Fluvoxamine In Patients Research Articles

Genetic Polymorphism in CYP2D6 and its Association with the Safety and Efficacy of Fluvoxamine in Patients with Major Depressive Disorder

Genetic Polymorphism in CYP2D6 and its Association with the Safety and Efficacy of Fluvoxamine in Patients with Major Depressive Disorder

Correction of Psychoemotional Disorders and Short-Term Prognosis in Patients with COVID-19.

This review discusses the importance of the main psychoemotional risk factors for the development of chronic noncommunicable diseases. Current data on the prevalence of anxiety and depressive disorders in patients with cardiovascular disease (CVD) are presented. Data on the relationship between the development of psychoemotional disorders and CVD are summarized and the prospects for managing such patients within the framework of interdisciplinary cooperation are discussed. The main pathogenetic mechanisms for the development of complications, including CNS damage in COVID-19, are considered. The significance of the selection of pathogenetic therapy for patients with comorbid somatic and mental diseases in the context of the COVID-19 pandemic is discussed. Results from multicenter placebo-controlled studies of the use of fluvoxamine in patients with COVID-19 of varying severity are addressed.

Difficulty in Repurposing Selective Serotonin Reuptake Inhibitors and Other Antidepressants with Functional Inhibition of Acid Sphingomyelinase in COVID-19 Infection.

The rapid spread of COVID-19 has become a health emergency causing an urgent need for drug treatments to control the outbreak, especially in more vulnerable individuals. This is reinforced by the fact that prophylactic vaccines and neutralizing monoclonal antibodies may not be fully effective against emerging variants. Despite all efforts made by the scientific community, efficient therapeutic options currently remain scarce, either in the initial, as well as in the advanced forms of the disease. From retrospective observational studies and prospective clinical trials, selective serotonin reuptake inhibitors (SSRIs), and other antidepressants with functional inhibition of acid sphingomyelinase (FIASMAs), have emerged as potential treatments of COVID-19. This has led to some prematurely optimistic points of view, promoting a large prescription of fluvoxamine in patients with COVID-19, that we think should be reasonably tempered.

Correction of psychoemotional disorders and short-term prognosis in patients with COVID-19

This review discusses the importance of the main psychosocial risk factors in the development of chronic non-communicable diseases. The current data on the prevalence of anxiety and depressive disorders in patients with cardiovascular diseases (CVD) are presented. The article summarizes information about the relationship between the development of psychoemotional disorders and CVD, discusses the prospects for the management of such patients in the framework of interdisciplinary cooperation. The main pathogenetic mechanisms of the development of complications, including damage to the central nervous system during infection with a new coronavirus infection, are considered. The significance of the choice of pathogenetic therapy for patients with comorbid somatic and mental diseases in the conditions of a pandemic of a new coronavirus infection is assessed. The results of multicenter placebo-controlled studies on the use of fluvoxamine in patients with a new coronavirus infection of varying severity are discussed.

Assessment of the impact of the steady state level of microRNA hsa-miR-370-3p concentration on the efficacy and safety profile of fluvoxamine in patients with depressive disorders disorder comorbid with alcohol use disorders

Fluvoxamine is used in therapy for patients with depressive spectrum disorders comorbid with alcohol addiction. At the same time, a large proportion of such patients do not respond properly to fluvoxamine therapy and many of them show dose-dependent adverse reactions. Previous studies have demonstrated that CYP2D6 participates in the fluvoxamine biotransformation and its activity depends on polymorphism of the encoding gene. The purpose of this study was to evaluate the effect of CYP2D6 genetic polymorphism on the efficacy and safety of fluvoxamine using data on CYP2D6 activity evaluated by the 6M-THBC/pinoline metabolic ratio, as well as data on CYP2D6 expression level obtained by measuring plasma concentration of hsa-miR-370-3p in patients with depressive disorders comorbid with alcohol use disorder. A group of 83 patients with depressive spectrum disorders comorbid with alcohol addiction demonstrated the effect of the 1846G > A polymorphism of the CYP2D6 gene (rs3892097) on the efficacy and safety of fluvoxamine. Unfortunately, hsa-miR-370-3p turned out to be not a valid marker for assessing the level of CYP2D6 expression, since its plasma concentration did not differ in carriers of different genotypes by 1846G > A polymorphic marker.

