Once daily flupenthixol in the treatment of elderly depressed patients: A multi-centre trial in general practice

Summary

Ninety-five elderly depressed patients were entered into an open trial of 0.5 to 1.0?mg flupenthixol dihydrochloride, as a single daily dose in the morning. Eighty-seven patients were treated and assessed for 14 days, 6 patients failed to attend follow-up appointments and 2 patients were withdrawn from the trial because of acute physical illness. After 14-days' treatment, a decrease in the severity of the illness was recorded on the Clinical Global Impression Scale in 77% of the patients, and statistically significant improvements were noted in the 5 individually rated symptoms of lowered mood, fatigue, tendency to weep, feelings of inadequacy and irritability. The number and severity of adverse effects recorded on a checklist decreased during the treatment period. The results suggest that flupenthixol is an effective antidepressant and is well tolerated by the elderly as a single daily dose.     

II. Functional Consequences of Intragastrically Administered Ethanol in Rats as Measured by the 2-[14C]Deoxyglucose Method: The Contribution of Dopamine

As outlined in the companion paper, many of the changes in functional activity produced by acute intragastric ethanol administration as determined by the quantitative autoradiographic 2-[¹⁴C]deoxyglucose method occur in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. In this study, a dopaminergic antagonist, flupenthixol, was used to determine the contribution of dopamine to the ethanol-induced increases in functional activity. To assess the ability of flupenthixol to block dopaminergic-induced increases in glucose utilization, it was first examined in conjunction with the indirect dopaminergic agonist methylphenidate. Pretreatment with flupenthixol significantly reduced methylphenidate-induced increases in glucose utilization in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. These findings indicate that this is an effective strategy for the determination of the neurochemical contributions to the changes in CNS functional activity. Flupenthixol pretreatment blocked many of the ethanol-induced increases in glucose utilization at the 0.25 g/kg dose, particularly in mesocorticolimbic and nigrostriatal structures. At the 1.0 and 2.0 g/kg ethanol doses, however, pretreatment with flupenthixol did not reverse the increases in glucose utilization in several brain regions, suggesting that dopaminergic activity is not responsible for the observed increases in glucose utilization and further, that these increases involve other neurotransmitter systems. In some regions, however, flupenthixol pretreatment resulted in augmented levels of glucose utilization above those rates produced by the administration of higher doses of ethanol alone. These findings suggest that the contribution of dopamine to the increases in functional activity are more complex at higher doses of ethanol.     

氟哌噻吨美利曲辛联合文娱作业疗法治疗脑卒中后抑郁的效果观察

目的 探讨氟哌噻吨美利曲辛联合文娱作业疗法治疗脑卒中后抑郁的临床效果.方法 按照随机数字表法将76例脑卒中后抑郁患者分为对照组及治疗组各38例,所有患者均接受常规疗法,治疗组在常规治疗基础上给予氟哌噻吨美利曲辛联合文娱作业疗法.用汉密尔顿抑郁量表（HAMD）评定两组的临床疗效.结果 治疗组4周末及8周末HAMD评分明显低于对照组（P＜0.05）.治疗8周后,治疗组临床疗效优于对照组（P＜0.05）.结论 氟哌噻吨美利曲辛联合文娱作业疗法治疗脑卒中后抑郁的疗效较好.     

