Gamma-aminobutyric acid (GABA) plays a key role in many physiological processes of brain. It is present in one third of synapses in the central nervous system, and modulates neurotransmission via GABAergic interneurons. Although the involvement of GABA in psychiatric disorders is well-known, understanding its role in their etiology is very difficult.
In order to achieve a deeper knowledge of GABA system, a good idea is scanning the brain of living humans to quantify GABA in vivo, and then comparing its presence and distribution in healthy and sick patients. To date, the only scan method that does not require the use of radioactive tracers is the proton magnetic resonance spectroscopy (1H-MRS).
Scientist from University Medical Center Utrecht (UMCU) of Utrecht, the Netherlands, have searched scientific literature in order to find studies describing the quantification of GABA using 1H-MRS in vivo in humans with a psychiatric disorder compared with healthy controls. They found 49 relevant studies covering seven psychiatric disorders – major depressive disorder (MDD), schizophrenia, autism spectrum disorder (ASD), bipolar disorder, panic disorder, post-traumatic stress disorder (PTSD), and attention deficit/hyperactivity disorder (ADHD) – and performed a meta-analysis, that is, a statistical analysis that compared the results of the studies.
Meta-analysis results showed that GABA levels in MDD patients were significantly lower than in remitted patients and in healthy controls. These findings are consistent with known loss of GABAergic interneurons in MDD patients, as well as with lower GABA levels in plasma and cerebrospinal fluid. Moreover, the differences were larger in occipital than in prefrontal regions.
Similarly, ASD patients had lower levels of GABA compared with healthy individuals. Other studies had formerly demonstrated a decrease of GABA receptors in the frontal cortex, in the nucleus accumbens and in the amygdala in ASD patients. So, these results are in line with pre-existing literature.
In MDD and ASD cases, there are two hypotheses that explain the decrease of GABA signal. The first, considers the loss of signal as a consequence of the loss of GABAergic interneurons; the second, refers to the inhibition of GABAergic system. Both hypotheses are not mutually exclusive.
Schizophrenia results showed more uncertainty: GABA levels tended towards lower levels in schizophrenic patients, but there was no statistical support. In this case, it is important to note that the use of antipsychotics probably affected the results by altering GABAergic transmission. Also, there was great heterogeneity among patient ages, gender, and duration of illness in the studies chosen for the meta-analysis.
Bipolar disorder, panic disorder, PTSD and ADHD patients didn’t show any difference when compared with healthy controls.
There are some methodological considerations to do about 1H-MRS technique. First of all, it is very difficult to properly separate the signal of GABA from the signal of creatine and other macromolecules. Signal contamination may be responsible for up to 50% of GABA signal, depending on the methods for reducing contamination used across the studies. It is no possible to normalize the results of the studies, because of the lack of consensus across scientific community on the method to be used to minimize the contamination.
Moreover, most of the studies focused on occipital cortex, due to the better resolution that can be obtained in comparison with other brain regions. However, this decision hindered the possibility to analyze the differences of GABA levels across brain regions. Also, inter-laboratory methodological differences, such as software used for GABA quantification, made (and makes) difficult to obtain accurate results.
So, an integrative approach that includes: neuroimmune, stress and epigenetic markers; availability of detailed information about disease history and medication use; and a wide consensus on 1H-MRS method, are conditions required for a deeper understanding of the role of GABA in psychiatric disorders.
1H-MRS in vivo studies have shown that GABA levels in brain of depressed MDD patients and ASD patients are lower compared to healthy individuals. Although it is necessary to get more accurate diagnostic precision, GABA system may be a promising pharmacological target on the way to improve personalized medicine.
Schür R.R. et al. Brain GABA Levels Across Psychiatric Disorders: A Systematic Literature Review and Meta-Analysis of 1H-MRS Studies. Hum Brain Mapp. 2016 Sep;37(9):3337-52
This work has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).