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MDs using the following key words: “gamma‑amino GABA were found in manic BD individuals. Moreover,
butyric acid” OR “GABA” OR “L‑glutamic‑acid they observed that patients with different types of
decarboxylase” OR “GAD” OR “autoantibodies” OR depressions, particularly those with familial loading,
“GADA” AND “mood disorder” OR “major depressive had plasma GABA levels significantly lower than
disorder” OR “bipolar disorder” OR “depression”. We control groups. Instead, GABA plasma levels in
found more than 200 publications and we selected all patients with reactive or bipolar depression did not
those with pertaining information on the association differ from those of controls. [12] As a result, it has been
of any MD and abnormalities in the GABA pathway. proposed that plasma levels of GABA might be a useful
marker to predict the susceptibility to a depressive
The aim of this review was to focus on: (1) reviewing disorder in people with a family history of MDs.
briefly on the role of GABAergic pathway in MDs; Furthermore, plasma levels of GABA may be specific
(2) describing the molecular functions of GAD; and predictive of response to treatment, [13] although
(3) discussing the specific role of GAD as an important GABA plasma level appears to show a low sensitivity
factor in the pathophysiology of MDs; and (4) providing as a test for depression.
future directions for the implementation of glutamic
acid decarboxylase autoantibodies (GADA) screening Several other studies showed a decreased concentration
in clinical practice. of GABA in cerebrospinal fluid (CSF) of patients
with severe depressive disorder. [14‑17] In particular,
GABA IN MDs MDD patients over 40 years of age had significantly
lower CSF levels of GABA than younger subjects. [17]
GABA is an inhibitory neurotransmitter present In addition, GABA levels in CSF of patients with
exclusively in the central nervous system (CNS). depression and schizoaffective disorder are lower than
In a pivotal case series of 4 patients reported by those with schizophrenia or neurological conditions,
[16]
Emrich et al., these authors demonstrated a marked Parkinson’s disease, Huntington’s disease, and
[9]
mood‑stabilizing effect of valproic acid (VPA) in the dementia, all conditions which present at times
management of acute manic episodes as well as in depressive features. [18] Of note, free GABA levels in CSF
the maintenance treatment of other 7 patients with were lower in depressive disorders than in BD manic
recurrent episodes of manic or manic‑schizoaffective patients or healthy subjects. [16,17] In addition to the
psychosis, irresponsive to lithium prophylaxis. association of GABA levels with depressive disorders,
The beneficial effect of VPA suggested a role of the low levels of GABA have been also found in anxiety
GABAergic pathway in MDD since this anticonvulsant disorders [19,20] and chronic migraine, [21] which is often
leads to increased cerebral concentrations of GABA comorbid with MDD. In a recent study, Mann et al. [20]
by inhibiting GABA‑transaminase which degrades found an inverse correlation between psychic anxiety
GABA and by facilitating the reuptake of released severity and free GABA levels in CSF, independently
GABA into cells. VPA also stimulates synthesis of of age. Interestingly, benzodiazepines, the most used
GABA by increasing the activity of glutamic acid anti‑anxiety agents, increased GABA synthesis in the
decarboxylase. [10] Subsequently, Emrich et al. CNS. [22]
[9]
discovered a lack of GABA in the CNS of mood disorder
patients, which was restored by VPA, hypothesizing Other proofs of the association between plasma GABA
that modifications of this neurobiological pathway levels and depressive disorders may derive from the
may be associated with MDs. A more recent study has effect of electroconvulsive therapy (ECT) on severe
suggested that in general, GABAergic anticonvulsants refractory depression, since this treatment has been
possess antimanic properties and that the specific associated with a down‑regulation of the GLU/GABA
antimanic effect of lithium is associated with an ratio (i.e. an increase in GABA and a decrease of GLU
increased action of GABA. [11] Furthermore, the same levels) in the hippocampus of rats. [23,24] In fact, this
authors [11] suggested that the increased inhibitory measure of the GABAergic tone appears to be more
neurotransmission induced by long‑term lithium informative than single neurotransmitter levels, given
treatment counteracts the increased excitatory that GLU (a precursor of GABA) and GABA exert
neurotransmission resulting from elevated levels of their effects in a neuromodulatory conjunction. [25]
glutamate (GLU) which was detected in postmortem Similar findings were observed in humans. GABA
brain tissue of BD patients. Following the same line concentrations measured with proton magnetic
of investigation, GABA plasma level may represent resonance spectroscopy were significantly elevated
a biological trait marker for MDD. Indeed, Petty and in the occipital cortex of depressed patients following
Schlesser [12] found significantly decreased GABA ECT. [26] The increased levels of GABA in association
plasma levels, compared to healthy controls, in 40% with ECT may explain its antidepressant actions.
of depressed patients, but higher levels of plasma In addition, increased GABA concentrations in the

238 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 239