米氮平替换三环类抗抑郁药治疗抑郁症对照研究

目的:了解米氮平替换三环类抗抑郁药(TCAs)治疗抑郁症的有效性和安全性.方法:将经TCAs足量治疗6周疗效好转及以下的抑郁症患者随机分为米氮平组和TCAs组.米氮平组渐停TCAs,渐加米氮平治疗;TCAs组继续使用TCAs治疗.采用Hamilton抑郁量表(HAMD)、大体评定量表(GAS)、临床疗效总评量表的病情严重程度(CGI-SI),分别于入组时,治疗1、2、4、8周末评定其病情变化;治疗中出现的症状量表(TESS)评定不良反应.结果:米氮平组治疗2周各量表评分即显著好转,TCAs组治疗4周HAMD、GAS评分有显著性好转,CGI-SI评分治疗8周末差异有显著性下降.米氮平组不良反应发生率显著少于TCAs组.结论:米氮平替换TCAs治疗抑郁症安全有效.     

Effect of flupenthixol on depression with special reference to combination use with tricyclic antidepressants

In an open, uncontrolled trial flupenthixol was administered to 45 patients with endogenous depression. The drug was markedly effective in eight patients, effective in nine patients, fairly effective in 12 patients, and ineffective or aggravating in 16 patients. Four patients showed transient manic symptoms. Dosage was 1–3 mg daily. In 36 patients flupenthixol was used in combination with previously administered tricyclic antidepressants, and in nine patients it was used alone. Clinical effect was quickly apparent. It appeared within 1 week in 63% and within 2 weeks in 93 % of subjects. Side-effects were observed in 13 patients: insomnia, five patients; slight extrapyramidal symptoms, nine patients. Sedative-hypnogenic effects were rarely seen. In 71 % of 17 patients in whom the drug was found to be markedly effective or effective, flupenthixol's influence on psychomotor retardation was particularly strking. Other clear benefits were relief of depressive mood, psychic anxiety, and agitation. It is recommended that flupenthixol is given, as supplementary medication, to patients (1) whose depressive symptoms other than psychomotor retardation have already improved with current tricyclic antidepressants, and (2) in whom, before antidepressant medication, psychomotor retardation is a principal feature.     

The complex binding of tricyclic antidepressants to rat brain: The case of nortriptyline

[3H]Nortriptyline (NT) binding to rat brain sections was characterized using saturation and competition experiments, quantitative autoradiographic localization and monoaminergic lesions. [3H]NT binding exhibits a saturable component in the nM range (high affinity binding). Final saturation is reached only in micromolar concentrations (low affinity binding). The high affinity binding sites of [3H]NT appear in areas rich in noradrenergic and serotonergic terminals, and are decreased by 6-OHDA and 5,7-DHT lesions, to an extent depending on the brain region and the relative density of noradrenergic and serotonergic terminals there. We conclude that [3H]NT binds with high affinity to both noradrenergic and serotonergic nerve terminals, and with low affinity to other yet uncharacterized entities. This complex binding pattern is compatible with the multiplicity of biochemical, physiological and behavioral effects of NT and tricyclic antidepressants in general.     

Effects of tricyclic antidepressants on human plasma levels of TSH, GH and prolactin.

Six healthy male volunteers were given chlorimipramine 25 mg t.i.d. or nortriptyline 25 mg t.i.d. in a randomized order of 7 days. Plasma samples were assayed for TSH, GH and prolactin before and after stimulation with TRH 200 microgram i.v. It was found that the tricyclic antidepressants did not exert any influence on plasma hormonal levels compared with no treatment conditions. Diminished TSH-responses following daily TRH injections were demonstrated in endogenously depressed and chronic schizophrenic patients. A decreased TSH-response was observed in healthy volunteers after a second TRH injection with an interval of 2 days between the TRH injections. A complete restoration of the TSH-response was obtained after an interval of 4 days.     

Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents

Obestatin has recently been discovered in the rat stomach. It is encoded by the ghrelin gene and has been claimed to be a functional opponent of ghrelin and to be the natural ligand of the GPR39 receptor. The latter could not be confirmed by Holst et al. (Endocrinology, 2006). Yet, in GPR39 knockout mice, gastric emptying is accelerated. We verified the effects of obestatin on gastric emptying and intestinal contractility in rodents. Gastric emptying was measured with the (14)C octanoic breath test in mice. In vitro, the effect of obestatin was studied on electrically stimulated and non-stimulated strips from the fundus and small intestine of mice and rats. Obestatin (60, 125, 250 nmol kg(-1)) did not affect gastric emptying parameters (T(half) and T(lag)) and did not inhibit the prokinetic effects of ghrelin. Mouse and rat intestinal and fundic smooth muscle strips did not respond to obestatin either in the absence or in the presence of electrical field stimulation. Obestatin (125 nmol kg(-1)) did not inhibit fasting-induced hyperphagia. Our results suggest that peripheral obestatin is not a satiety signal that plays a role in the regulation of gastric emptying and do not support the concept that obestatin is a physiological opponent of ghrelin.     

