Comparative study of the effects of amitriptyline, fluoxetine, and tianeptine on the amplitude of transcallosal evoked potentials

The influence of amitriptyline, fluoxetine and tianeptine upon transcallosal responses has been studied in male albino rats. It is established that amitriptyline does not influence, fluoxetine reduces, and tianeptine increases the amplitude of evoked potentials. These data show evidence that tianeptine facilitates, fluoxetine impairs, and amitriptyline does not affect the interhemispheric transmission.     

Chronobiological similarity of the specific activity of anxiolytic and antidepressant drugs

An analysis of the recent achievements in chronobiology shows that the specific activity of anxiolytic and antidepressant drugs can be related to identical reorganization of the biological rhythms and the function of brain structures, which control rhythmical processes.     

Neurobiological and clinical effects of the antidepressant tianeptine

The precise neurobiological processes involved in depression are not clear, but it is recognized that numerous factors are involved, including changes in neurotransmitter systems and brain plasticity. Neuroplasticity refers to the ability of the brain to adapt functionally and structurally to stimuli. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, learning, memory and emotions are altered in depression. The mechanisms underlying alterations in neuroplasticity are believed to relate to changes in neurotransmitters, hormones and growth factors. Structural changes in the hippocampus that have been proposed to be associated with depression include dendritic atrophy, reduced levels of cerebral metabolites, decreased adult neurogenesis (generation of new nerve cells) and reduced volume. Increased dendritic branching occurs in the basolateral nucleus of the amygdala. Reduced neuronal size and glial cell density occur in the prefrontal cortex. Clinically, tianeptine is an antidepressant effective in reducing symptoms of depression in mild to moderate-to-severe major depression, including over the long term. Tianeptine is also effective in alleviating the symptoms of depression-associated anxiety. It is generally well tolerated, with little sedation or cognitive impairment. The efficacy profile of tianeptine could be explained by its neurobiological properties observed in animal models. Tianeptine prevents or reverses stress-associated structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission. In particular, in the hippocampus, it prevents stress-induced dendritic atrophy, improves neurogenesis, reduces apoptosis and normalizes metabolite levels and hippocampal volume. Tianeptine also has beneficial effects in the amygdala and cortex and can reverse the effects of stress on neuronal and synaptic functioning. The neurobiological properties of tianeptine may provide an explanation not only for its antidepressant activity, but also for its anxiolytic effects in depressed patients and its lack of adverse effects on cognitive function and memory.     

In vivo and in vitro estrogenic activity of the antidepressant fluoxetine

Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.     

Antinociceptive effects induced by desipramine and fluoxetine are dissociated from their antidepressant or anxiolytic action in mice

This study aimed to evaluate the relationship between some aspects of experimental depression, anxiety and the antinociceptive effects of fluoxetine and desipramine in mice. Acute administration of fluoxetine and desipramine (5, 10 and 20 mg/kg, i.p.) showed significant antinociceptive effects in the hot-plate test and against the early and late phase of the mouse formalin test, dissociated from its antidepressant and anxiolytic effects as measured in the forced swimming and in the plus-maze tests, respectively. Neither fluoxetine nor desipramine, at the doses tested, produced significant effects on locomotor activity. Furthermore, both compounds were ineffective in the tail-flick phasic model of nociception. In conclusion, the results suggest that without the distinction of serotonergic and noradrenergic contributions, the acute antinociceptive effects of fluoxetine and desipramine in mice are independent of their sedative, antidepressant and anti-anxiety properties.     

Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on alertness and happiness     

Serum fluoxetine and norfluoxetine concentrations and antidepressant response

A high-performance liquid chromatography assay for fluoxetine and its major metabolite, norfluoxetine, was established. Serum concentrations of the two were measured in 13 depressed outpatients following a 6-week trial of the drug. No significant correlations were obvious between clinical improvement as measured by the Hamilton Rating Scale for Depression and the Clinical Global Impression scores and the serum concentrations of fluoxetine and its major metabolite, norfluoxetine, according to these initial pilot data.     

Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study

Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.     

Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats

Background

Cholesterol may have a role in the pathophysiology of depression. Lowering cholesterol levels with statins reduces risks for cardiovascular events, and there is clinical evidence that statins exert neuroprotective properties not fully explained by their effects on serum cholesterol levels. Altered cholesterol levels can affect serotonergic neurotransmission, which might be involved in the clinical efficacy of standard antidepressants.

Methods

We examined interactions between a statin (lovastatin) and a selective serotonin reuptake inhibitor (fluoxetine) using the forced swim test (FST) in rats, a behavioral assay that identifies treatments with antidepressant effects in humans. Specifically, we determined if the addition of lovastatin to the diet would increase the efficacy of a subeffective dose of fluoxetine.

Results

Rats maintained on a lovastatin-enriched diet for 30 days were more sensitive to the antidepressant-like effects of a low (subthreshold) dose of fluoxetine. The behavior of rats treated with this combination resembled that normally seen with higher doses of fluoxetine. No effects were observed in rats maintained on a lovastatin-enriched diet for 3 days.

Conclusions

Lovastatin can augment the antidepressant-like effects of a low dose of fluoxetine in rats, raising the possibility that statins could be used to facilitate the effects of antidepressants in humans.     

Comparative study of the effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane

Summary Tianeptine is a tricyclic antidepressant which enhances serotonin uptake in certain brain areas. Tianeptine has been reported to improve both working and reference memories in rodents. The effects of tianeptine on the spontaneous activity of medial septal neurons were studied in rats anesthetized with urethane. Systemic administrations (0.2–1 mg/kg i. v.) of tianeptine decreased the spontaneous activity and disorganized or suppressed the rhythmically bursting activity of medial septal neurons, in a dose related manner. Iontophoretic administrations of tianeptine did not modify the spontaneous activity of medial septal neurons. Changes of the bursting activity were inconsistent. However, tianeptine blocked partially or completely the inhibition induced by the serotonin in 68% of the cases. In contrast, other antidepressants (amitriptyline, clomipramine and fluoxetine) potentiated the inhibitory effect of serotonin in 50%–60% of the cases. Our results show that tianeptine, applied by iontophoresis, has an effect on the medial septal neurons which was opposite to that of other antidepressants. On the basis of our findings, it can be tentatively proposed that tianeptine may have a beneficial effect on memory by counteracting the serotonin-induced inhibition of medial septal neurons. Send offprint requests to M. H. Bassant at the above address     

Synthesis of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives and evaluation of their antidepressant and anxiolytic activity

Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.     

藏药佐太的抗抑郁抗焦虑作用研究

目的 观察藏药佐太的抗抑郁和抗焦虑作用,并探讨其可能作用机制。方法 1）初步评价实验：在小鼠ig给予6.07、60.70、303.49、606.97 mg/kg佐太14 d后,通过强迫游泳实验和开场实验初步评价佐太对抑郁和焦虑的影响,同时通过检测小鼠血清中5-羟色胺（5-HT）和去甲肾上腺素（NE）水平来探讨佐太产生影响的可能作用机制。2）不可预测性慢性温和应激模型（CUMS）实验：建立CUMS模型,ig给予6.07、60.70、606.97 mg/kg佐太后,通过小鼠体质量变化、糖水偏爱实验、小鼠悬尾实验、开场实验和埋珠实验评价佐太对CUMS模型小鼠的抗抑郁和抗焦虑作用,同时检测小鼠血清中皮质酮（CORT）、促肾上腺皮质激素（ACTH）和下丘脑中促肾上腺皮质激素释放激素（CRH）水平,测定佐太对CUMS模型小鼠下丘脑-垂体-肾上腺（HPA）轴的影响。结果 1）佐太能够显著减少小鼠强迫游泳实验中不动时间（6.07、60.70、303.49、606.97 mg/kg）;增加小鼠在开场实验中中央区停留时间百分率（606.97 mg/kg）和中央区运动百分比（303.49、606.97 mg/kg）;增加小鼠血清中5-HT（6.07、606.97 mg/kg）和NE（6.07、303.49、606.97 mg/kg）水平。2）CUMS实验中,与对照组比较,经过42 d CUMS慢性应激小鼠表现出明显的抑郁和焦虑样行为,包括糖水偏爱率的降低、悬尾不动时间显著增加、开场实验中运动时间、中央区域停留时间及运动距离的减少和周边区域运动距离的增加、埋珠实验中埋珠个数的增加。而ig给予佐太（6.07、60.70、606.97 mg/kg）能够显著改善CUMS模型引起的上述症状,并且佐太（6.07、60.70 mg/kg）能够显著降低CORT、ACTH和CRH水平,抑制CUMS模型引起的HPA轴亢进。结论 佐太具有一定的抗抑郁和抗焦虑作用,并且其作用机制可能与升高5-HT、NE水平和抑制HPA轴亢进有关。     

