Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients

Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before comedication, plasma concentrations of fluvoxamine increased after administration of a tricyclic antidepressant, thus indicating bidirectional drug interactions. The inhibitory effects of fluvoxamine on the metabolism of classical antidepressants disappeared after discontinuation of concomitant fluvoxamine treatment within at least 1–2 weeks. The reported alterations in drug metabolism observed in depressed patients who were under fluvoxamine/tricyclic antidepressant comedication suggested that careful supervision and regular drug monitoring are necessary in such patients.This work contains results of the PhD-thesis of S. Härtter     

The antinociceptive effect of fluvoxamine

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 K_j-opioid receptor subtype (P<.005) and to a lesser extent, at the μ-, δ-, and K₁-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by a 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.     

Cardiovascular effects of fluvoxamine and maprotiline in depressed patients

In the choice of an antidepressant drug the clinician must often consider the presence of a cardiovascular comorbidity in depressed patients. In the present study the cardiovascular effects of fluvoxamine and maprotiline were compared in a double-blind trial in which the quantitative changes in ECGs were assessed before and during a 3-week treatment. A total of 33 patients (mean age 44 years; range 20–65 years) with major depressive disorder (RDC) who were free from clinically relevant organic diseases were investigated. After a 7-day wash-out period, a 3 week treatment phase was started with 200 mg daily of either fluvoxamine (n=18) or maprotiline (n=15). On days 0, 7, 14 and 21 a 12-lead standard ECG was performed and the drug plasma levels were determined. All ECGs were analysed in a blind fashion by an internist. Maprotiline caused a significant prolongation of the PR interval (P<0.001) and of the QRS interval (P<0.01) was well as an increase in heart rate (P<0.001). The QT_c interval was only tendentially prolonged (P<0.10) and the P-wave duration and T-wave amplitude were not affected by maprotiline. No significant changes in ECG parameters were observed during treatment with fluvoxamine; and there was a nonsignificant trend (P<0.10) for a lower heart rate during treatment. Blood pressure was not affected by treatment with either antidepressant. In both groups no significant correlations were found between ECG findings and the plasma levels of the drugs. Our results confirm that fluvoxamine in therapeutic dose causes no alteration in surface ECG regarding cardiac conduction and repolarization. Conversely, maprotiline caused a significant prolongation of atrioventricular and intraventricular conduction and a rise in heart rate. Although these effects were not clinically relevant in our sample of patients without overt heart disease, they should be taken into account when treating depressed patients with concomitant cardiac disease.     

氟伏沙明联合喹硫平治疗强迫症的对照研究

目的：比较氟伏沙明联合喹硫平与单用氟伏沙明治疗强迫症的疗效。方法：将58例首发强迫症患者随机分为实验组（氟伏沙明联合喹硫平）和对照组（单用氟伏沙明）各29例,两组氟伏沙明剂量均为200～300mg/d;实验组加用喹硫平100～300mg/d;疗程8周。以治疗前后耶鲁布朗强迫量表（Y-BOCS）、汉密尔顿焦虑量表（HAMA）减分率评价疗效。结果：8周末实验组显效率72.4%,对照组为44.8%,差异有统计学意义（χ2=4.549,P〈0.05）。实验组Y-BOCS评分由（22.1±3.1）分减至（10.3±2.6）分,HAMA评分由（12.6±2.1）分减至（7.1±2.7）分,两组治疗后Y-BOCS（t=6.432,P〈0.01）、HAMA（t=3.002,P〈0.01）评分比较,实验组下降更明显。结论：氟伏沙明联合喹硫平比单独使用氟伏沙明治疗强迫症效果更显著。     

齐拉西酮与氟伏沙明联合治疗难治性抑郁症的临床对照研究

目的探讨齐拉西酮与氟伏沙明联合治疗难治性抑郁症临床治疗效果。方法收集2010年5月～2011年5月来我院就诊的难治性抑郁症患者78例,随机分为对照组和观察组,每组39例。对照组患者单独给予氟伏沙明治疗,观察组患者给予齐拉西酮和氟伏沙明联合治疗,在治疗前和治疗后第2、4、6、8、10、12周采用HAMD、HAMA评定治疗效果,用TESS评定其副作用。结果观察组治疗第2周后HAMD、HAMA评分均显著降低;对照组治疗第4周后HAMD、HAMA评分显著降低。两组治疗第6周后HAMD评分、治疗第4周后HAMA评分比较差异有统计学意义（P〈0．05）。观察组治疗有效率明显高于对照组,两组不良反应发生率比较差异无统计学意义（P〉0．05）o结论齐拉西酮和氟伏沙明联合使用治疗难治性抑郁症效果较好,且不良反应的发生率较低,可以在临床推广应用。     

