Differential effects of the 5-HT2 receptor antagonist on the anti-immobility effects of noradrenaline and serotonin reuptake inhibitors in the forced swimming test

The effects of the 5-HT(2) receptor antagonist, LY 53857 on the effects of noradrenaline and serotonin reuptake inhibitors were investigated using the forced swimming test. LY 53857 enhanced anti-immobility effects of clomipramine and maprotiline, which can inhibit reuptake of noradrenaline. However, LY 53857 did not affect the immobility time of mice treated with the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine. These results suggest that antagonism of the 5-HT(2) receptor leads to potentiation of the antidepressant effects of noradrenaline reuptake inhibitors but not SSRIs and that LY 53857 may modify the activity of noradrenergic neurons.     

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD₁₇), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD₁₇ total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.     

中药联合抗抑郁剂治疗早泄50例临床研究

目的：探讨中药联合小剂量抗抑郁剂治疗早泄的疗效。方法：采用分组对照的研究方法，对符合诊断标准的150例早泄患者按其意愿分为3组，每组50例。Ⅰ组给予知柏固精汤，Ⅱ组给予盐酸舍曲林，Ⅲ组给予知柏固精汤合盐酸舍曲林，均连续用药4周，分别观察患者用药前后的射精潜伏期、夫妻对性生活的满意程度和药物副作用。结果：治疗后3组患者射精潜伏期均明显延长，对性生插的满意程度均明显提高（P〈0．01），且Ⅲ组疗效优于另外两组（P〈0．01）。结论：知柏固精汤联合小剂量盐酸舍曲林治疗早泄疗效显著，明显优于单纯应用知柏固精汤或盐酸舍曲林治疗，是一种治疗早泄的有效方法。     

我国部分精神科医生关于抗抑郁治疗与转躁认识的初步调查

目的：了解我国精神科高级职称医生对双相抑郁治疗过程中抗抑郁药物与躁狂转化的认识。方法：自编与双相抑郁治疗有关的因素评价表让全国各地的专科医生根据自己的经验进行选择。结果：调查信回收率70％，有56位医生回答了全部问题。医生认为，使用抗抑郁药物(94．6％)、联合多种抗抑郁药物(64．2％)、不同时应用心境稳定剂(50．9％)与双相抑郁治疗过程中引发躁狂有关。结论：我国精神科高级职称医生对双相抑郁治疗过程中药物引起躁狂发作的认识比较全面。     

Rolipram, an Antidepressant That Increases the Availability of cAMP, Transiently Enhances Wakefulness in Rats

A study was carried out on the effects on sleep of rolipram, an antidepressant that increases the availability of cAMP by inhibiting a phosphodiesterase isoenzyme. Rats were treated with rolipram (0.1 or 1 mg/kg) twice a day (at light and dark onset) for 11 days, after a chronic period of injection of physiological saline for habituation purposes. The sleep–wake activity was recorded for 12 h following the injection at light onset on the baseline day (physiological saline), on rolipram days 1, 5, and 11, and also on day 12, when physiological saline was injected again (withdrawal day). The high (1 mg/kg) dose of rolipram enhanced wakefulness (W) in postinjection h 1 on day 1 of rolipram treatment. After administration of 0.1 mg/kg rolipram, only a tendency to an increase in W was noted. The promotion of W might be attributed, at least in part, to an increased release of noradrenaline due to a cAMP-mediated stimulation of tyrosine hydroxylase.     

Inhibition of noradrenaline stimulated increase in [Ca]i in cultured astrocytes by chronic treatment with a therapeutically relevant lithium concentration

Chronic treatment of mouse astrocytes in primary cultures with 1 mM lithium chloride for 7–14 days decreased the basal level of free cytosolic calcium concentration ([Ca²⁺]_i) from 50–70 nM to 70% of this value and reduced the increase in [Ca²⁺]_i caused by exposure to 1 μM noradrenaline (normally to 500–700 nM) by almost one half. A similar, but much smaller, response to serotonin was unaffected by chronic treatment with lithium. Acute exposure to lithium (30 min) had no effect on either basal or noradrenaline stimulated [Ca²⁺]_i The dependence on chronic, versus acute treatment suggests that this effect may be related to the therapeutic effect of lithium as a mood-stabilizing drug, which likewise requires chronic treatment. Since good evidence is found that noradrenaline increases [Ca²⁺]_i by activation of the phosphoinositol second messenger system the present findings are also consistent with literature data that lithium acts by interfering with this system.     