艾司西酞普兰与氟西汀治疗老年抑郁症疗效对照研究

目的 比较艾司西酞普兰与氟西汀治疗老年抑郁症的疗效和安全性.方法 将70例老年抑郁症患者随机分为观察组和对照组各35例.观察组给予艾司西酞普兰治疗,对照组给予氟西汀治疗.用汉密顿抑郁量表（HAMD）评定其疗效,采用副反应量表评价安全性,分别在治疗0、1、2、4、6周末评定疗效和不良反应.结果 观察组痊愈率为68.57%高于对照组的65.71%,有效率为82.86%高于对照组的80.00%,但2组差异无统计学意义（P〉0 05）.HAMD评分2组治疗第1、2、6周均低于治疗前,观察组治疗第1周HAMD总分和睡眠障碍因子分值低于对照组,差异有统计学意义（P〈0.05）.2组不良反应的发生率比较差异无统计学意义（P〉0.05）.结论 艾司西酞普兰治疗老年抑郁症有效且安全,且起效时间早于氟西汀.     

米氮平和氟西汀治疗抑郁症的对照研究

目的比较研究米氮平和氟西汀治疗抑郁症的疗效和不良反应。方法将70例符合CCMD-3诊断标准的抑郁症患者随机分组,分别给予米氮平和氟西汀单药治疗,疗程共8周,采用汉密尔顿抑郁量表（HAMD）进行疗效评定,以不良反应症状量表（TESS）评定药物不良反应。结果 8周末米氮平组缓解率64.5%、有效率93.5%,显效率77.5%,氟西汀组缓解率39.4%、有效率91.0%,显效率72.8%。米氮平组缓解率高于氟西汀组,差异有显著性（P〈0.05）,而两组疗效无显著性差异（P〉0.05）,但米氮平对焦虑/躯体化症状起效快,需要合并服用苯二氮艹卓类药物的例数更少。两药不良反应少,TESS评分总体相当,米氮平更多引起嗜睡、头晕,氟西汀组的烦躁、恶心发生率稍高于米氮平。结论米氮平和氟西汀对抑郁症疗效相当,不良反应轻、安全性高,米氮平起效快、有更高的缓解率。     

氟西汀合并奥氮平治疗精神分裂症对照研究

目的:观察氟西汀合并奥氮平治疗精神分裂症阴性症状的疗效和不良反应.方法:对47例慢性精神分裂症患者随机分为两组:氟西汀加奥氮平研究组(n=23)和奥氮平对照组(n=24),于治疗前和治疗后2、4、8、12周末利用PANSS和TESS进行疗效及不良反应评价.结果:治疗4周后研究组总分及阴性因子分比治疗前明显降低,且阴性因子及焦虑/抑郁因子分值显著低于对照组,体质量增加明显低于对照组.结论:氟西汀合并奥氮平能明显改善精神分裂症患者的阴性症状及焦虑/抑郁症状,不良反应少.     

Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine*

Depression is treated by a great variety of antidepressant treatments. SSRIs (such as fluoxetine) are well known: it is, however, sure that further progress is needed and the search for antidepressants with other mechanisms of action (such as tianeptine) or different efficacy is still of interest. A multinational study compared tianeptine with fluoxetine in 387 patients with Depressive Episode, or Recurrent Depressive Disorder, or Bipolar Affective Disorder (ICD-10), in a double-blind parallel group design. They were treated for six weeks. At inclusion, no significant difference between groups was shown. Final MADRS scores were 15.7 and 15.8 with tianeptine and fluoxetine, respectively (ITT population) (p = 0.944). MADRS responders were 58% and 56% with tianeptine and fluoxetine, respectively (p = 0.710). No statistical difference was observed for the other efficacy parameters. Thirty-six withdrawals occurred in each group, without any difference for the reasons of discontinuation. There was no major difference between groups for the other safety parameters. In this study, both tianeptine and fluoxetine exhibited a good efficacy and safety. Copyright 1999 Elsevier Science B. V. All rights reserved.     