Оценка влияния активности CYP3A на профиль эффективности и безопасности флувоксамина у пациентов с депрессивными расстройствами, коморбидными с алкогольной зависимостью

Оценка влияния активности CYP3A на профиль эффективности и безопасности флувоксамина у пациентов с депрессивными расстройствами, коморбидными с алкогольной зависимостью

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and alcohol use disorder

This study is conducted to investigate the effects differences of escitalopram with or without combined electroacupuncture (EA) among male inpatients with a diagnosis of alcohol dependence and comorbid protracted alcohol withdrawal symptoms (PAWS).A total of 62 participants who met the inclusion criteria were enrolled in a two-arm randomized, placebo controlled, patients-blind trial and allocated to an escitalopram with real-EA group (real-EA group, patients= 31) and an escitalopram with sham-EA group (sham-EA group, patients= 31), respectively. In addition to the oral administration of escitalopram for total four weeks, patients in each group received corresponding EA treatment five days per week and two days off for consecutive four weeks. Both serum homocysteine (Hcy) test and electrophysiological tests, including event-related potentials (ERPs) and exploratory eye movement (EEM) were performed at pre- and post-treatment. Additionally, the global scores of Penn Alcohol Craving Scale (PACS), 17-items Hamilton Depression Rating Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) were used for assessing the subjective emotion experience of patients, respectively. Meanwhile, adverse effects were monitored and recorded.After four-week treatment, the global scores of PACS and HAMD-17 declined significantly in both groups (both P<0.05). Furthermore, the decline in the real-EA group was superior to that in the sham-EA group (P<0.05). Meanwhile, the total scores of HAMA only decreased in the real-EA group (P<0.05) but not in the sham-EA group (P>0.05). According to the parameters of ERPs, significant declines for N2PL, P3PL, and P3amp were observed in both two groups (all P<0.05), and the decreases for P3PL and P3amp in the real-EA group was much superior to that in the sham-EA group (both P<0.05). According to the parameters of EEM, significant increase for NEF was observed only in the real-EA group (P<0.05). Besides, there was a dramatic decline for serum Hcy level only in the real-EA group (P<0.05). One case in the sham-EA group withdrew from the trial due to self-reported nausea and bitter taste, and outcomes of the remaining 61 patients were adopted for analysis.(1) Escitalopram with EA may be a potential alternative therapy for mitigating PAWS among male inpatients with alcohol dependence. (2) Escitalopram with EA might improve the alcohol-dependence induced cognitive dysfunctions via upregulating the expression of Hcy.

Efficacy and tolerability of fluvoxamine in adults with social anxiety disorder: A meta-analysis.