The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial.

Antidepressants are commonly prescribed for patients with functional dyspepsia. However, the effect of tricyclic antidepressants on satiation and gastric emptying remains unclear, and there are no data for tetracyclic compounds. To compare the effects of nortriptyline (maximum dose: 50 mg daily) and mirtazapine (30 mg daily) vs placebo on gastric emptying, gastric satiation and postprandial symptoms after a nutrient load in healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 14 days of nortriptyline (n = 13), mirtazapine (n = 13), or placebo (n = 14) in healthy volunteers. Validated methods were used to study gastric emptying ((13)C-octanoate) and satiation postnutrient drink test. The three arms were comparable with regard to age, gender, body mass index and hospital anxiety/depression scale. There were no statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared to placebo (P = 0.34). Maximum tolerated volume was similar on drug and placebo (P = 0.56). Aggregate symptom score 30 min postmaximum tolerated volume after nutrient drink challenge on placebo was 132 (+/-21), vs 165 (+/-21) on mirtazapine, and 126 (+/-21) on nortriptyline 50 mg respectively (P = 0.28). Tricyclic and tetracyclic antidepressant agents do not appear to have significant effects on gastric motor or satiation postnutrient challenge in healthy individuals at the doses tested.     

Oxytocin receptor expressed on the smooth muscle mediates the excitatory effect of oxytocin on gastric motility in rats

Abstract  The aim of this study was to localize oxytocin receptor (OTR) in the stomach and to investigate the effect of OT on gastric motility in rats. Western blot and immunohistochemistry methods were used to localize OTR in stomach. The motility of stomach was recorded in vivo (recording of the intragastric pressure), in vitro (recording of the contraction of muscle strips) and on isolated smooth muscle cells. OTR was expressed on cells of both circular and longitudinal muscle of stomach. Systemic administration of OT induced an early transient decrease and a subsequent increase on intragastric pressure. Devazepide (1 mg kg⁻¹, i.v.), a cholecystokinin-1 (CCK₁) receptor antagonist, completely abolished the transient response but did not influence the subsequent one. OT (10⁻⁹–10⁻⁶ mol L⁻¹) dose-dependently increased the contraction of the muscle strips of gastric body, antrum, and pyloric sphincter, and decreased the average cell length of isolated smooth muscle cells. Tetrodotoxin and atropine did not influence the effect of OT on muscle strips. Pretreatment with atosiban, an OTR antagonist, inhibited the spontaneous contraction of muscle strips and abolished the excitatory effect of OT on the muscle strips and the isolated cells. These results suggest that the OTR is expressed on the smooth muscle of the stomach and mediates excitatory effect of OT on gastric motility.     

文拉法辛与三环类抗抑郁药治疗抑郁症痊愈率的循证医学研究

目的　比较文拉法辛与三环抗抑郁药治疗抑郁症临床痊愈率的差异。方法　应用循证医学的Me-ta分析,采用固定效应模型(fixed effects model,FEM)法对符合标准的16项对照研究文献进行评价。结果　文拉法辛与三环抗抑郁药治疗抑郁症的临床痊愈率不同,差异有显著性(χ2=4.773,df=1,P<0.05);综合的ORs=1.36,95%CI为1.04~1.78。提示文拉法辛治疗抑郁症的临床痊愈率是三环抗抑郁药的 1.36倍。结论　治疗抑郁症,文拉法辛比三环抗抑郁药有更可靠的临床痊愈率。     

Effects of the Tibetan herbal formula Padma® Lax on visceral nociception and contractility of longitudinal smooth muscle in a rat model

Background The high prevalence of functional bowel disorders among the general population contrasts with the limited number of pharmacological treatment options for this condition. This has led to an interest for alternative therapeutic approaches. Padma® Lax is an herbal laxative on the basis of Tibetan formulas. Our aim is to examine the effect of Padma Lax (A) on visceral nociception in vivo and (B) on contractile activity of longitudinal smooth muscle of the lower gut in vitro and ex vivo. Methods (A) Visceral sensory function in response to colorectal distension was assessed by abdominal wall electromyography in male Wistar rats pretreated with Padma Lax. (B) Effects of Padma Lax on contractility of gut smooth muscles were studied both in vitro with superfusion of the agent and ex vivo following oral administration of the preparation. Activities were measured as area under the curve. Key Results (A) For visceral sensitivity, no differences were observed between the Padma Lax and the control group. (B) Proximal colon muscle strips of the Padma Lax pretreated group showed significantly lower spontaneous contractility ex vivo than controls. Cholinergic procontractile stimulation was reduced in Padma Lax pretreated group and in colon strips of naive rats when Padma Lax was superfused in vitro (all P < 0.05). Conclusion & Inferences Cholinergic mechanisms appear to be important in the modulation of rat proximal colon contractility of orally and directly applied Padma Lax. These findings help elucidate a potential mechanism of action of this herbal remedy which has undergone clinical testing in patients with constipation predominant irritable bowel syndrome.     

