Promoter variation in the catechol-O-methyltransferase gene is associated with remission of symptoms during fluvoxamine treatment for major depression

We investigated the association between remission of depressive symptoms in fluvoxamine treatment and catechol-O-methyltransferase (COMT) gene. Sixteen SNPs in the COMT gene were investigated in 123 outpatients with major depression. Three single nucleotide polymorphisms located in the 5′ region were associated with remission in fluvoxamine-treated outpatients with moderate to severe depression.     

HPLC method for the determination of fluvoxamine in human plasma and urine for application to pharmacokinetic studies

A simple, specific and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the assay of fluvoxamine in human plasma and urine. The method was based on reaction of fluvoxamine with 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS) forming orange colored product. The fluvoxamine-NQ derivative was separated by isocratic reversed-phase HPLC and detected at 450 nm. The chromatographic conditions were as follows: Phenomenex C(18) (250 mm x 4.6 mm i.d., 5 microm) column, mobile phase consisting of acetonitrile/water (80:20 v/v) at a flow rate of 1 ml/min. Tryptamine was selected as an internal standard. The assay was linear over the concentration range of 5-145 and 2-100 ng/ml for plasma and urine, respectively. The limits of detection (LOD) were 1.4 and 1 ng/ml for plasma and urine estimation at a signal-to-noise (S/N) ratio of 3. The limits of quantification (LOQ) were 5 and 2 ng/ml for plasma and urine, respectively. The extraction recoveries were found to be 96.66+/-0.69 and 96.73+/-2.17% for plasma and urine, respectively. The intra-day and inter-day standard deviations (S.D.) were less than 1. The method indicated good performance in terms of specificity, linearity, detection and quantification limits, precision and accuracy. This assay was demonstrated to be applicable for clinical pharmacokinetic studies.     

氟伏沙明合并认知行为疗法治疗强迫症的研究

目的评价氟伏沙明合并认知行为疗法对强迫症的治疗效果。方法将符合中国精神障碍分类与诊断标准的55例强迫症患者随机分为治疗组和对照组,治疗组给予氟伏沙明合并认知行为治疗,对照组给予氟伏沙明治疗。应用临床疗效标准及耶鲁布朗强迫量表(Y-BOCS)定期评定,观察6个月。结果在治疗1、2、4个月和6个月末,治疗组疗效显著优于对照组,尤其对强迫行为疗效更好,具有极显著统计学意义(P<0.01)。结论氟伏沙明合并认知行为疗法联合治疗强迫症效果优于单用氟伏沙明治疗。     

黄连阿胶汤加味合并氟伏沙明治疗焦虑症患者60例临床观察

目的：探讨黄连阿胶汤加味合并氟伏沙明治疗焦虑症的临床疗效与副反应。方法：将焦虑症患者中医辨证为阴虚火旺,心肾不交型60例随机分为两组,对照组30例以氟伏沙明治疗,合用组30例,以黄连阿胶汤加味治疗。两组均以4W为一疗程。结果：治疗结束时,两组HAMA的评分均显著降低,更以合并黄连阿胶汤组明显,两组间副反应比较,合用组出现嗜睡、乏力、头晕、口干、胃肠道症,药物依赖均显著低于对照组,差异有显著性意义（P〈0．01）。结论：黄连阿胶汤加味治疗焦虑症患者可以显著提高疗效。     

Potentiation of morphine-induced conditioned place preference with concurrent use of amantadine and fluvoxamine by the intraperitoneal and intracerebroventricular injection in rat

In this study, the effect of concurrent use of fluvoxamine and amantadine on morphine-induced conditioned place preference (CPP) was investigated by the intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection in rat. The CPP paradigms took place on 6 consecutive days by using an unbiased procedure. Our results showed that i.p. injection of morphine sulfate (2.5–10 mg/kg) induced CPP in rat. On day 6, fluvoxamine (5 and 10 mg/kg, i.p.), and amantadine (5 and 10 mg/kg, i.p.) both increased morphine-induced conditioned place preference. Intracerebroventricular injection of fluvoxamine (10 μg/rat) and amantadine (10 μg/rat) were also increased morphine-induced conditioned preference significantly. Concurrent use of fluvoxamine (5 mg/kg, i.p.; 10 μg/rat i.c.v.) and amantadine (10 mg/kg, i.p.; 10 μg/rat, i.c.v.) potentiated morphine-induced conditioned preference significantly. Release of dopamine from neurons cause reinforcing behavior. Morphine produces reinforcement (reward) effect by activation of μ receptors which facilitated dopaminergic transmission through dopamine release. Fluvoxamine, a serotonin reuptake inhibitor, increase serotonin concentration in synaptic clefts, which is a potent stimulator of dopamine release. Amantadine also appears to work by increasing dopamine release from neuron. In conclusion, our results show that concurrent use of fluvoxamine and amantadine potentiate morphine-like effect on CPP through increasing dopaminergic transmission and this combination may simulate the rewarding effect of morphine and can be candidate for controlling the drug compulsive seeking in morphine dependent subjects.     

Rapid analysis of sertraline,fluvoxamine, and paroxetine in serum specimens by LC-MS-MS using a new polymer column

Three selective serotonin reuptake inhibitors (sertraline, fluvoxamine, and paroxetine) in human serum specimens were analyzed by liquid chromatography-tandem mass spectrometry using a new polymer column (Shim-pack MAYI-ODS), which enabled direct injection of crude biological samples without complicated pretreatments. Quantitation was made by mass chromatography for each product ion using dextromethorphan as internal standard. The recoveries of the three drugs from human serum were 29.2%–45.7% at 20 ng/ml and 52.0%–53.7% at 80 ng/ml. The regression equations showed good linearity for the three drugs in the range of 5–80 ng/ml. Each drug had a detection limit of 1–3 ng/ml. Thus, the present method of using a new polymer column is effective for rapid and sensitive analysis of both therapeutic and toxic levels of sertraline, fluvoxamine, and paroxetine in biological specimens.     

In-vitro and in-vivo evaluation of the drug-drug interaction between fluvoxamine and clozapine

The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P < 0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P < 0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P < 0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration. Received: 19 October 1998/Final version: 5 February 1999     

Psycho-neuro-immunological treatment of hepatocellular carcinoma with major depression - a single case report

Summary

A female patient, who was suffering major depression and advanced hepatocellular carcinoma (hepatoma), sought treatment in the Jozuka Mental Clinic. She was treated using a psycho-neuro-immunological approach. The treatments applied were psychotherapy, the antidepressant fluvoxamine, glycyrrhizinic acid and dehydroepiandrosterone (DHEA). Biochemical, endocrinological and immunological examinations were performed regularly. Improvement of liver function and reduction of α-fetoprotein were observed. The levels of DHEA, natural killer cell activity and cytokines (interleukines IL-2, IL-6, IL-12, interferon IFN-γ) were normalised. Now, more than two and a half years after her admission, the patient is still well and symptom-free. While this may be a case of spontaneous regression, the results suggest that a psycho-neuro-immunological approach to treating the patient's depression and cancer was helpful for her recovery.     

Fluvoxamine but not citalopram increases serum melatonin in healthy subjects – an indication that cytochrome P 450 CYP1A2 and CYP2C19 hydroxylate melatonin

Objective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P ₄₅₀ (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC_0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC_0–20 by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies. Received: 25 October 1999 / Accepted in revised form: 2 February 2000     

氟伏沙明在精神科的应用

作者主要综述氟伏沙明治疗抑郁症、焦虑障碍、躯体变形障碍的功效，并综述了其不良反应、药代动力学、剂量和药物相互作用。