The effects of losartan and diazepam on emotional processing

Abstract

Given the prevalence and substantial economic costs of anxiety disorders, and the shortcomings of current treatments, there is dire need for research that helps inform the development of new treatments and medications. The aim of this thesis was to further our understanding of the effects of two medications relevant to anxiety, losartan and diazepam, to help inform the use of existing treatments and lead to more effective ones. Research has indicated that the angiotensin receptor antagonist losartan may potentially be a promising candidate to enhance the efficacy of exposure-based therapies. It however remains to be fully clarified how losartan affects some of the mechanisms relevant to exposure success. In the first study, a single dose of losartan was shown to increase activation in the paracingulate gyrus, insular cortex, lingual gyrus, and fusiform gyrus in healthy, high trait anxious volunteers, which possibly reflects modulation of higher-order visual processing. There was however no evidence found for an effect of losartan on neural responses in the hippocampus during non-emotional memory encoding. Losartan was also shown to increase positive attentional bias, which was reflected in attention being more firmly held by positive stimuli compared to neutral stimuli. Given that both greater reactivity in higher-order visual regions and positive valence training have been shown to be relevant for therapy success, these results may provide further support that losartan might potentially have synergistic effects with exposure therapy, but this remains to be tested directly. The most common pharmacological treatments for anxiety disorders include selective serotonin reuptake inhibitors and benzodiazepines, but both groups of medications have limitations. A better understanding of how existing medications exert their anxiolytic effects may help guide development of new medications. As benzodiazepines are not effective in treating depression, researching their effects provide a means of teasing apart antidepressant and anxiolytic effects. A comprehensive understanding of the cognitive neuropsychological mechanisms behind their anxiolytic effects is still lacking. In the second study, a 7-day treatment of diazepam was shown to lower connectivity between the amygdala and the pre- and post-central gyrus during cognitive reappraisal, and between limbic regions and the precuneous cortex in response to aversive pictures in healthy volunteers. The treatment also led to a decrease in activation in the right vlPFC during reappraisal, and to an increase in activation in the left vlPFC and right ACC in response to positive stimuli, without any subjective changes in mood and state anxiety. Diazepam may thus potentially be exerting its short-term anxiolytic effects by modulating activity within these brain areas. Taken together, these findings provide valuable insights into potential mechanisms through which diazepam and losartan may exert their therapeutic effects. A better understanding of these mechanisms can hopefully help inform the development of future anxiolytics and combination treatments.