Rationale: Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients.
Objectives: The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation.
Methods: In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40 mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8 mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression.
Results: Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions.
Conclusion: The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressants.