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Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), significantly potentiates analgesia when administered in animals together with opioids. The aim of the present study was to investigate the effects of fluvoxamine on sufentanil antinociception and tolerance. Following animal care committee approval, the effects of continuous infusions of fluvoxamine and sufentanil were studied in behavioural tests (hot-plate test, tail-flick test, catalepsy test) in Sprague-Dawley rats with a jugular vein catheter. Saline was administered as a control. The time-effect curves for continuous intravenous sufentanil indicate dose-related antinociception and rapid development of tolerance in the hot-plate and tail-flick tests. Co-administration of fluvoxamine with continuous sufentanil enhances antinociception and attenuates development of tolerance, most clearly seen in the tail-flick test. Fluvoxamine alone and saline were not effective. No animal showed catalepsy. As a side effect we observed a marked loss of body weight. The IC50 values of sufentanil binding with and without fluvoxamine addition are 0.56+/-0.17 nM and 0.3+/-0.15 nM, respectively, indicating no direct effect on the occupancy of sufentanil on the mu-receptor by this serotonin reuptake inhibitor. In conclusion, we were able to show that the combination of an opioid with an SSRI at low doses improves analgesia and decreases development of tolerance in nociceptive tests in rats. The clinical implications of these promising results in an animal model, however, await further investigation.
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Acute treatment with antidepressant drugs is known to increase the mean interresponse time (IRT) in the IRT > 72-s schedule of reinforcement. In order to examine the possibility that this effect may reflect an action of the antidepressants on timing processes, we tested the effects of two antidepressants, desipramine and fluvoxamine, on behaviour maintained under two other timing schedules in rats. In the fixed-interval peak procedure (fixed-interval 30-s), acute treatment with desipramine (8 mg kg-1) reduced response rate, whereas acute treatment with fluvoxamine (8 mg kg-1) increased it. Neither drug significantly altered the time to attainment of peak response rate or the Weber fraction. In the interval bisection task (standard durations 2 s and 8 s), the bisection point was not significantly altered by acute treatment with either drug. Chronic treatment with desipramine (8 mg kg-1 b.d.) had no effect on any of the indices of timing under either schedule. Chronic treatment with fluvoxamine (8 mg kg-1 b.d.) reduced the time to attainment of peak response rate but had no effect on the Weber fraction under the fixed-interval peak procedure, and did not alter the bisection point or Weber fraction under the interval bisection procedure. The failure of desipramine and fluvoxamine to increase the time to peak response rate or the bisection point at doses that significantly altered operant response rate suggests that the effect of these drugs on IRT schedule performance is unlikely to reflect an interaction with timing processes.
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Focal issues of recent research on obsessive-compulsive disorders have been the involvement of the frontostriatal system in the patho-physiology, as well as the manner of effect and efficacy of the serotonin reuptake inhibitors that unfold their specific efficacy in the frontostriatal system. The course of treatment among adolescent inpatients with obsessive-compulsive disorder was analyzed with regard to the medications used and their effects upon the course of treatment.
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We confirmed the effectiveness of behavior therapy and fluvoxamine for Japanese patients with OCD. Behavior therapy improved the condition of OCD patients more than fluvoxamine.
The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied.
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Objective. The clinical characteristics and response to pharmacotherapy of adult patients with early-onset and late-onset obsessive-compulsive disorder (OCD) were compared in this study. Methods. A total of 50 outpatients with OCD diagnosed according to DSM-IV criteria (early-onset: 20; late-onset: 30) were included in the study. After initial clinical evaluation with The Structured Clinical Interview for DSM-IV/Clinical Version (SCID-I/CV), The Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), all patients were treated with fluvoxamine, sertraline or paroxetine for 12 weeks. Treatment response was defined as a ≥35% reduction in the Y-BOCS-total scores from baseline in a 12-week follow-up period. Results. Forty-three patients (early-onset: 16; late-onset: 27) completed the study. The early-onset group had higher frequencies of symmetry/exactness obsessions and ordering/arranging compulsions, and the late-onset group had higher mean age at assessment. Nine (56.3%) patients with early-onset and 18 (66.7%) with late-onset responded to pharmacotherapy. The difference between response rates was not statistically significant. Conclusions. Our study suggests that although there are some phenomenological differences between patients with early-onset OCD and late-onset OCD, these patients have similar responses to pharmacotherapy.
During fluvoxamine use, the median of the total clearance of chloroguanide decreased in a statistically significant way from 1282 ml/min to 782 ml/min among the extensive metabolizers, whereas there was no change among the poor metabolizers. The partial clearance of chloroguanide by means of cydoguanil and 4-chlorphenylbiguanide formation among the extensive metabolizers decreased from 222 ml/min and 97 ml/min before to 33 ml/min and 11 ml/min during fluvoxamine intake, respectively. Among poor metabolizers the corresponding values were 35 ml/min and 7.6 ml/min before and 38 ml/min and 6.9 ml/min during fluvoxamine intake. For each metabolite clearance the change was statistically significant among the extensive metabolizers but not among the poor metabolizers. Both cycloguanil and 4-chlorphenylbiguanide formation clearances were statistically significantly higher among the extensive metabolizers than the poor metabolizers in period A but not in period B (phenocopy).
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The effects of the selective serotonin (5-hydroxytryptamine (5-HT)) reuptake inhibitor fluvoxamine, given alone or in combination with the benzodiazepine anxiolytic diazepam on the defensive freezing behavior of mice in the conditioned fear stress paradigm were examined. Fluvoxamine (5-20 mg/kg, i.p.) induced a dose-dependent reduction in freezing behavior. In contrast, while low doses of diazepam (0.125 and 0.25 mg/kg, i.p.) reduced the freezing behavior, such effects were not observed with high doses of diazepam (0.5 and 1 mg/kg, i.p.). In the combination study, fluvoxamine (20 mg/kg, i.p. ) did not reduce the freezing behavior in mice that had been pretreated with diazepam (0.125-1 mg/kg, i.p.). None of the doses of fluvoxamine and diazepam used in the present study had any effects on motor activity under non-stressed conditions. These results suggest that benzodiazepines may negatively influence the clinical efficacy of selective 5-HT reuptake inhibitors in the treatment of anxiety disorders.
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Of 122 outpatients with primary DSM-III-R-defined OCD originally enrolled in 2 randomized controlled trials, 102 patients (45 male/57 female; mean +/- SD age = 36.2 +/- 10.7 years; range, 19-64 years) were available to be assessed for the presence and severity of OCD and comorbid psychopathology at follow-up. Follow-up data were collected from November 1996 to June 1999.
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Obsessive-compulsive disorder (OCD) is a heterogenous disorder with different clinical presentations. The most common symptoms are those that involve contamination, possible harm, ordering/symmetry, aggressive/sexual/religious concerns and hoarding. A variety of less common symptoms have been described. Unusual OCD symptoms may lead to misdiagnosis, inappropriate treatment with possible serious side effects. In this report we present a case of an adolescent girl in which unusual OCD presentation and symptoms were misinterpreted to represent psychosis and exacerbation of OCD symptoms with risperidone and clozapine treatment. We discuss the possible pathophysiological mechanisms of OCD symptom exacerbation, clinical implications, and successful management of this case, with fluvoxamine therapy. This case may represent the first report of musical obsessions successfully managed with fluvoxamine therapy.
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Sigma1-receptors are an independent class of intracellular receptors which are implicated in the regulation of cell bioenergetics that suggest their involvement in different neuropsychiatric diseases. Sigma1-receptors regulate different ion channels, including calcium channels, NMDA-receptors, and are involved in the neurotransmitter release, neurogenesis and synaptogenesis. These receptors recognize with a different affinity a variety of ligands of different structural classes with different therapeutic applications. High affinity to sigma1-receptors may play an important role in the mechanism of action of some antidepressants, in particular fluvoxamine.
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A 79-year-old white woman was admitted for suicidal thoughts. Her medical history included depression, chronic obstructive pulmonary disorder, asthma, hypertension, atrial fibrillation with pacemaker placement, and breast cancer with lumpectomy and subsequent left mastectomy. Her medication list prior to admission was extensive, including warfarin 5 mg on Sunday, Monday, Wednesday, and Friday; warfarin 2.5 mg on Tuesday, Thursday, and Saturday, and citalopram 10 mg/d. Citalopram was changed to fluvoxamine during her hospital stay. This resulted in an elevated INR that persisted for approximately 7 days.
Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1,000 nmol/L)for muscarinic, histaminergic H1, adrenergic alpha1, and dopaminergic D2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL72 test.
To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy.
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In vivo microdialysis was performed in conscious rats that underwent OBX or sham surgery. Alterations in the functioning of the serotonergic system were assessed by administration of fluvoxamine, fenfluramine, and 3-hydroxybenzylhydrazine (NSD-1015). Animals were also repeatedly tested in an open field.
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The mean age of the study group (47 males, 94 females) was 51.8 (range 19-65) years. Of these 141 patients, 56 had episode duration longer than 1 year, 48 had mood congruent psychotic features, and 138 patients received medication. Seven patients did not complete the medication trial. The total number of patients using concurrent medication was 12/138 (8.6%). On the primary outcome criteria patients on imipramine improved significantly better on the change of illness severity score of the CGI (chi2 exact trend test=4.089, df=1, P=-0.048). There was no significant difference in 50% or more reduction on the HRSD, the other primary outcome criterion. On the secondary outcome criteria the mean reduction of the HRSD scores was significantly larger in the imipramine group than in the fluvoxamine group (mean difference=3.1, standard error (SE)=1.4, t=2.15, df=136, P=0.033). There was no significant difference in the number of patients with an HRSD < or =7 at the final evaluation.
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Meta-analytic reviews of placebo-controlled studies for obsessive-compulsive disorder have found that clomipramine is more effective than drugs with more selective actions on serotonin reuptake, whereas in most direct comparisons, clomipramine's superiority has been less obvious. The authors used metaregression to identify sources of he-terogeneity in placebo-controlled trials of clomipramine, fluvoxamine, sertraline, and paroxetine. They evaluated such patient characteristics as age, gender, age of obsessive-compulsive disorder (OCD) onset, and baseline severity of OCD and depression, and such study characteristics as exclusion or inclusion criteria, length of single-blind prerandomization period, length of trial, number of subjects, and publication year. We found considerable heterogeneity across studies that was associated, in part, with publication year, length of single-blind prerandomization period, length of trial, and severity of patients' OCD. The apparent superiority of clomipramine persisted after controlling for these factors. The authors also confirmed previous reports that placebo response is higher in more recent studies. Meta-analyses can help characterize responders and nonresponders. The authors urge investigators to provide summaries of patient characteristics, especially baseline severity, age at onset, and duration of OCD, by patients' response.
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In this prospective, open-label study, 63% of BDD subjects responded to fluvoxamine. Delusional and nondelusional subjects had similar improvement in BDD symptoms. In addition, insight significantly improved in both delusional and nondelusional subjects. Baseline BABS scores did not contribute significantly to endpoint BDD-YBOCS scores in a regression analysis.
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Anxiety disorders are relatively common psychiatric illnesses in children and adolescents. In young people, such disorders are likely to show severe outcomes and adversely impact on multiple aspects of personality and social integration.
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The authors conducted a study in order to evaluate the antinociceptive effects of the serotonin-selective reuptake inhibitor (SSRI) antidepressant fluvoxamine and its interaction with various opioid receptor subtypes. Male ICR mice were tested with a hotplate analgesia meter. Fluvoxamine elicited antinociceptive effect in a dose-dependent manner following i.p., i.t. and i.c.v. injection. Naloxone 10 mg/kg s.c. did not abolish the fluvoxamine antinociceptive effect. At the next stage fluvoxamine was administered together with various agonists of opioid receptors. When administered together with opiates, fluvoxamine significantly potentiated analgesia at the kappa(3)-opioid receptor subtype (P < .005) and to a lesser extent, at the mu-, delta-, and kappa(1)-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by non-opioid mechanism of action. These results suggest a potential role for fluvoxamine in the management of pain when co-administered with opioids at low doses.