No meta-analysis for estimating the comprehensive efficacy and tolerability of fluvoxamine in patients with social anxiety disorder (SAD) has been published. To investigate the efficacy and tolerability of fluvoxamine in adults with SAD, trials meeting the following criteria were identified: population: ≥18 years of age with a diagnosis of SAD; intervention: fluvoxamine; study design: placebo-controlled randomized controlled trials (RCTs); outcomes: efficacy and tolerability outcomes. We conducted a comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for RCTs on January 3, 2018. Review Manager 5.3 and Stata Version 12.0 software were used for all statistical analyses. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous variables, and odds ratios (ORs) with 95% CIs were calculated for dichotomous variables. Cochrane Collaboration's risk of bias tool was used to assess the likelihood of risk of bias. Efficacy was assessed by mean changes in the Liebowitz Social Anxiety scale (LSAS) total score and the Clinical Global Impression Severity of Illness (CGI-S) score as well as the response rate. Tolerability was mainly assessed by the discontinuation rate due to adverse events (AEs) and the incidence of most frequent treatment-emergent AEs (TEAEs). This meta-analysis included 5 RCTs. Mean changes in LSAS total and CGI-S scores were both significantly greater in patients treated with fluvoxamine than those treated with placebo (LSAS: MD = 11.90, 95% CI = 8.09-15.71, P < .001; CGI-S: MD = 0.52, 95% CI = 0.33-0.72, P < .001). Response rate was higher in fluvoxamine group as compared with placebo (OR = 1.71, 95% CI = 1.30-2.24, P < .001). Additionally, mean change in the Sheehan disability scale score was significantly greater in fluvoxamine group than placebo group (OR = 2.11, 95% CI = 1.03-3.18, P < .001). The discontinuation rate due to AEs was higher in patients that received fluvoxamine compared to those received placebo (OR = 5.99, 95% CI = 2.24-15.99, P < .001), as was the incidence of overall TEAEs (any AE) (OR = 2.66, 95% CI = 1.77-4.02, P < .001). However, the incidence of serious AEs was not significantly different between the 2 groups (OR = 0.99, 95% CI = 0.25-3.89, P = .99). Fluvoxamine was found to be effective in adult patients with SAD, with acceptable tolerability.

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

BackgroundFluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis.ObjectiveThe primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance.MethodsThe study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction.ResultsAccording to results of Mann–Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day).ConclusionThis study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

Evaluation of the Effect of Fluvoxamine in Patients With Schizophrenia Under Risperidone Treatment: A Clinical Trial.

The effectiveness of selective-serotonin reuptake inhibitors in the improvement of schizophrenia is a controversial issue. The aim of this study was to evaluate the effect of fluvoxamine on the symptoms of schizophrenia including positive and negative symptoms, cognitive impairment, and quality of life. This clinical trial was performed on 68 patients with chronic schizophrenia, treated with risperidone at 22 Bahman Hospital of Qazvin, Iran during 2015 to 2016. The patients were randomly divided into control and intervention groups (34 patients per group). The control group was treated with risperidone and biperiden, whereas the intervention group received fluvoxamine, besides risperidone, and biperiden. The participants completed the Wechsler Memory Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and the World Health Organization Quality of Life Scale, and the findings were statistically analyzed at baseline and postintervention (8 and 10 weeks). The mean ± SD Wechsler Memory Scale scores in the evaluated intervals (baseline, week 8, and week 10), respectively, were 70.58 ± 11.51, 70.76 ± 11.36, and 70.88 ± 11.40 in the control group and 74.76 ± 10.56, 77.76 ± 10.56, and 77.76 ± 10.73 in the intervention group (F = 126.73, P ≤ 0.001). The difference between the groups in terms of SANS and quality of life scores was significant in the specified intervals, SANS (F = 6.36, P = 0.004), and quality of life (F = 15.13, P ≤ 0.001). Nevertheless, no difference was observed in terms of Scale for the Assessment of Positive Symptoms scores (P > 0.05). The results indicated that risperidone augmentation with fluvoxamine could significantly improve cognitive impairments and negative symptoms among patients with schizophrenia. Moreover, this augmentation led to higher quality of life among these patients.

A drug-drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors.

Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1-3, FGFR 1-3, and PDGFR. This study was performed to investigate the potential drug-drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Non-smoking patients of ≥ 18years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300mg in 5days on/2days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Forty-five patients were enrolled; 24 were evaluable for drug-drug interaction assessment. Median age was 60years (range 30-85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration-time curve (AUC0-72h) and maximum concentration (C max) were 2880ng/mLh (47%) and 144ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC0-72h and C max were 8290ng/mLh (60%) and 259ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0-72h and C max (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug-drug interaction. Fluvoxamine co-administration resulted in a 80% increase in C max and a 188% increase in AUC0-72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.

Ondansetron or placebo in the augmentation of fluvoxamine response over 8 weeks in obsessive-compulsive disorder.

