Currently, standard antidepressants – the selective serotonin reuptake inhibitors (SSRIs) – target serotonin. But serotonin is far from the only transmitter that is out of balance in depression.
In fact, there is "evidence that defects in glutamatergic and GABAergic transmission are just as important, or more important," Bernhard Luscher told BioWorld Today, though "there has been relatively little attention in terms of the function of GABA and glutamate in the context of major depressive disorders."
In depressed patients, as well as in mouse models of depression, the basic balance between neural excitation, for which glutamate is the major transmitter, and inhibition, which is GABA's job, is shifted in favor of glutamate.
Part of the reason that glutamate and GABA aren't getting more attention is that GABA receptor-activating drugs that are currently available, such as the benzodiazepines, are simply ineffective as antidepressants.
"Based on that, people have dismissed the idea that GABAergic transmission could be important" in depression, Luscher said.
In results published in the Nov. 8, 2016, online issue of Translational Psychiatry, though, Luscher, who is a professor of biology and of biochemistry and molecular biology at Pennsylvania State University, and his team published a study that "brings the idea back into the market that potentiating GABAergic transmission should have beneficial effects" in depression, he said.
In their work, Luscher and his team used genetic methods to target a subset of GABAergic neurons that also express somatostatin. Increasing the signaling of those neurons decreased depressive symptoms in mouse models.
"The reason why currently used drugs are not effective is unclear – possibly because they are not selective enough," Luscher said. The same transmitter systems play different roles in different circuits, and the brain's tendency toward recycling its transmitter systems often makes it challenging to target only one function of those transmitters. (See BioWorld Today, Nov. 10, 2016.)
Dopamine's role in both psychosis and motor functions, for example, means that antipsychotics can have motor side effects, while trying to increase dopamine signaling in Parkinson's disease patients can lead to psychotic symptoms.
GABA, too, wears multiple hats. Its signaling is involved in anxiety in the cortex, but is also important for motor coordination in the cerebellum.
Though the team targeted somatostatin-expressing GABAergic neurons, the effects were not due to somatostatin, which remained unchanged. The results are due to the specific connectivities of that neural subgroup.
Though the work implies that selectively increasing the signaling of certain GABA circuits could be a useful antidepressant strategy, significant obstacles remain to doing so in a way that is clinically feasible.
For now, Luscher acknowledged, "we don't really have a pharmaceutical strategy" for specific targeting.
And a specific problem for industry is that there are already many patents surrounding GABA signaling, complicating the path to successful commercialization.
The solution might come from another result of the work now published in Translational Psychiatry. In their work, Luscher said, "we showed that potentiating GABAergic transmission results in the same biochemical changes as treatment with ketamine," suggesting that "ketamine ultimately . . . enhances GABAergic transmission."
Ketamine is an anesthetic drug that can lead to extremely rapid relief from depressive symptoms – within hours, rather than the weeks that it typically takes for SSRIs to have an effect. (See BioWorld Today, Aug. 20, 2010.)
Ketamine affects glutamate signaling, and efforts are underway to understand the biochemistry that underlies its rapid effects. (See BioWorld Today, July 5, 2011, Jan. 22, 2014, and May 5, 2016.)
In their work, the team showed that like ketamine treatment, their approach affected eEF2, though, unlike ketamine treatment, the effects did not depend on activation of the mTOR complex. Because eEF2 is involved in translation of mRNAs, it affects multiple other proteins, and Luscher said that "hopefully, that will give us new targets."