氟伏沙明对纤维肌痛综合征的疗效与安全性观察

目的：观察氟伏沙明治疗纤维肌痛综合征的疗效与安全性。方法：将60例门诊纤维肌痛综合征的患者,随机分为氟伏沙明组30例和安慰剂组30例。对照组治疗8周,氟伏沙明剂量50～150mg／d,采用汉密尔顿抑郁量表（HAMD）和汉密尔顿焦虑量表（HAMA）评价疗效。结果：54例完成了8周的临床观察,治疗后两组HAMD评分均有下降,氟伏沙明组评分明显低于安慰剂组。治疗后各个时间段评定（2、4、8周）两组的差异均具有统计学意义（P〈0．05）。治疗8周后氟伏沙明组HAMA评分明显低于安慰剂组（6．7±4．5,11．7±8．3,P〈0．01）,氟伏沙明组HAMD评分明显低于安慰剂组（10．5±6．5,19．8±6．9,P〈0．01）。8周的治疗中氟伏沙明组仅出现轻度不良反应。结论：氟伏沙明治疗纤维肌痛综合征的疗效较好,具有良好的安全性和耐受性。     

Photoisomerization of fluvoxamine generates an isomer that has reduced activity on the 5-hydroxytryptamine transporter and does not affect cell proliferation

Fluvoxamine, a selective serotonin re-uptake inhibitor, is used as antidepressant/anxiolytic. The presence of a C=N double bond in the structure of fluvoxamine implies the existence of two geometric isomers: E- (trans) and Z- (cis), and suggests the hypothetical susceptibility of the molecule to photoisomerization. Clinically effective fluvoxamine is in its trans form. UVB (ultraviolet light, class B, wavelength range 290–320 nm) irradiation of aqueous solutions of fluvoxamine generated a photoproduct, which was isolated and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS), and identified as the cis isomer of fluvoxamine. This cis-isomer lost capacity to inhibit serotonin uptake, suggesting that light exposure might reduce the clinical efficacy of fluvoxamine. Alternatively, the photoproduct could be used as an inactive isomer in the studies of antidepressant mechanisms. Recent proposal suggests that antidepressants increase neurogenesis in the adult brain, whereas either an inhibitory or a stimulatory action of antidepressants on [³H]thymidine uptake in vitro has been attributed to their interaction with serotonergic mechanisms. Lower concentrations (i.e., 2 μM) of fluvoxamine and fluoxetine (another selective serotonin re-uptake inhibitor) stimulated [³H]thymidine uptake in mature, but inhibited it in immature cultures of rat cerebellar granule cells; the photoproduct was ineffective. A high concentration of fluvoxamine (i.e., 20 μM) but not the photoproduct was toxic to both immature and mature cultures. We suggest that a mechanism sensitive to fluvoxamine photoisomerization might be involved in the action of antidepressants on cell proliferation.     

Antidepressant response and fluvoxamine plasma concentrations: a pilot study

The objective of this pilot study was to examine the relation between fluvoxamine (FVX) plasma concentrations, therapeutic response and side effects during a four-week treatment period. Twentytwo patients who met the DSMIV criteria for major depression received 100 mg FVX during the first 2 days of treatment and then 150 or 200 mg/day. No clear relationship between plasma concentrations and side effects was detectable. A relationship between plasma concentrations and clinical efficacy was detectable after 21 days but not after 28 days of treatment. These preliminary results indicate that therapeutic drug monitoring might be useful for patients treated with FVX.     

Low-dose fluvoxamine treatment of children and adolescents with pervasive developmental disorders: a prospective,open-label study

The objective of this study was to assess the efficacy and tolerability of low-dose fluvoxamine (1.5 mg/kg/day) in youngsters with pervasive developmental disorders (PDDs). This was a prospective, open-label trial that included 18 subjects with a mean age of 11.3 ± 3.6 years. Fourteen children (78%) completed the 10-week study. Premature discontinuation due to behavioral activation occurred in three participants. Although there was no response for the group as a whole, eight subjects (including all four females) were considered at least partial responders in intent-to-treat analyses. Neither pubertal status nor serotonin levels predicted clinical response. Fluvoxamine can be beneficial in the treatment of select children and adolescents with PDDs. Gender differences in selective serotonin reuptake inhibitor (SSRI) response warrant further investigation.