氟哌噻吨美利曲辛联合质子泵抑制剂对伴焦虑抑郁的非糜烂性胃食管反流病的临床效果观察

目的探讨氟哌噻吨美利曲辛联合质子泵抑制剂(PPI)对伴焦虑抑郁的非糜烂性胃食管反流病(NERD)的疗效。方法采用汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)对2011年1月-2013年6月新疆医科大学第五附属医院收治的265例NERD患者进行心理测评,随机抽取80例伴焦虑抑郁的NERD患者分为A组和B组,每组40例,40例不伴焦虑抑郁的NERD患者为C组。A组予氟哌噻吨美利曲辛联合埃索美拉唑镁治疗,B组、C组只给予埃索美拉唑镁治疗,对比治疗前后反流性疾病诊断问卷(RDQ)、匹兹堡睡眠质量指数(PSQI)量表,以及HAMA、HAMD的评分。结果 RDQ问卷症状程度、频度总分、HAMA、HAMD、PSQI评分治疗前后差值三组间比较差异有统计学意义(F=46.93、42.64、37.36、39.73、21.35,P均0.05);A组治疗前后RDQ症状程度、频度总分的差值(分别为12.31±3.54、14.11±2.46)大于B组(5.62±3.45、5.30±2.13)(Post-hoc检验,P=0.032、0.025);A组治疗前后HAMA、HAMD、PSQI评分的差值(分别为10.23±4.31、10.22±3.32、7.10±4.02)均大于B组(分别为4.90±4.38、3.56±5.26、2.76±4.21)和C组(3.10±1.27、1.91±1.32、3.09±1.38)(Post-hoc分析,A组与B组比较,P=0.003、0.002、0.003;A组与C组比较,P=0.002、0.001、0.004)。结论氟哌噻吨美利曲辛联合PPI在治疗NERD躯体症状的同时,能显著改善伴焦虑抑郁的NERD患者的精神症状,其疗效优于单用PPI。     

Role of hypothalamic dopaminergic receptors in the control of lordosis behavior in the female rat.

The role of hypothalamic dopaminergic receptors in lordotic behavior was studied by infusing dopaminergic agents into either the medial preoptic area (MPOA), arcuate-ventromedial area (ARC-VM) or lateral hypothalamic area (LHA). Dopaminergic receptor stimulants, dopamine (DA) and apomorphine (APO), enhanced sexual receptivity when infused into the MPOA or ARC-VM in ovariectomized (OVX) rats primed with low doses of estrone. Under these conditions of low preinfusion receptivity (mean preinfusion $\text{L}\text{M}\text{=0.159}$), haloperidol (HALO), a dopaminergic receptor blocker, had no statistically significant effect upon lordotic behavior. Infusions of DA, APO, or HALO into the LHA also had no effect upon lordotic behavior in this model. A second experiment, in which OVX rats were primed with higher doses of estrone to maintain high preinfusion receptivity (mean preinfusion $\text{L}\text{M}\text{=0.869}$), was used to evaluate the effects of dopaminergic receptor blockade upon elevated sexual behavior. Using the second protocol, dopaminergic blockers, HALO and α flupenthixol, were observed to significantly depress lordotic behavior when infused into the MPOA and ARC-VM. In this model no alterations in sexual behavior were observed following MPOA or ARC-VM infusions of APO or the inactive stereoisomer of α flupenthixol, β fluqenthixol. Thus, the hypothalamic activation of dopaminergic receptors was shown to be stimulatory upon lordotic behavior. A third experiment was designed to evaluate the effects of dopaminergic receptor blockade upon luteinizing hormone-releasing hormone (LRH) enhanced lordotic behavior. In this protocol comparisons were made among the lordotic responses to MPOA and ARC-VM infusions of LRH, LRH with HALO and vehicle. Infusions of LRH into the MPOA and ARC-VM significantly enhanced lordotic behavior, whereas the addition of HALO to the LRH infusates abolished this response. It was proposed that hypothalamic dopaminergic receptor activation may contribute to the stimulatory effects of LRH upon lordotic behavior.     

Gender-related differences in pharmacological relapse prevention with flupenthixol decanoate in detoxified alcoholics