Metabolic activation of the new tricyclic antidepressant tianeptine by human liver cytochrome P450

Incubation of [14C]tianeptine (0.5 mM) with human liver microsomes and a NADPH-generating system resulted in the in vitro covalent binding of a tianeptine metabolite to microsomal proteins. This covalent binding required oxygen and NADPH. It was decreased by piperonyl butoxide (4 mM) by 81%, and SKF 525-A (4 mM) by 87%, two relatively non-specific inhibitors of cytochrome P450, and by glutathione (4 mM) by 70%, a nucleophile. Covalent binding was decreased by 54% in the presence of troleandomycin (0.1 mM), a specific inhibitor of the glucocorticoid-inducible cytochrome P450 IIIA3, but remained unchanged in the presence of quinidine (0.1 mM) or dextromethorphan (0.1 mM), two inhibitors of cytochrome P450 IID6. Preincubation with IgG antibodies directed against cytochrome P450 IIIA3 decreased covalent binding by 65% whereas either preimmune IgG or IgG antibodies directed against P450 IA1, an isoenzyme inducible by polycyclic aromatic compounds, exhibited no significant inhibitory effect. We conclude that tianeptine is activated by human liver cytochrome P450 into a reactive metabolite. This activation is mediated in part by glucocorticoid-inducible isoenzymes but not by P450 IID6 (the isoenzyme which oxidizes debrisoquine) nor by P450 IA1 (an isoenzyme inducible by polycyclic aromatic compounds). The predictive value of this study regarding possible idiosyncratic and immunoallergic reactions in humans remains unknown.     

Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats

Recent research has suggested that cognitive disorders are a persistent trait of mental illnesses such as schizophrenia. Cognitive deficits in the course of schizophrenia may be due to the disease and/or drug therapy, especially with old-generation drugs. Several clinical experiments have indicated the beneficial effects of new-generation antipsychotics on cognitive processes in patients treated for mental disorders. Aripiprazole is a new, atypical antipsychotic with a unique mechanism of action, which may have positive effects on cognitive functions. The aim of this study was to investigate the effects of aripiprazole on spatial memory in the Morris water maze and antidepressant activity in the Porsolt test. In addition, we examined whether aripiprazole had any side effects in the chimney test. The behavioral tests showed that aripiprazole improved spatial memory in rats and had antidepressant and anxiolytic effects after a single treatment; however, aripiprazole impaired motor coordination after repeated administration. We concluded that aripiprazole could be an effective antipsychotic for the treatment of patients with schizophrenia or bipolar disorder who have associated anxiety and cognitive deficits.     

Effect of repeated treatment with tianeptine and fluoxetine on the central alpha(1)-adrenergic system

Tianeptine (TIA) is an antidepressant drug which enhances the reuptake of serotonin but, in contrast to tricyclics, shows no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced adaptive changes in the alpha(1)-adrenergic system, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. TIA was administered at a dose of 5 or 10mg/kg once or repeatedly (twice daily for 14 days) and fluoxetine (FLU), used as a reference compound, at a dose of 10mg/kg. The obtained results showed that TIA administered repeatedly potentiated the methoxamine- and phenylephrine (PHEN)-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, the effects mediated by alpha(1)-adrenoceptors. TIA given repeatedly (but not acutely) increased the binding (B(max)) of alpha(1)-adrenergic receptors in cerebral cortex for [(3)H]prazosin. However, the ability of the alpha(1)-adrenoceptor agonist PHEN to compete for these sites was not significantly changed. The above results indicate that repeated TIA administration increases the responsiveness of the alpha(1)-adrenergic system (behavioural and biochemical changes). On the other hand, FLU did not affect any behavioural and biochemical changes in this system.