ABSTRACT
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)-autoreceptors. 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.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Heart/drug effects , Heart/innervation , Morpholines/therapeutic use , Parasympathetic Fibers, Postganglionic/drug effects , Sympathetic Fibers, Postganglionic/drug effects , Adrenergic Uptake Inhibitors/therapeutic use , Adult , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/physiopathology , Female , Heart Conduction System/drug effects , Humans , Male , Middle Aged , Norepinephrine/antagonists & inhibitors , Norepinephrine/metabolism , Parasympathetic Fibers, Postganglionic/physiology , Reboxetine , Statistics, Nonparametric , Sympathetic Fibers, Postganglionic/physiologyABSTRACT
OBJECTIVES: To evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DESIGN: Prospective, randomized clinical study. SETTING: University teaching hospital. PATIENTS: Forty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. INTERVENTIONS: Serial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). MEASUREMENTS AND MAIN RESULTS: The average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. CONCLUSIONS: Benzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the gamma-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.