Summary ¶A study recently finished by our research group elucidated the effectiveness of flupenthixol decanoate (FLX) in maintaining abstinence in detoxified alcoholics. Flupenthixol decanoate is an established antipsychotic drug, which is well known for its mild antidepressant and anxiolytic activity as well as for its minimal sedation at low doses. It blocks dopamine binding at a number of receptor subtypes, primarily at D-1, D-2, D-3 and with less affinity at D4-receptors. It also affects serotonin binding at 5-HT2A and 5-HT2C receptors. In a double-blind placebo-controlled multicenter trial, 77 women and 204 men suffering from moderate or severe DSM-II-R alcohol dependence were randomly assigned to either 10mg FLX or placebo both injected every second week over a period of 24 weeks (treatment phase) succeeded by a medication-free 24-weeks follow-up period. In the overall analysis the number of patients relapsed after 24 weeks of treatment (=main criterion of efficacy) was significantly higher in the FLX treated group (85.2%) than under placebo (65.5%). However, when differentiating this result according to sex the analysis revealed a gender-related discrepancy: while male patients had an almost 4-fold higher risk to relapse under FLX than under placebo (OR=3.95) this risk was barely elevated for female patients (OR=1.51). A significantly negative outcome due to FLX treatment was restricted to male alcoholics solely. In conclusion, gender-related differences to pharmacological relapse prevention with FLX have probably contributed to a better treatment outcome in women than in men.Received February 3, 2003; accepted March 11, 2003 Published online June 26, 2003     

Pharmacokinetic studies on flupenthixol and flupenthixol decanoate in man using tritium labelled compounds

Two groups of 5 patients were given tritium labelled flupenthixol orally or tritium labelled flupenthixol decanoate in oil intramuscularly. The patients were schizophrenics, who had been treated with one of the two drugs for at least 6 months prior to the study. Blood samples were drawn from the patients at different times after administration. From the flupenthixol decanoate group was also drawn a sample of cerebrospinal fluid 11 days after administration. Total radioactivity was measured in serum and cerebrospinal fluid. After oral administration of flupenthixol peak concentrations were seen at 3–8 h after administration. After injection of flupenthixol decanoate the maximum values were found at 11 to 17 days after injection. A plateau with a duration of 2–3 weeks surrounded the maximum. The concentrations in the samples of cerebrospinal fluid were estimated to 29–55% of the corresponding serum values. The study indicates that the depot preparation given with intervals of 2–3 weeks can replace the normal oral flupenthixol treatment. In addition the study support the clinical impression of drug sparing effect seen when changing from oral tablet treatment to injection of the depot preparation. The discrepancies between the present study and the clinical impression of flupenthixol decanoate are discussed.     

Influence of flupenthixol and flupenthixol-decanoate on methylphenidate and apomorphine-induced compulsive gnawing in mice

-Flupenthixol and -flupenthixol decanoate were tested in mice against methylphenidate-induced stereotyped gnaw-compulsions. The effect of both -flupenthixol, and -flupenthixol decanoate disappeared 2 days after administration.In addition, the influence of -flupenthixol and -flupenthixol decanoate on the apomorphine-induced behaviour in mice was followed over a period of 12 days. Under these conditions apomorphine-induced compulsive gnawing was seen on the days on which the methylphenidate antagonistic effect had subsided.The apomorphine-induced compulsive gnawing seen in -flupenthixol and -flupenthixol decanoate pretreated animals could be antagonized by additional small doses of -flupenthixol given 2 h before apomorphine. The interference of the neuroleptic drugs with dopaminergic receptors is discussed.     

Long-term behavioural and biochemical effects following prolonged treatment with a neuroleptic drug (flupenthixol) in rats

The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14–18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here.     

Atypical neuroleptics increase self-administration of cocaine: An evaluation of a behavioural screen for antipsychotic activity

Several drugs have been shown to exert antipsychotic effects, yet they display an atypical profile with respect to standard neuroleptic drug screens. Low doses of traditional neuroleptics are known to increase self-administration of psychomotor stimulants; we sought to determine whether these atypical drugs would cause a comparable effect. Sulpiride, metoclopramide and thioridazine produced a dose-dependent increase in cocaine intake similar to that found for chlorpromazine, haloperidol, pimozide and flupenthixol. This effect was found to correlate (r=0.94) with daily clinical dose. Clozapine, however, produced a dose-dependent decrease in cocaine intake. The advantages and disadvantages of using this measure as a screening procedure for neuroleptic drugs are discussed.