Review Article

Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety

Xia Chen1,2,3,4, Joop van Gerven4,5, Adam Cohen4, Gabriel Jacobs4
1 China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
2 College of Pharmaceutical Sciences, Capital Medical University, Beijing 100070, China
3 Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
4 Centre for Human Drug Research, Leiden 2333 CL, The Netherlands
5 Central Committee on Research Involving Human Subjects (CCMO), The Hague 2500 BH, The Netherlands
Correspondence to: Xia Chen:, Joop van Gerven:, Gabriel Jacobs:,
DOI: 10.1038/s41401-018-0185-5
Received: 25 March 2018
Accepted: 10 October 2018
Advance online: 5 December 2018


Anxiety disorders arise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behavioral responses observed in anxiety disorders. There is considerable preclinical evidence that the GABAergic system, in general, and its α2- and/or α5-subunit-containing GABA(A) receptor subtypes, in particular, are involved in the pathophysiology of anxiety disorders. However, the clinical efficacy of GABA-A α2-selective agonists for the treatment of anxiety disorders has not been unequivocally demonstrated. In this review, we present several human pharmacological studies that have been performed with the aim of identifying the pharmacologically active doses/exposure levels of several GABA-A subtype-selective novel compounds with potential anxiolytic effects. The pharmacological selectivity of novel α2-subtype-selective GABA(A) receptor partial agonists has been demonstrated by their distinct effect profiles on the neurophysiological and neuropsychological measurements that reflect the functions of multiple CNS domains compared with those of benzodiazepines, which are nonselective, full GABA(A) agonists. Normalizing the undesired pharmacodynamic side effects against the desired on-target effects on the saccadic peak velocity is a useful approach for presenting the pharmacological features of GABA(A)-ergic modulators. Moreover, combining the anxiogenic symptom provocation paradigm with validated neurophysiological and neuropsychological biomarkers may provide further construct validity for the clinical effects of novel anxiolytic agents. In addition, the observed drug effects on serum prolactin levels support the use of serum prolactin levels as a complementary neuroendocrine biomarker to further validate the pharmacodynamic measurements used during the clinical pharmacological study of novel anxiolytic agents.
Keywords: anxiety disorders; GABA-A receptors; clinical pharmacology

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