Introduction: With regard to anxiety, the role of the balance between glutamatergic and GABAergic systems was pursued for many years. The majority of drugs used presently as effective anxiolytics enhance the GABAergic system activity, thus increasing inhibition within the central nervous system (CNS). On the other hand, decreasing the activity of glutamatergic neurotransmission may attenuate excitation in the CNS, thus resulting in anxiolysis.
Areas covered: The present review focuses on clinical data of well-known and recently discovered glutamatergic and, to a lesser extent, GABAergic agents, which reached at least the Phase II criteria.
Expert opinion: A variety of glutamatergic agents active at both N-acetylo-D-asparaginian and metabotropic glutamate (mGlu) receptors have been tested in humans to examine their potential anxiolytic activity. Many compounds acting on the glutamatergic system and approved for the treatment of other disorders than anxiety were shown to exert anxiolytic effects in clinical trials. Those are mainly voltage-dependent ion channel ligands as well as d-cycloserin and memantine. Also, ligands active at mGlu receptors, such as fenobam and LY354740, exhibited activity in controlled clinical trials. However, relatively few trials are found on the agents that are focused on GABAergic neurotransmission. Therefore, it seems that glutamatergic system may become a novel target for modern and effective anxiolytics.