Effects of reboxetine, a selective norepinephrine reuptake inhibitor, on sympathetic and parasympathetic outflow to the heart: preliminary data

Rationale: Antidepressants exert distinct effects on cardiac autonomic nervous system (ANS) function, depending on their receptor profile. Reboxetine is a selective norepinephrine (NE) reuptake inhibitor and shows only low affinity for adrenergic and muscarinic receptors. Data on reboxetine's effects on ANS function in patients with major depression (MD) are sparse. Objective: This study evaluates the effects of reboxetine on cardiac ANS function assessed by standardized measurements of heart rate variability (HRV). Methods: Twenty-five MD patients (DSM-III-R) underwent serial ANS function tests (n=94) including conventional electrocardiograms and standardized measurements of HRV and blood pressure prior to reboxetine treatment as well as on days 2, 10 and 21 during reboxetine therapy. The starting dose was 4 mg; on day 10, reboxetine was increased to 8 mg/day. The effects of reboxetine on ANS function were evaluated using the paired Wilcoxon test. Results: Reboxetine treatment was associated with 1) a significant decrease in absolute and relative low-frequency power as well as in mean arterial pressure on day 2, and 2) a significant decrease in the average low- to high-frequency ratio on days 2 and 10, No significant changes in any of the vagally mediated HRV indices occurred. Conclusion: These preliminary findings are compatible with the hypothesis that inhibition of brain NE reuptake by reboxetine resulted in an inhibition of central noradrenergic activity via a local increase of NE concentration at inhibitory alpha(2)-autoroceptors. Long-term treatment (21 days) may cause desensitization and down-regulation of alpha(2)-autoreceptors, so that attenuation of the inhibitory restraint on sympathetic outflow results.