^Citation18
OCC	18 non-treatment-resistant depressed versus 24 healthy controls	NC	^Citation18
OCC	15 recovered depressed versus 18 healthy controls	Down	^Citation27
OCC/ACC	12 recovered depressed versus 11 healthy controls	Down	^Citation28
OCC	11 depressed subjects, before and after SSRI treatment	Up	^Citation22
OCC	8 depressed subjects, before and after ECT treatment	Up	^Citation23
OCC	15 medication-free depressed subjects, before and after CBT (8 subjects completed experiment)	Trend down	^Citation26
ACC	15 treatment-resistant depressed versus 24 healthy controls	Trend down	^Citation18
ACC	15 treatment-resistant depressed versus 18 non-treatment resistant depressed	Trend down	^Citation18
ACC	18 non-treatment-resistant depressed versus 24 healthy controls	NC	^Citation18
Dorsal PFC	20 depressed patients (medication-free for 4–8 weeks) versus 20 healthy controls	Down	^Citation21
Dorsal PFC	16 recovered depressed subjects versus 15 healthy controls	NC	^Citation24
VM PFC	20 depressed patients (medication-free for 4–8 weeks) versus 20 healthy controls	NC	^Citation21
VM PFC	16 recovered depressed subjects versus 15 healthy controls	NC	^Citation24

Abbreviations: ACC, anterior cingulate cortex; CBT, cognitive behavioral therapy; ECT, electroconvulsive therapy; NC, no change; OCC, occipital cortex; PFC, prefrontal cortex; SSRI, selective serotonin-reuptake inhibitor; VM, ventromedial.

Table 2 The relationship between major depressive disorder and glutamic acid decarboxylase expression or function

Brain region	Target	Technique	Comparison groups	Direction	Reference
DLPFC	GAD67	WB	13 medication-free depressed patients versus 13 controls	Down	^Citation30
DLPFC	GAD67	WB	8 medicated depressed patients versus 13 controls	NC	^Citation30
PFC	GAD67	WB	15 depressed patients (mostly treated) versus 15 controls	NC	^Citation32
DLPFC	GAD67	IHC	15 depressed patients versus 15 controls	NC	^Citation33
DLPFC	GAD67	qPCR	19 depressed patients (mix of treated and untreated) versus 19 controls	NC	^Citation34
DLPFC	GAD65	WB	13 medication-free depressed patients versus 13 controls	NC	^Citation30
DLPFC	GAD65	WB	8 medicated depressed patients versus 13 controls	NC	^Citation30
PFC	GAD65	WB	15 depressed patients (mostly treated) versus 15 controls	NC	^Citation32
DLPFC	GAD65	qPCR	19 depressed patients (mix of treated and untreated) versus 19 controls	NC	^Citation34
DLPFC	GAD	IHC	9 depressed patients versus 19 controls	Up	^Citation35
DLPFC	GAD	IHC	7 nonsuicide depressed patients (of a total of 21 depressed patients) versus 18 controls	Down	^Citation36
FC	GAD	Enzyme function	21 suicide victims (13 untreated, 6 on antidepressants, 2 on another drug) versus 21 controls	NC	^Citation38
DLPFC	GAD	IHC	9 depressed patients versus 18 controls	NC	^Citation37
OFC	GAD	IHC	9 depressed patients versus 19 controls	Up	^Citation35
OFC	GAD	IHC	9 depressed patients versus 18 controls	NC	^Citation37
ACC	GAD	IHC	9 depressed patients versus 19 controls	NC	^Citation35
ACC	GAD	IHC	9 depressed patients versus 18 controls	NC	^Citation37
STC	GAD	IHC	9 depressed patients versus 19 controls	Up	^Citation35
TC	GAD	Enzyme function	21 suicide victims (13 untreated, 6 on antidepressants, 2 on another drug) versus 21 controls	NC	^Citation38
EC (layer III)	GAD	IHC	21 depressed patients (including 14 suicide victims) versus 18 controls	Up	^Citation36
EC	GAD	IHC	9 depressed patients versus 18 controls	Up	^Citation37
HC	GAD	IHC	14 depressed suicide victims (of 21 total depressed patients) versus 18 controls	Up	^Citation36
HC	GAD	IHC	9 depressed patients versus 18 controls	Up	^Citation37
HC	GAD	IHC	9 depressed patients versus 19 controls	Up	^Citation35
MDT	GAD	IHC	9 depressed patients versus 19 controls	NC	^Citation35
MDT	GAD	IHC	9 depressed patients versus 18 controls	NC	^Citation37
LDT	GAD	IHC	9 depressed patients versus 18 controls	Up	^Citation37
CB	GAD67	WB	15 depressed patients versus 15 controls	Down	^Citation31
CB	GAD65	WB	15 depressed patients versus 15 controls	Down	^Citation31

Abbreviations: ACC, anterior cingulate cortex; CB, cerebellum; DLPFC, dorsolateral prefrontal cortex; EC, entorhinal cortex; FC, frontal cortex; GAD, glutamic acid decarboxylase; HC, hippocampus; IHC, immunohistochemistry; LDT, lateral dorsal thalamus; MDT, mediodorsal thalamus; NC, no change; OFC, orbitofrontal cortex; PFC, prefrontal cortex; qPCR, quantitative polymerase chain reaction; STC, superior temporal cortex; TC, temporal cortex; WB, Western blot.

Figure 2 Serotonergic influence on GABAergic neurotransmission in limbic system brain regions. Serotonergic heteroreceptors expressed on GABAergic interneurons and glutamatergic principal cells can modulate the excitatory state of neural networks associated with the control of cognitive function and mood. Vortioxetine may be an example of a drug that inhibits GABA neurotransmission via serotonergic mechanisms. Question marks denote receptors where expression on GABAergic interneurons has been indirectly suggested but no immunohistochemical verification exists for limbic brain regions.

Abbreviations: ag, agonist; antag, antagonist; GABA, γ-aminobutyric acid; GLU, glutamate; 5-HT, 5-hydroxytryptamine; Vor, vortioxetine.

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