Block by fluoxetine of volume-regulated anion channels.
1. We have used the whole-cell patch clamp technique to study the effect of fluoxetine, a commonly used antidepressant drug, on the volume-regulated anion channel (VRAC) in calf pulmonary artery endothelial (CPAE) cells. We also examined its effects on other Cl- channels, i.e. the Ca2(+)-activated Cl- current (I(Cl,Ca) and the cystic fibrosis transmembrane conductance regulator (CFTR) to assess the specificity of this compound for VRAC. 2. At pH 7.4 fluoxetine induced a fast and reversible block of the volume-sensitive chloride current (I(Cl,swell)), with a Ki value of 6.0+/-0.5 microM (n = 6-9). The blocking efficiency increased with increasing extracellular pH (Ki= 0.32+/-0.01 microM at pH 8.8, n = 3-9), indicating that the blockade is mediated by the uncharged form of fluoxetine. 3. Fluoxetine inhibited Ca2(+)-activated Cl(-) currents, I(Cl,Ca), activated by loading CPAE cells via the patch pipette with 1000 nM free Ca2+ (Ki= 10.7+/-1.6 microm at pH 7.4, n=3-5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a Ki value of 26.9+/-9.4 microM at pH 7.4 (n = 3). 4. This study describes for the first time the effects of fluoxetine on anion channels. Our data reveal a potent block of VRAC at fluoxetine concentrations close to plasma concentrations. The results suggest a hydrophobic interaction with high affinity between uncharged fluoxetine and volume-activated chloride channels. Ca(2+)-activated Cl- currents and CFTR are also blocked by fluoxetine, revealing a novel characteristic of the drug as a chloride channel modulator. (+info)
Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion.
There is now some evidence that major depression is accompanied by activation of the inflammatory response system. There is also some evidence that antidepressants may suppress the release of cytokines, such as interleukin-1 beta (IL-1 beta) and IL-6 by activated monocytes and IL-2 and interferon-gamma (IFN gamma) by activated T cells. This study was carried out to examine the effects of clomipramine, sertraline, and trazodone on the stimulated production of IFN gamma, a pro-inflammatory cytokine, and IL-10, a negative immunoregulatory cytokine. Whole blood of nine healthy volunteers was stimulated with PHA, 5 micrograms/mL and LPS, 25 micrograms/mL for 72 hr with and without incubation with clomipramine, 10(-6) and 10(-9) M, sertraline, 10(-6) and 10(-8) M, and trazodone, 10(-6) and 10(-8) M. All three antidepressants significantly reduced IFN gamma secretion, whereas clomipramine and sertraline significantly increased IL-10 secretion in culture supernatant. All three antidepressants significantly reduced the IFN gamma/IL-10 ratio. The results suggest that antidepressants, at concentrations in the therapeutical range, have negative immunoregulatory effects through inhibition of IFN gamma and stimulation of IL-10 release. (+info)
A cost-effective approach to the use of selective serotonin reuptake inhibitors in a Veterans Affairs Medical Center.
In light of the tremendous expansion in the number of selective serotonin reuptake inhibitors available to the clinician, the Pharmacy and Therapeutics Committee of the Denver Veterans Affairs Medical Center considered the advantages and disadvantages of fluoxethine, paroxetine, and sertraline, to determine which agent or agents would be carried on the formulary. The committed recommended sertraline as the preferred agent for the treatment of depression, panic disorders, and obsessive-compulsive disorders. The purpose of this retrospective study was to assess the economic outcome of that decision. The study population consisted of patients at the medical center who were receiving selective serotonin reuptake inhibitors during January through March of 1994 and those were receiving these agents between September 1995 and January 1996. The expanded collection period in 1995-96 was due to a relatively new medical center policy to offer 90-day fills on medication to reduce costs. The extended collection period assured a 100% sample of patients receiving these agents. The 1994 fluoxetine to sertraline dosage equivalency ratio was 20 mg:55.6 mg, based on average daily doses of fluoxetine and sertraline of 32.7 and 90.9 mg, respectively. The cost to the medical center for an average daily dose of fluoxetine was $1.86; sertraline cost $1.22 per day. The 1996 fluoxetine to sertraline dosage equivalency ratio (20 mg:51.3 mg) had not changed significantly since 1994, indicating that the dose of 20 mg of fluoxetine remained very close to a 50-mg dose of sertraline. The average daily doses of fluoxetine and sertraline (34.9 mg and 89.7 mg, respectively) were not significantly different than the 1994 doses. Only 33 patients had been prescribed paroxetine (average daily dose, 32.4 mg). On the basis of these values, the average daily cost of fluoxetine to the medical center was $2.01, compared with $1.18 for sertraline and $1.24 for paroxetine. This $0.83 per patient per day drug acquisition cost difference between fluoxetine and sertraline results in a drug cost reduction of $302,674 per year. (+info)
Course of antidepressant treatment with tricyclic versus selective serotonin reuptake inhibitor agents: a comparison in managed care and fee-for-service environments.