The aim of this study was to investigate the efficacy and safety of ondansetron as an augmentative agent to fluvoxamine in the treatment of patients with obsessive-compulsive disorder (OCD). Forty-six men and women, aged 18-60 years, who fulfilled the diagnostic criteria of OCD on the basis of the DSM-IV-TR and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21 were recruited into the study. The patients randomly received either ondansetron (8 mg/day) or placebo for 8 weeks. All patients received fluvoxamine (100 mg/day) for the first 4 weeks, followed by 200 mg/day for the rest of the trial. The patients were assessed using the Y-BOCS and the adverse event checklists at baseline, and the second, fourth, sixth, and eighth week. Forty-four patients completed the study. The Y-BOCS total score as well as the Y-BOCS obsession subscale score and compulsion subscale score showed significantly greater reduction in the ondansetron group than in the placebo group. There was no significant difference in adverse events between the two groups. In this 8-week double-blind randomized-controlled trial, ondansetron showed significant beneficial effect as an augmentative agent with fluvoxamine in patients with moderate to severe OCD and it was generally well tolerated.

Post-Marketing Surveillance of Fluvoxamine Maleate Used Long-Term in Patients with Social Anxiety Disorder in Japan

BackgroundNo data on the long-term ‘real-world’ use of fluvoxamine for the treatment of social anxiety disorder (SAD) in Japanese patients are currently available.ObjectiveTo evaluate the long-term safety and efficacy of fluvoxamine for SAD in the clinical setting.MethodsJapanese patients with SAD who initiated treatment with fluvoxamine were enrolled in this 53-week post-marketing survey from 407 institutions nationwide. Data including rates of adverse drug reactions (ADRs) and efficacy were collected. Overall improvement was assessed using the Clinical Global Impression for Improvement. SAD symptoms and treatment responses were assessed with the Japanese version of the Liebowitz Social Anxiety Scale.ResultsFrom the 1,974 patients surveyed, 1,790 and 1,504 patients were eligible for analysis of safety and efficacy, respectively. ADRs were reported in 18.2 % of patients, with nausea, somnolence, and constipation the most common. Over 50 % of these ADRs developed in the first 4 weeks of treatment. Serious ADRs were reported in 0.8 % of patients and included six cases of suicide attempt and three cases of suicidal ideation. Response to fluvoxamine was reported in 78.4 % of patients. In patients comorbid with depression, improvement in SAD symptoms with fluvoxamine treatment was significantly affected by clinical improvement in the depression.ConclusionsThese findings support the long-term safety and efficacy of fluvoxamine in patients with SAD. Most ADRs developed during the early treatment phase, and higher doses during the later phase were not associated with an increase in ADRs.Electronic supplementary materialThe online version of this article (doi:10.1007/s40801-014-0005-2) contains supplementary material, which is available to authorized users.

Serum proBDNF/BDNF and response to fluvoxamine in drug-naïve first-episode major depressive disorder patients.

BackgroundWe investigated the association between serum proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and response to fluvoxamine in patients with major depressive disorder (MDD) using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders.MethodsFifty-one patients with MDD (M/F, 19:32; age, 38 ± 19 years) and 51 healthy controls (M/F, 22:29; age, 34 ± 17 years) were studied using DSM-IV-TR: physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Serum levels of proBDNF and MDNF were measured by sandwich enzyme-linked immunosorbent assay (ELISA).ResultsSerum mature BDNF levels in the MDD patients were significantly lower than those in the healthy controls (t = 3.046, p = 0.0018). On the other hand, no difference was found in serum proBDNF between the MDD patients and the healthy controls (t = −0.979, p = 0.833). A trend of negative correlation was found between baseline serum BDNF and baseline scores of the 17 items of the Hamilton Rating Scale for Depression (HAMD17) (r = −0.183, p = 0.071). No correlation was however found between HAMD17 scores and proBDNF at baseline (r = 0.092, p = 0.421). Furthermore, no correlation was observed between baseline HAMD17 scores and baseline proBDNF/BDNF (r = −0.130, p = 0.190). No changes were observed in serum levels of proBDNF and BDNF during the treatment periods.ConclusionsThese results suggest that there is no association between serum proBDNF/BDNF and fluvoxamine response in MDD patients at least within 4 weeks of the treatment.

