The GABAergic system has been implicated in the pathogenesis of various anxiety disorders. Pharmacological treatments, like benzodiazepines, have been proven to target the GABA(A) receptors and... Show moreThe GABAergic system has been implicated in the pathogenesis of various anxiety disorders. Pharmacological treatments, like benzodiazepines, have been proven to target the GABA(A) receptors and exert quick-onset anxiolytic effect in anxiety patients. However, the side effects of these non-selective GABA(A)ergic compounds, such as sedation, postural imbalance, or potential abuse, limit their use for clinical anxiolysis. Based on the understanding of benzodiazepines’ mechanism of action, the emergence of α2,3 subtype-selective GABA(A) modulator is expected to provide a novel pharmacological approach that alleviates anxiety symptoms but spares the common undesired side effects. Most of these compounds are still in early clinical development, in which stage proof-of-mechanism studies are usually performed in healthy volunteers. The findings from our studies consistently present a similar pattern in the pharmacodynamic effect profiles of the α2,3 subtype-selective GABA(A) modulators versus those of the non-selective full GABA(A) agonist, lorazepam. Future application of anxiogenic symptom provocation models that combine subjective measurements and/or neuroendocrine biomarker assays may provide further construct validity for clinical anxiolytic effects of α2,3 subtype-selective GABA(A) modulators. Also, such findings are expected to provide insights into the translation of preclinical pharmacological properties of α2,3-subtype-selective GABA(A)ergic compounds to clinical effects in anxiety patients through human pharmacology studies. Show less
The studies in this thesis together show different ways of studying human pharmacology, give an impression of the current drug development in schizophrenia, and provide examples how human... Show moreThe studies in this thesis together show different ways of studying human pharmacology, give an impression of the current drug development in schizophrenia, and provide examples how human pharmacology can be applied in an early stage of drug development in healthy volunteers. The investigated compounds show that the main pharmacological focus in this area has shifted from psychosis to improvement of individual negative or cognitive symptom complexes, from direct receptor inhibition to indirect receptor modulation, and from single drug strategies to combination therapies, each targeted at different symptoms. We have tried to create a pharmacological fingerprint of the investigated compounds by making use of an intensive CNS test battery to measure effects in different functional domains of the brain and additional 'tools' (i.e. positive controls, dose escalation, PK-PD modeling and pharmacological challenge tests) to improve the reliability of the tests. This diversity of drug development strategies and range of neurotransmitters in schizophrenia reflects the increasing complexity of neuropharmacological hypotheses in this field. Despite these difficulties, incremental changes in drug characteristics and treatment strategies may well lead to the introduction of new classes or combinations of drugs in the future. Show less