Long-term effects of tricyclic antidepressants on norepinephrine kinetics in humans

Summary. The nature of the discrepancy between short-term pharmacokinetic data (hours) on the one hand and long-term pharmacodynamic effects and the clinical latency of therapeutic amelioration on the other hand by tricyclic antidepressants is still unclear. A relapsed sensibilization of neuronal, immunologic, and endocrinologic systems by changes in receptor sensitivity has been proposed. However, the discrepancy may have a strong influence on many aspects of antidepressive therapy in humans. The aim of our study was to demonstrate long-term pharmacodynamic effects by single-dose antidepressive treatment in humans by measuring heart rate parameters in response to neurochemical parameters. 25 young healthy probands, divided into three treatment groups (amitriptyline, n = 10; clomipramine, n = 10; placebo, n = 5), were challenged by a noradrenaline infusion test at baseline and one and 21 days after a single dose of antidepressant. Heart rate and blood pressure as well as plasma levels of antidepressants and of noradrenaline and adrenaline were measured in response to noradrenaline infusion test. Noradrenaline infusion rate to reach an increase in blood pressure of RR > 30 mmHg was significantly decreased for both antidepressants on day 1. The same effect was true for the amitriptyline group on day 21. Furthermore, pretreated probands respond to antidepressants in a different way when compared to untreated probands. Like depressed patients under therapy they respond with a dramatic increase in sensitivity of the α1-adrenergic receptor. We could demonstrate that the long-term pharmacodynamic effects have a strong influence on antidepressive therapy. A prolonged pharmacodynamic effect influences further clinical studies as well as our thinking about adverse drug effects. In clinical studies, washout periods may be to short to overcome the benefits of a previous medication. Adverse drug effects are often seen during periods when drugs were changed. The negative effect may be due to an additional effect of both medicaments. Received May 15, 2000; accepted September 25, 2000     

Somatostatin receptor subtypes mediate contractility on human colonic smooth muscle cells

This study demonstrates the expression of functional somatostatin receptor (sstr) subtypes in human circular and longitudinal colonic smooth muscle cells (SMC). Native somatostatin (SS) and sstr subtype-specific analogues were used to characterize the sstr subtypes present in both cell types by contraction/relaxation studies. Qualitative and quantitative mRNA analysis and immunohistochemistry of sstr subtypes were also carried out. sstr subtype 2 mRNA was expressed in circular SMC, and various levels of subtypes 1, 2 and 3 mRNA were expressed in longitudinal colonic SMC. Native SS and each subtype-specific analogue exerted a modest, but significant, contraction, although inhibition of carbachol-induced contraction (relaxation) was the main effect on SMC from both layers. CH-288, a sstr subtype 1-specific analogue, and octreotide, a sstr subtype 2-specific analogue, were the most effective relaxant analogues on longitudinal and circular SMC, respectively. sstr subtypes display a distinct expression pattern on human colonic SMC; on circular SMC, subtype 2 is the only sstr, whereas sstr subtypes 1, 2 and 3 are expressed on human SMC isolated from the longitudinal layer. The contractile effects of SS are mediated through sstr subtype 2 and sstr subtype 1 on circular and longitudinal human colonic SMC, respectively.     

Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use

van Reedt Dortland AKB, Giltay EJ, van Veen T, Zitman FG, Penninx BWJH. Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Objective: The metabolic syndrome (MetSyn) predisposes to cardiovascular disease and diabetes mellitus. There might also be an association between the MetSyn and anxiety and depression, but its nature is unclear. We aimed to investigate whether diagnosis, symptom severity and antidepressant use are associated with the MetSyn. Method: We addressed the odds for the MetSyn and its components among 1217 depressed and/or anxious subjects and 629 controls, and their associations with symptom severity and antidepressant use. Results: Symptom severity was positively associated with prevalence of the MetSyn, [adjusted odds ratio (OR) 2.21 for very severe depression: 95% confidence interval (CI): 1.06–4.64, P = 0.04], which could be attributed to abdominal obesity and dyslipidemia. Tricyclic antidepressant (TCA) use also increased odds for the MetSyn (OR 2.30, 95% CI: 1.21–4.36, P = 0.01), independent of depression severity. Conclusion: The most severely depressed people and TCA users more often have the MetSyn, which is driven by abdominal adiposity and dyslipidemia.     