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Twenty OCD outpatients of both sexes who were already taking fluvoxamine (mean dose ± SD: 216.7 ± 86.2) for at least 4 weeks were included in the study. The severity of OCD was assessed by means of the Yale-Brown obsessive-compulsive scale (Y-BOCS). The fluvoxamine plasma levels were measured by high-performance liquid chromatography analysis. All evaluations were performed after 4 weeks (t1) and 6 months (t2) of fluvoxamine intake.
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Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide.
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The etiology and optimum treatment of panic disorder remain unclear. Imipramine and alprazolam are reasonably well established treatments. Several reports have suggested that serotonin reuptake inhibitors may also be effective for this condition. To investigate this issue, 27 published or presented placebo-controlled, double-blind studies of DSM-III or DSM-III-R panic disorder were subjected to meta-analysis. The serotonin reuptake inhibitors included paroxetine, fluvoxamine, zimelidine, and clomipramine. The standard treatments were imipramine or alprazolam. All three treatments were highly significantly superior to placebo in alleviating panic. The serotonin reuptake inhibitors were also significantly superior to both imipramine and alprazolam. The superiority of the serotonin reuptake inhibitors remained, but was less pronounced, when they were compared to the studies which used higher doses of imipramine or alprazolam. These findings underscore the importance of serotonin reuptake inhibitors in the treatment of panic disorder and indirectly add to the evidence that serotonergic abnormalities may have a role in its etiology.
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Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective class of drugs for treatment of depressive and obsessive-compulsive disorders. Among this class of drugs, pharmacodynamic actions, antidepressant efficacy and adverse effect profiles are remarkably similar. However, pharmacokinetic profiles of SSRIs are substantially different especially with respect to pharmacokinetically mediated drug-drug interactions. For example, fluoxetine and paroxetine produce clinically significant inhibition of cytochrome P450 2D6 at their usually effective antidepressant dose, whereas citalopram, fluvoxamine or sertraline do not. There is also a substantial difference between SSRIs with respect to their capacity to inhibit other cytochrome P450 enzymes including IA2, 2C19, 3A4 and possibly 2C9/10. The inhibition of these enzymes can reduce the clearance of concomitantly administered drugs which are dependent on oxidative metabolism mediated by these enzymes as a necessary prerequisite for their subsequent elimination. The accumulation of unusually high levels of such drugs can result in an increase in nuisance and/or more serious, even life-threatening, adverse effects depending on the pharmacology of the co-prescribed drug. Knowledge of these issues will enable clinicians to predict and make appropriate dose adjustments to avoid potential drug-drug interactions that otherwise could result in toxicity.
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An original HPLC-UV method has been developed for the simultaneous determination of the atypical antipsychotic quetiapine and the geometric isomers of the second-generation antidepressant fluvoxamine. The analytes were separated on a reversed-phase C8 column (150 mm x 4.6mm i.d., 5 microm) using a mobile phase composed of acetonitrile (30%) and a 10.5mM, pH 3.5 phosphate buffer containing 0.12% triethylamine (70%). The flow rate was 1.2 mL min(-1) and the detection wavelength was 245 nm. Sample pretreatment was carried out by an original solid-phase extraction procedure using mixed-mode cation exchange (DSC-MCAX) cartridges; only 300 microL of plasma were needed for one analysis. Citalopram was used as the internal standard. The method was validated in terms of linearity, extraction yield, precision and accuracy. Good linearity was obtained in plasma over the 5.0-160.0 ng mL(-1) concentration range for each fluvoxamine isomer and over the 2.5-400.0 ng mL(-1) concentration range for quetiapine. Extraction yield values were always higher than 93%, with precision (expressed as relative standard deviation values) better than 4.0%. The method was successfully applied to human plasma samples drawn from patients undergoing polypharmacy with the two drugs. Satisfactory accuracy values were obtained, with mean recovery higher than 94%.
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It has been suggested that increased platelet activation increases the risk of acute myocardial infarction (AMI) in patients with depression. Selective serotonin reuptake inhibitors (SSRIs) may attenuate platelet activation by serotonin depletion in platelets. Observational studies have shown discrepant results of AMI risk associated with the use of SSRIs.