fluvoxamine and Arrhythmias--Cardiac

It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias.. We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats.. MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique.. Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (I. Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and I

Topics: Action Potentials; Animals; Antidepressive Agents, Second-Generation; Arrhythmias, Cardiac; Behavior, Animal; Calcium Channels; Depressive Disorder, Major; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Ligands; Male; Myocardium; Patch-Clamp Techniques; Potassium Channels; Rats; Receptors, sigma; Sigma-1 Receptor

The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs).. To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining.. Activation of S1R could decrease the vulnerability to VAs by inhibiting I

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Depression; Depressive Disorder; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Ion Channels; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Ventricular Remodeling

QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB).. Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD.. In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients.. This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

Topics: Adult; Aged; Arrhythmias, Cardiac; Citalopram; Databases, Factual; Female; Fluvoxamine; Humans; Long QT Syndrome; Male; Middle Aged; Paroxetine; Pharmacovigilance; Selective Serotonin Reuptake Inhibitors; Sertraline

Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

Topics: Animals; Arrhythmias, Cardiac; Calcium Channels; Contraindications; Depression, Chemical; Dogs; Dose-Response Relationship, Drug; Fluvoxamine; Heart Conduction System; Heart Rate; Hypotension; Infusions, Intravenous; Long QT Syndrome; Male; Myocardial Contraction; Selective Serotonin Reuptake Inhibitors; Sodium Channels

The effect of fluvoxamine (FLV) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. FLV (8-64 microM) caused a dose-dependent decrease in the rate of contractions (7-52%) and in the contractile force (11-57%). Ouabain alone (2 microM) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 microM) significantly increased the time required to produce arrhythmia by ouabain to 14.6 min, prolonged the beating of atria to more than 58.6 min and delayed the occurrence of asystolia. The pattern of contractile force induced by FLV+ouabain was more regular than that produced by ouabain alone. These findings indicate that FLV produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that FLV may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.

Topics: Animals; Anti-Arrhythmia Agents; Antidepressive Agents, Second-Generation; Arrhythmias, Cardiac; Atrial Function; Female; Fluvoxamine; Guinea Pigs; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Ouabain; Selective Serotonin Reuptake Inhibitors

Among several classes of antidepressants, tricyclic antidepressants are known to prolong QTc intervals (QT interval corrected by heart rate) in electrocardiograms, while selective serotonin uptake inhibitors (SSRI) are considered to be devoid of arrhythmogenicity. In this study, we aimed to compare the arrhythmogenic potencies of imipramine (IMI), a typical tricyclic antidepressant, and fluvoxamine (FLV), an SSRI, at therapeutic and supratherapeutic concentrations using guinea pigs in vivo. Guinea pigs were anesthetized, and IMI (10 and 20 mg/kg/h) or FLV (20 mg/kg/h) was intravenously administered for 90 minutes to obtain the time-courses of drug concentrations in plasma and the changes in the QTc intervals during and after the drug administration. IMI induced distinct QTc prolongation in a dose-dependent manner, while FLV prolonged QTc intervals only slightly. A pharmacokinetic-pharmacodynamic analysis revealed that the potency for QTc prolongation of IMI was 1.7-fold higher than that of FLV. Taking the therapeutic concentration into account, the clinical risk of FLV for QTc prolongation was suggested to be 5-fold lower than that of IMI. Therefore, this SSRI agent was suggested to be safer than the tricyclic antidepressant for patients with cardiac risk factors, including arrhythmia, or for those taking other arrhythmogenic drugs concomitantly.

Topics: Animals; Antidepressive Agents; Arrhythmias, Cardiac; Electrocardiography; Fluvoxamine; Guinea Pigs; Imipramine; Male

The effects of continuous infusion of amitriptyline (0.35 mg/kg/min), mianserin (0.70 mg/kg/min) or fluvoxamine (0.70 mg/kg/min) were studied on electrocardiogram (ECG), heart contractility and temperature in conscious rabbits. Lethal doses for amitriptyline (median 13.6 mg/kg) were much lower than for mianserin (median 56.0 mg/kg) or fluvoxamine (median 59.5 mg/kg). Amitriptyline induced severe arrhythmias and ECG disturbances at relatively low doses. Mianserin induced arrhythmias and ECG disturbances at higher doses, while arrhythmias were infrequently seen with fluvoxamine. ECG disturbances were observed at fluvoxamine doses approaching lethality. Amitriptyline very much lowered contractility as assessed by LVdP/dt. With fluvoxamine a decrease in LVdP/dt was only observed at moderate doses while at nearly lethal doses neither fluvoxamine nor mianserin induced a decrease in LVdP/dt. Fluvoxamine raised body temperature significantly. Fluvoxamine seems, at least in this animal model, a drug which induces far fewer cardiac disturbances than amitriptyline and even fewer than mianserin. It is concluded that fluvoxamine is relatively free from cardiotoxicity.

Topics: Animals; Antidepressive Agents; Arrhythmias, Cardiac; Body Temperature; Electrocardiography; Fluvoxamine; Heart; Heart Rate; Myocardial Contraction; Oximes; Rabbits