A quantitative approach to the initial clinical trial of tricyclic antidepressants: A comparison of Leo 640 and nortriptyline

Summary This report describes a phase I clinical trial of a new tricyclic imipramine analogue (Leo 640) with a hydrogen atom in one of the N-methylgroups substituted by a p-chlorobensoyl. To get an objective assessment of the effects of Leo 640 we utilized the fact that tricyclic antidepressants inhibit the uptake of tyramine (thereby blocking its indirect sympathomimetic effects) and noradrenaline into peripheral adrenergic nerves. Dose-response (systolic pressor effects) curves for tyramine (TA) were established before and during treatment with Leo 640. Adrenergic nerves from the rat iris were incubated in the patient's plasma drawn immediately before the TA tests. The inhibitory effect of the endogenous plasma level of Leo 640 (and/or its metabolites) on the uptake of³H-noradrenaline (³H-NA) in these nerves was then determined. — Leo 640 was given orally in successively increasing doses (up to 1.1–5.6 mg/kg/day) to fifteen patients with various forms of depression. The duration of treatment was usually 3–4 weeks. Leo 640 caused a blockade of TA- pressor responses. Plasma of all treated patients inhibited the uptake of³H-NA in the rat iris. The results in the two tests were reasonably well correlated (p<0.01). — The results in the TA- and rat-iris tests were compared with those obtained with nortriptyline (NT) in the same dose-range in nine other patients. In comparison with NT, Leo 640 had a more pronounced inhibitory effect on TA-responsesin vivo than of³H-NA uptake in adrenergic nervesin vitro. A possible explanation might be that Leo 640 has an -receptor blocking effect. — For both Leo 640 and NT, poor correlations were found between the doses (mg/kg) used and the objective effects, when different patients were compared, probably due to marked interindividual differences in pharmacokinetics. — It is concluded that the dose-range of Leo 640 should be similar to that of NT in terms of the effects onperipheral adrenergic neurons.A preliminary account of this paper has appeared (Siwerset al. 1969).     

Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Rationale Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants. Objectives We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(−)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters. Results F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC₅₀=1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED₅₀=530.3 μg/kg i.v.), an effect completely abolished by the 5-HT_1A antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED)=10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED₅₀=2 mg/kg) and reduced the immobility in the tail suspension test (MED=10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg⁻¹ day⁻¹, p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine. Conclusions F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities. A preliminary report of this work was presented at the 30th Annual Meeting of the Society for Neuroscience, New Orleans, LA, 2000.     

Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial

Rationale There is a need for new pharmacological treatments for generalized social anxiety disorder (GSAD), which is a common, often disabling condition.Objective To compare the efficacy and safety over 6 months duration of two dose ranges of venlafaxine extended-release (ER) with placebo in patients with GSAD.Method Twenty-eight-week, double-blind, multi-center study in 386 adult outpatients with DSM-IV GSAD. Patients were randomized to placebo, venlafaxine ER fixed low dose (75 mg/day), or venlafaxine ER flexible higher dose (150–225 mg/day). Primary efficacy variable was change on the Liebowitz Social Anxiety Scale (LSAS). Secondary efficacy variables included, among others, the proportion of responders on the CGI Global Improvement Item (score 1 or 2), and the proportion of remitters (defined as an LSAS score of 30).Results Improvement on the LSAS was greater with venlafaxine ER (at 75 mg/day or 150–225 mg/day) than placebo, and was sustained throughout the 6-month trial. Of patients receiving venlafaxine ER (at any dose), 58% responded to treatment compared to 33% of those receiving placebo (P<0.001); corresponding remission rates were 31% and 16% (P<0.01). There were no differences in outcome according to venlafaxine ER dosage.Conclusions Venlafaxine ER was effective in the treatment of GSAD. The comparable efficacy at low and higher doses may indicate that norepinephrine reuptake blockade does not contribute to therapeutic effect in GSAD. This hypothesis should be tested using agents with specific actions on norepinephrine reuptake blockade.