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
This thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain... Show moreThis thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain activation and resting state functional connectivity. All participants were scanned three times in a six-month period. In between scan sessions the adolescents from the clinical group received treatment as usual. Adolescents from the control group were scanned within the same time interval but did not receive treatment. During a scan session several MRI parameters were collected including task based fMRI (emotional face processing task) and resting state fMRI. We also administered several questionnaires about derpession and anxiety symptomatology. It was demonstrated that adolescents with depressive and anxiety disorders show differentiating patterns of amygdala reactivity and connectivity compared to a healthy control group. Furthermore, using a dimensional approach and taking individual differences in self-reported depression and anxiety symptoms into account highlighted the role of self-reported anxiety symptoms in amygdala reactivity during emotional faces processing. These findings indicate that the amygdala indeed is an important region involved in emotional face processing and that focusing on this region can provide further insights in the development and persistence of depressive and anxiety disorders in adolescents. Show less