MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.     

气相色谱法测定马来酸氟伏沙明中有机溶剂残留量

目的: 建立了测定马来酸氟伏沙明中有机溶剂乙腈与甲苯残留量的顶空进样气相色谱方法.方法: 采用HP-5石英毛细管柱;载气为氮气;检测器为FID.结果: 方法回收率分别为101.6%,102.1%.最低检测量均为1.0μg.结论: 本方法可应用于测定马来酸氟伏沙明中有机溶剂乙腈与甲苯的残留量.     

Serotonin (5-hydroxytryptamine) glucuronidation in vitro : assay development,human liver microsome activities and species differences

1. The main purpose was to develop a high-performance liquid chromatography (HPLC)-based method to assay serotonin glucuronidation activity using liver microsomal fractions. Application of this method was then demonstrated by determining serotonin UDP-glucuronosyltransferase (UGT) enzyme kinetics using human liver microsomes and recombinant human UGT1A6. Interspecies differences were also evaluated using liver microsomes from 10 different mammalian species. 2. Incubation of liver microsomes with serotonin, UDP-glucuronic acid and magnesium resulted in the formation of a single product peak using HPLC with fluorescence and ultraviolet absorbance detection. This peak was confirmed as serotonin glucuronide based on sensitivity to β-glucuronidase and by obtaining the expected mass of 352 with positive-ion mass spectrometry. 3. Following a preparative HPLC isolation, the structure of this metabolite was established as serotonin-5- O -glucuronide by 1 H-NMR spectroscopy. 4. Enzyme kinetic studies showed apparent K m and V max of 8.8 ±0.3 mM and 43.4 ±0.4 nmoles min <1 mg <1 protein, respectively, for human liver microsomes, and 5.9 ±0.2 mM and 15.8 ±0.2 nmoles min <1 mg <1, respectively, for recombinant UGT1A6. 5. The order of serotonin-UGT activities in animal liver microsomes was rat > mouse > human > cow > pig > horse > dog > rabbit > monkey > ferret. Cat livers showed no serotonin-UGT activity. Heterozygous and homozygous mutant Gunn rat livers had 40 and 13%, respectively, of the activity of the normal Wistar rat, indicating a significant contribution by a rat UGT1A isoform to serotonin glucuronidation. 6. This assay provides a novel sensitive and specific technique for the measurement of serotonin-UGT activity in vitro.     

马来酸氟伏沙明治疗脑卒中后抑郁患者的对照研究

目的:比较马来酸氟伏沙明与阿米替林治疗脑卒中后抑郁患者的疗效和安全性。方法:符合诊断标准的脑卒中后抑郁患者共60例,随机分为两组,分别应用马来酸氟伏沙明和阿米替林治疗6周,采用汉密尔顿抑郁量表(HAMD)和副反应量表(TESS)于患者治疗前和治疗后2、4、6周分别评定疗效和不良反应,并于治疗前和治疗后2、4、6周分别检查患者血常规、肝功能、肾功能和心电图。结果:两组患者疗效无显著差异(P>0.05),马来酸氟伏沙明组和阿米替林组患者治疗后2、4、6周,HAMD评分均较治疗前显著下降(P均<0.01),两组患者间比较差异无显著性(P>0.05)。马来酸氟伏沙明组患者的不良反应较阿米替林组少而轻,两组间比较有统计学意义(P<0.01)。结论:马来酸氟伏沙明抗抑郁的作用显著,疗效与阿米替林相仿,患者的不良反应较阿米替林少且程度轻,具有良好的依从性和耐受性,可作为治疗脑卒中后抑郁首选药物。     

短程团体认知行为疗法联合氟伏沙明治疗强迫症患者的效果

目的:观察短程团体认知行为疗法联合氟伏沙明治疗强迫症患者的效果。方法:选取120例强迫症患者为研究对象,按照随机数字表法分为观察组与对照组各60例。对照组采用氟伏沙明治疗,观察组在对照组基础上联合短程团体认知行为疗法治疗,比较两组耶鲁-布朗强迫症量表(Y-BOCS)评分、临床疗效、汉密顿焦虑量表(HAMA)评分、汉密顿抑郁量表(HAMD)评分、汤旦林(TDL)生命质量量表评分和强迫信念问卷(OBQ-44)评分。结果:治疗后,两组Y-BOCS评分均低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05);观察组治疗总有效率为96.67%,明显高于对照组的81.67%,差异有统计学意义(P<0.05);治疗后,两组HAMA、HAMD评分均低于治疗前,且观察组明显低于对照组,差异有统计学意义(P<0.05);治疗后,两组TDL评分均高于治疗前,且观察组高于对照组,差异有统计学意义(P<0.05);治疗后,两组OBQ-44评分均低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)。结论:短程团体认知行为疗法联合氟伏沙明治疗强迫症患者可提高治疗总有效率和TDL评分,降低Y-BOCS、OBQ-44、HAMA和HAMD评分,效果优于单纯氟伏沙明治疗。     

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.     

CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine

Numerous neuropsychological studies have reported deficits in cognitive and attentional functioning in depressed patients. However, there are limited data available about unmedicated depressed patients and the effects of antidepressant treatment on attentional performance. In this study, a Continuous Performance Test (CPT) was employed to evaluate the attentional performance of depressed inpatients during a drugfree period (n=52) in comparison to healthy control subjects (n=73). After 4 weeks of double-blind treatment with imipramine (TCA) or fluvoxamine (SSRI) at adequate plasma levels the CPT performance was studied again. We found that the unmedicated patients had a significantly impaired performance on all CPT parameters (reaction time, omission errors and commission errors) in comparison to the controls. None of the CPT parameters correlated with the severity of the depression or the level of psychomotor retardation. However, the CPT performance in the patient group was significantly related to subjective mood state (depression, tension). Double-blind treatment with imipramine or fluvoxamine resulted in an improvement of the CPT performance. In the imipramine treatment group the mean reaction time decreased significantly, and after treatment with fluvoxamine a significant decrease of the mean reaction time and the number of omission errors was detected. Both antidepressants induced a significant improvement of clinical state, but we did not find a relationship between the altered CPT performance and the changes on the clinical scales. Future studies should investigate other mechanisms underlying the improved attentional performance after treatment.     

A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients

Objective To compare the efficacy of imipramine and fluvoxamine in inpatients from two centers suffering from a depressive disorder according to DSM IV criteria.Methods The study included 141 patients with a depressive disorder according to DSM IV criteria. After a drug-free and placebo run-in period of 1 week, patients were randomized to imipramine or fluvoxamine; doses of both drugs were adjusted to a predefined target blood level. Efficacy was evaluated 4 weeks after attaining predefined adequate plasma level.Results 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 (² 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 7 at the final evaluation.Conclusions In depressed inpatients imipramine is more efficacious than fluvoxamine. Both drugs were well tolerated by all patients.     

氯氮平与氟伏沙明合并治疗精神分裂症的研究

目的 研究氯氯平与氟伏沙明合并治疗精神分裂症时的疗效及副作用,为临床更加合理的用药提供依据.方法 选取符合CCMD-3诊断标准的,有需要合并应用氯伏沙明的症状的精神分裂症病人30例.单一应用氯氮平.逐渐调整剂量到200～250mg/D,稳定一周后于清晨6时采取患者肘静脉血测定血浆胰岛素、泌乳素水平.并于当日加用氟伏沙明50mg/D.在合并用药后的第4周清晨6时采取患者肘静脉血测定胰岛素、泌乳素水平.合并用药前后测定空腹血糖、血脂、肝功能、心电图.结果 合并用药前和合并用药第四周胰岛素、泌乳素异常人数之间无显著差异.合并用药前后空腹血糖异常、心电图异常(除心率)人数无显著差异.合并用药前后肝功能异常、血脂异常、心率异常人数有显著增多.结论 建议合并用药时在动态监测氯氮平浓度的情况下结合临床表现及时调整药物用量.合并用药后肝功能异常、心率异常、血脂异常人数有增加,程度较轻不影响治疗.     

Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers

Rationale: Spontaneous fluctuations in the size of the pupil in darkness are a recognised index of ”sleepiness”. Objective: To evaluate the effects of single oral doses of three antidepressants: reboxetine (4 mg), a selective noradrenaline reuptake inhibitor, fluvoxamine (100 mg), a selective serotonin reuptake inhibitor, and amitriptyline (100 mg), a tricyclic antidepressant of known sedative property, upon spontaneous pupillary fluctuations in healthy male volunteers (n=16). Methods: Using the recently developed pupillographic sleepiness test (PST), resting pupil diameter was recorded and two measures of pupillary fluctuations were obtained: total power obtained from a fast Fourier transform and spectral analysis, and the pupillary unrest index (PUI), a cumulative measure of changes in pupil size. Subjects also rated themselves on a battery of visual analogue scales for ”alertness”, ”anxiety” and ”contentedness”. Results: Resting pupil diameter was enhanced by reboxetine, but remained unaffected by the other two antidepressants. Amitriptyline, consistent with its sedative property, increased the total power of pupillary fluctuations and showed a tendency to increase PUI. These pupillary effects of amitriptyline were paralleled by reduced scores on the ”alertness”, ”contentedness” and ”anxiety” self ratings. Neither fluvoxamine nor reboxetine affected pupillary fatigue waves or subjective ratings of ”alertness”. Reboxetine caused a small reduction in subjectively rated ”anxiety”. Conclusions: The mydriatic effect of reboxetine may be due to noradrenaline reuptake blockade in the iris and/or in the central nervous system. The enhancement of pupillary fatigue waves by the sedative antidepressant amitriptyline, but not by the non-sedative antidepressants fluvoxamine and reboxetine, indicates that the PST is a suitable quantitative objective test for the detection of drug-induced changes in the level of arousal. Received: 9 July 1999 / Final version: 26 October 1999