Modulation of rat brain alpha 2- and beta-adrenergic receptor sensitivity following long-term treatment with antidepressants

After 7 days of treatment with a variety of antidepressant drugs (desipramine, imipramine, clomipramine, nortriptyline, nialamide), both an increase in alpha 2-receptor density and a decrease in beta-receptor density were observed in the cerebral cortex but not limbic forebrain. However, mianserin caused a marked increase in alpha 2-receptors without any change in beta-receptors. Nisoxetine did not produce any change in these two adrenergic receptors. It is suggested that intrasynaptic norepinephrine is important but that, in addition, other factors may be involved in the increase in alpha 2-receptors induced by antidepressant drugs.     

Effects of colchicine and vinblastine on platelet contractility and release

Pre-incubation of normal platelet-rich plasma for 30 minutes at 37°C with concentrations of colchicine (2.5×10^?4M) or vinblastine (1.1×10^?4M) which disrupt platelet microtubles did not inhibit aggregation induced by ADP or collagen. Even following pre-incubation of platelets with a 10-fold higher concentration of colchicine (2.5×10^?3M), platelets released ¹⁴C-serotonin and aggregated in response to collagen. In the presence of a 10-fold higher vinblastine concentration (1.1×10^?3M), platelets lysed and released ⁵¹Cr. Dynamic viscoelastic measurements on recalcified platelet-rich plasma in a Weissenberg rheogoniometer demonstrated that neither colchicine (2.5×10^?4M to 5×10^?3M) nor vinblastine (1.1×10^?4M) interferes with the initiation, rate of generation, or extent of contractile force produced in platelet-fibrin clots. These results indicate that polymerized tubulin is not essential for collagen-induced release of platelet dense granule contents. In addition, intact tubulin polymers are not required to support the platelet surface configuration necessary for platelet-fibrin adherence and the platelet contractile events which result in platelet-fibrin clot retraction.     

The effect of Taraxacum officinale on gastric emptying and smooth muscle motility in Rodents

Background Taraxacum officinale (TO) is a traditional herbal medicine that has been widely used for abdominal illnesses. However, the efficacy and the mechanism of TO on gastric emptying (GE) and smooth muscle motility are unknown. Methods Ethyl acetate fraction (EA), n‐butanol fraction (BF), and aqueous fraction (AF) were prepared in succession from 70% ethanol extract (EE) of TO using solvent polarity chromatography. Phenol red meal was adopted to estimate GE in mice. A polygraph was used to measure the smooth muscle motility in rats. Key Results The percentage of GE was 48.8 ± 6.1% (vehicle control), 75.3 ± 6.5% (cisapride positive control), 68.0 ± 6.7% (EE), 53.3 ± 6.0% (EA), 54.1 ± 6.3% (AF), and 86.0 ± 6.5% (BF). Thus, BF was determined to be most effective in accelerating GE. This stimulatory effect of BF on GE was also supported by the observation that BF increased spontaneous contraction of gastric fundus and antrum and decreased the spontaneous motility of pyloric sphincter in vitro. Atropine blocked the stimulatory effect of BF on GE, whereas phentolamine and propranolol had no effect. Conclusions & Inferences BF seems to be a promising prokinetic agent. BF‐induced increase in the contraction of fundus and antrum contributes to an increase in the intra‐gastric pressure. BF‐induced decrease in the motility of pyloric sphincter contributes to a decrease in the resistance of food from the stomach to the small intestine. The acceleration of GE by BF is likely to be exerted through cholinergic stimulation.     

Effects of the selective serotonin reuptake inhibitor, fluoxetine, on regional gastric contractility.

Selective serotonin reuptake inhibitors (SSRIs) are increasingly used to treat a variety of disorders but have gastrointestinal side-effects. AIM: To determine the effects of the SSRI, fluoxetine, on gastric smooth muscle contractility. METHODS: Fundic, antral, and pyloric circular muscle contractility of guinea pig muscle strips were measured in vitro. Fluoxetine was added in concentrations from 0.1 nmol L(-1) to 100 mumol L(-1). Receptor antagonists were used to determine the neural pathways involved. RESULTS: Fluoxetine caused concentration dependent contractions, which were greatest in fundus compared with the antrum or pylorus. The contractile effects of fluoxetine in the antrum were reduced by tetrodotoxin, atropine, phentolamine, and the 5-HT(4) receptor antagonist GR 113808. The contractile effects of fluoxetine in the fundus were reduced by atropine, phentolamine, and GR 113808. CONCLUSIONS: Fluoxetine affects gastric contractility with regional variability - contracting the fundus more than the antrum or pylorus. The fluoxetine contractile effect is reduced by tetrodotoxin, atropine, phentolamine, and a 5-HT(4) receptor antagonist. These results suggest fluoxetine interacts with muscarinic, alpha-adrenergic, and serotoninergic receptors and/or ongoing reuptake/release of serotonin in the stomach.