Granisetron Adjunct to Fluvoxamine for Moderate to Severe Obsessive-Compulsive Disorder

Several small studies have shown beneficial effects of ondansetron, a serotonin 5-HT(3) receptor antagonist, in the treatment of obsessive-compulsive disorder (OCD). The efficacy of other 5-HT(3) receptor antagonists in patients with OCD is still unclear. Granisetron does not alter cytochrome P450 activity and might have a lower risk of drug interactions, a longer duration of action and a better tolerability profile than other 5-HT(3) receptor antagonists. The objective of this study was to assess the efficacy and tolerability of granisetron augmentation of fluvoxamine in patients with OCD. This was a two-centre, randomized, double-blind, placebo-controlled, parallel-group study conducted from November 2011 to March 2012. The study setting was outpatient clinics of two large referral centres. Study participants were men and women, aged 18-60 years, who met the diagnostic criteria of OCD based on the DSM-IV-TR and who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21. Participants were randomly assigned to granisetron (Kytril(®); SmithKline Beecham, Philadelphia, PA, USA) 1 mg every 12 hours or placebo every 12 hours in addition to fluvoxamine for 8 weeks. Patients were assessed using the Y-BOCS at baseline, second, fourth, sixth and eighth weeks. The primary outcome measure was the difference in the score change of Y-BOCS total score from baseline to week 8 between the two groups. We also compared changes in the obsession and compulsion subscales of the Y-BOCS, and frequencies of partial response (≥25% reduction in Y-BOCS score), complete response (≥35% reduction in Y-BOCS score) and remission (Y-BOCS score ≤16) between the two groups. Of the 42 included patients, 39 (20 in the placebo group, 19 in the granisetron group) completed the study. Significant time X treatment interaction was observed for total Y-BOCS (F [2.097, 79.678] = 4.941, p = 0.009), obsession (F [2.337, 88.799] = 4.938, p = 0.006) and compulsion (F [2.050, 77.899] = 4.674, p = 0.012) subscales. By week 8, complete response and remission were achieved by 20 (100%) and 18 (90%) patients in the granisetron group and by 7 (35%) patients in the placebo group (p-value of Fisher's exact test <0.001, risk ratio (RR) [95% CI] = 3.857 [2.039, 7.297]). There was no significant difference in the tolerability between the two regimens. Granisetron is an efficacious adjunct for the short-term treatment of patients with moderate to severe OCD and is well tolerated. IRCT201202041556N32.

Cognitive Therapy versus Fluvoxamine as a Second-Step Treatment in Obsessive-Compulsive Disorder Nonresponsive to First-Step Behavior Therapy

Background: To compare the effectiveness of second-step treatment with cognitive therapy (CT) versus fluvoxamine in patients with obsessive-compulsive disorder (OCD) who are nonresponsive to exposure in vivo with response prevention (ERP). Methods: A 12-week randomized controlled trial at an outpatient clinic in the Netherlands comparing CT with fluvoxamine in OCD. Of 118 subjects with OCD treated with 12 weeks of ERP, 48 appeared to be nonresponders (Y-BOCS improvement score of less than one third). These nonresponders were randomized to CT (n = 22) or fluvoxamine (n = 26). The main outcome measure was the Y-BOCS severity scale. Statistical analyses were conducted in the intention-to-treat sample (n = 45) on an ‘as randomized basis’ and in the per-protocol sample (n = 30). Due to selective dropout in the fluvoxamine group, two additional sensitivity analyses were performed. Results: Complete data could be obtained from 45 subjects (94%) after 12 weeks. Fifty percent of the patients refused fluvoxamine after randomization compared to 13% who refused CT [χ²(1) = 7.10; p = 0.01]. CT as a second-step treatment did not appear to be effective in this sample of nonresponders. Fluvoxamine was significantly superior to CT in the intention-to-treat sample, in the per-protocol sample and in the two separately defined samples in which the sensitivity analyses were performed. Conclusions: OCD patients who are nonresponsive to ERP may benefit more from a switch to treatment with an antidepressant instead of switching to CT. In clinical practice, it may be important to motivate this subgroup of patients to undergo psychopharmacological treatment, as this may improve their outcome considerably.