We compared course of treatment with tricyclic antidepressant drugs (TCADs) and selective serotonin reuptake inhibitors (SSRIs) to assess interactive effects of antidepressant type with payer type and patient characteristics. A nationwide sampling of adults (n = 4,252) from approximately equal numbers of health maintenance organization (HMO) and indemnity enrollees were prescribed no antidepressants for 9 months, and thereafter prescribed a TCAD or SSRI. Using a retrospective analysis of prescription claims, these cohorts of TCAD and SSRI utilizers were followed for 13 to 16 months after their initial antidepressant prescription. Outcome measures included (1) termination of antidepressant treatment before 1 month; and (2) failure to receive at least one therapeutic dose during treatment lasting 3 months or more. Rates of premature termination and subtherapeutic dosing were significantly higher for TCAD-treated than SSRI-treated patients, and for HMO than indemnity enrollees. The interaction of HMO enrollment and TCAD use was associated with particularly high rates. Excluding patients terminating in the first month, the proportions of TCAD and SSRI utilizers remaining in treatment over time were not significantly different. We conclude that SSRIs may provide advantages in treatment adherence and therapeutic dosing, particularly in environments with limited prescriber time. The first month of treatment may be especially critical in determining compliance. (+info)
Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers.
Using in vivo extracellular unitary recording, the effect of short term (2-day) and long-term (21-day) administration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine (10 mg kg(-1) day(-1), s.c. using osmotic minipumps) was examined on the spontaneous firing activity of locus coeruleus noradrenergic neurons. Long-term but not short-term treatment significantly decreased firing activity. Thus, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. The SSRI paroxetine therefore alters the activity of noradrenergic neurons with a delay that is consistent with its therapeutic action in depression and panic disorder. (+info)
d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.
Reduced serotonergic activity has been associated with impulsive aggression in personality disordered patients in metabolite and pharmacologic challenge studies. This study used positron emission tomography to explore whether reduced serotonergic function occurs in critical brain regions such as orbital frontal and cingulate cortex that, may play a role in modulating aggression. Six impulsive-aggressive patients and five healthy volunteers were evaluated for changes in regional glucose metabolism after administration of the serotonergic releasing agent d,l-fenfluramine (60 mg, p.o.) or placebo. Volunteers demonstrated increases in orbital frontal and adjacent ventral medial frontal cortex, cingulate, and inferior parietal cortex, whereas impulsive-aggressive patients showed no significant increases in glucose metabolism after fenfluramine in any region. Compared with volunteers, patients showed significantly blunted metabolic responses in orbital frontal, adjacent ventral medial and cingulate cortex, but not in inferior parietal lobe. These results are consistent with reduced serotonergic modulation of orbital frontal, ventral medial frontal, and cingulate cortex in patients with impulsive-aggressive personality disorders. (+info)
O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants.
The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, K(m) = 41 microM, and Ks 22901 microM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 microM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 microM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, -2C19, and -2D6. CYP2D6 was dominant with the lowest K(m), 23.2 microM, and highest intrinsic clearance (Vmax/K(m) ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and K(m) = 2504 microM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, -2C19, and -3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 microM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and -3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF. (+info)
Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study.
OBJECTIVES: The purpose of the study was to determine whether the well tolerated serotonin reuptake inhibitor paroxetine hydrochloride could prevent vasovagal syncope in patients resistant to or intolerant of previous traditional therapies. BACKGROUND: Serotonergic mechanisms play a major role in the processes leading to neurocardiogenic vasovagal syncope, and serotonin reuptake inhibitors have been reported to be effective in preventing refractory syncope. METHODS: Sixty-eight consecutive patients (26 men and 42 women, mean age 44.7+/-16.5 years) with recurrent syncope and positive head-up tilt test and in whom standard therapies with beta-adrenergic blocking agents, vagolytic, negative inotropic or mineral corticoid agents were ineffectual or poorly tolerated were referred for study. Patients randomly received either paroxetine at 20 mg once a day or a placebo. A head-up tilt test was then reperformed after one month of treatment, and the clinical effect was noted over a mean follow-up of 25.4+/-7.9 months. RESULTS: The response rates (negative tilt test) after one month of treatment were 61.8% versus 38.2% (p < 0.001) in the paroxetine and placebo groups, respectively. During follow-up spontaneous syncope was reported in six patients (17.6%) in the paroxetine group as compared to 18 patients (52.9%) in the placebo group (p < 0.0001). Only one patient (2.9%) asked to be discontinued from the drug for severe side effects. CONCLUSIONS: Paroxetine was found to significantly improve the symptoms of patients with vasovagal syncope unresponsive to or intolerant of traditional medications and was well tolerated by patients. (+info)