Assay and therapeutic monitoring of fluvoxamine

A highly sensitive and reproducible method for assay of fluvoxamine in biological samples using HPLC combined with various detection methods (spectrophotometry and tandem mass spectrometry) was developed. These methods were completely interchangeable and correlation analysis demonstrated high consistency in the results obtained by different detection methods: the Pearson correlation coefficient was 0.982 (p < 0.0001) and the slope of the regression line was close to unity. The methods were suitable for routine therapeutic monitoring of fluvoxamine in patients’ serum.

Effects of Cigarette Smoking and Cytochrome P450 2D6 Genotype on Fluvoxamine Concentration in Plasma of Japanese Patients

Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiatric diseases. The aim of this study was to assess the clinical impact of cigarette smoking on plasma fluvoxamine concentration in Japanese patients, and evaluate whether the cytochrome P450 (CYP) 1A2 and CYP2D6 genotypes have effects on that concentration. Thirty-two Japanese patients receiving fluvoxamine were enrolled. They were maintained on the same daily dose of fluvoxamine (mean + or - S.D., 109.4 + or - 66.2 mg/d) for at least 4 weeks to obtain the steady-state plasma concentration. The steady-state plasma concentration-to-dose (C/D) ratio of fluvoxamine in patients who smoked (n = 6, 11.8 + or - 6.5 ng/ml/dose) was significantly lower than that in non-smoker patients (n = 26, 22.8 + or - 11.2 ng/ml/dose). There was no significant difference for the C/D ratio of fluvoxamine in patients with CYP1A2 -3860G/G, -3860G/A, and -3860A/A between non-smokers and smokers. Among non-smoker patients, the C/D ratios of fluvoxamine in those with one and two mutated alleles of CYP2D6 were 1.6- and 1.4-fold higher, respectively, than those with no mutated alleles, though the differences among those three genotype groups were not significant. Furthermore, stepwise multiple regression analysis revealed that cigarette smoking and daily dose had significant positive correlations with the plasma concentration of fluvoxamine. Our findings suggest that cigarette smoking has a significant impact on the steady-state plasma concentration of fluvoxamine in Japanese patients.

Treatment of bulimia nervosa with fluvoxamine: A randomized controlled trial

Bulimia nervosa (BN) is one of the most common eating disorders in industrialized societies. It has been suggested that reduced serotonin activity triggers some of the cognitive and mood disturbances associated with BN. For this reason, the pharmacologic treatment of BN consists mainly of selective serotonin reuptake inhibitors (SSRIs), which have been proven effective. At present, the physiologic bases of this disorder are not yet completely understood. We conducted a randomized controlled trial to verify the efficacy of the SSRI fluvoxamine in patients with a diagnosis of BN. Twelve female outpatients aged 21 to 34 years with a diagnosis of BN-binge purging (as defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM IV]) were randomly assigned to 2 treatment groups: the fluvoxamine 200 mg/day group and the placebo group. The patients underwent weekly clinical assessments for 12 weeks. At the end of the observation period, there was a statistically significant reduction in the number of binge-eating crises and purging episodes in the fluvoxamine group compared with placebo. In no case was treatment interrupted because of emergent side effects. These findings support the hypothesis that fluvoxamine is well tolerated and effective in reducing binge-eating crises and purging episodes in patients with BN.

Dose‐Dependent Alternations in the Pharmacokinetics of Olanzapine During Coadministration of Fluvoxamine in Patients With Schizophrenia

Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.