Predictors of an acute antidepressant response to fluoxetine and sertraline.

Sertraline and fluoxetine have different pharmacologic and pharmacokinetic profiles which may be of clinical relevance in the determination of response in different subtypes of depression. A randomized, double-blind, 6-week study comparing sertraline (50-100 mg/day) with fluoxetine (20-40 mg/day) in 286 outpatients with major depression, who had demonstrated comparable efficacy and tolerability for the two drugs, was analysed by subgroups of patients at baseline with melancholia, severe depression, single depressive episode, multiple depressive episodes, high anxiety, low anxiety, psychomotor retardation and psychomotor agitation. Multiple logistic regression with regressors including treatment-by-subgroup variables revealed that, within certain subgroups, the efficacy might differ substantially from that of the whole treatment group. However, the only treatment-by-subgroup interaction term that was significant was anxiety (P < 0.05). There was no evidence of interaction in single or recurrent episode subgroups, and these were not included in subsequent analyses. Subsequent two-sample statistical comparison tests of response (i.e. Hamilton Depression Scale reduction > or = 50%) rates at study endpoint between treatment groups demonstrated that patients with melancholic depression and those with symptoms of psychomotor agitation yielded a significantly greater proportion of responders with sertraline compared to fluoxetine (P < 0.05). Response rates in sertraline- and fluoxetine-treated patients, respectively, were: overall study 59%, 51%; melancholia 59%, 44%; severe depression 59%, 41%; low anxiety 71%, 55%; high anxiety 47%, 48%; psychomotor retardation, 48%, 46%; and psychomotor agitation 62%, 39%. Multiple logistic regression adjusting for possible confounding factors, that included a treatment by anxiety interaction term, also led to similar findings. In particular, the analysis showed that significant differences existed in favour of sertraline in patients with low anxiety in the melancholia and severe depression subgroups (P < 0.05), indicating that these characteristics predicted a superior response to 6 weeks of treatment with sertraline relative to fluoxetine. Sertraline also demonstrated advantages over fluoxetine on parameters such as sleep and weight disturbance in severely depressed patients, and sleep disturbance, weight, cognitive disturbance and retardation in melancholic patients.     

Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders     

Comparative study of the antidepressant and anxiolytic activity of fluoxetine and tianeptine

The activity of fluoxetine (prozac) and tianeptine (coaxil) was studied in outbred male rats under Porsolt and S. Nomura modified forced swim tests. The antidepressant effect of tianeptine was much more pronounced that that of fluoxetine. In the conflict situation test, fluoxetine produced anxiogenic action. In contrast, tianeptine decreased (albeit not reliably) the anxiety. In combination with bicuculline (GABAA receptor blocker), the anxiolytic action was more pronounced for both antidepressants, which was manifested by a significant increase in the number of punished water takes. A neural network explaining the observed behavior is proposed, which includes GABA-ergic intemeurons inhibiting serotonin release from serotoninergic terminals.     

Effects of acute and chronic antidepressant treatments on memory performance: a comparison between paroxetine and imipramine

Rationale The cognitive impairments apparent in many depressed patients appear to be alleviated by chronic treatments with antidepressants. However, evaluation of antidepressant treatments in rodents rarely includes investigation of their effects on cognitive performance. Objectives The aim of this study was to investigate in rat the effects of paroxetine, a selective serotonin reuptake inhibitor antidepressant, and imipramine, a tricyclic antidepressant, on learning and memory in spatial and non-spatial tasks. Materials and methods Adult male Sprague–Dawley rats weighing 230–250 g were used in two sets of experiments. Results Spatial working memory was first tested in a radial-arm maze using the delayed spatial win-shift task. During the course of a 10-day treatment, paroxetine-treated rats (10 mg/kg) did not show any deficit in memory performance. Conversely, imipramine-treated rats (10 mg/kg) made significantly more errors than controls. Secondly, we tested temporal order memory for objects. Rats received one injection or chronic injections (28 days) of imipramine (10 mg/kg), paroxetine (10 mg/kg) or saline. In contrast to controls, on the day after the acute injection, both imipramine- and paroxetine-treated rats were unable to discriminate the old from the recent objects. After chronic treatment, the imipramine-treated rats were unable to differentiate between the two objects, whereas paroxetine-treated rats, as controls, spent more time exploring the old one. When the delay before the test phase was increased to 4 h, controls could not discriminate the objects, whereas rats treated for 28 days with paroxetine were able to distinguish the old from the recent object. Conclusions In contrast to the persistent harmful effects of imipramine, chronic treatment with paroxetine does not alter spatial working memory performance and appears to improve temporal order memory performance.     

Differential modulation of antipredator defensive behavior in Swiss-Webster mice following acute or chronic administration of imipramine and fluoxetine

The Mouse Defense Test Battery (MDTB) has been designed to assess defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat. Primary measures taken before, during and after predator confrontation comprise escape attempts, predator assessment, defensive attack and flight. Previous reports from this laboratory have shown that the panic-promoting drug yohimbine potentiated flight behavior, while long-term treatment with the panicolytic agent alprazolam reduced this response. In order to evaluate further the possibility that the MDTB may represent an effective animal model of panic attacks, the present study investigated the behavioral effect of imipramine and fluoxetine, two serotonin reuptake inhibitors (SRIs) known to alleviate panic symptoms when given on a repeated basis. Both drugs were administered acutely and chronically (one daily IP injection for 21 days) at 5, 10 and 15 mg/kg. Our results showed that a single dose of imipramine or fluoxetine strongly potentiated flight reactions in response to an approaching predator and increased defensive attack toward the rat. This was in contrast to chronic treatment with each drug which dramatically decreased flight responses and defensive attack behaviors. In addition, long-term administration with both SRIs produced a reliable attenuation of predator assessment activities. Taken together, these findings suggest an acute anxiogenic-like effect of imipramine and fluoxetine followed by a fear/anxiety reducing effect after repeated administrations. These results support clinical observations revealing an acute anxiogenic effect of SRIs followed by an anxiolytic and/or panicolytic effect after chronic use, and support previous results suggesting that the MDTB may be useful for the investigation of panic-modulating agents.     

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.     

Effects of acute and chronic treatment with an atypical antidepressant drug,nomifensine, on the sleep-wake activity in rats

After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental anxiety and antidepressant drugs: the effects of moclobemide, a selective reversible MAO-A inhibitor, fluoxetine and imipramine in mice

Available evidence derived from behavioural and clinical studies indicates that antidepressant drugs may be effective as anxiolytic agents. In this connection, the present study was designed to assess the behavioural effects of three antidepressant drugs, i.e. imipramine (IMI), a non selective serotonin (5-HT) and noradrenaline re-uptake (NA) inhibitor, Fuoxetine (FLU), a selective 5-HT re-uptake inhibitor (SSRI) and moclobemide (MOC), a reversible inhibitor of type A monoamine-oxidase enzyme (RIMA) on anxiety, exploratory and locomotor activities in mice. The experiments used two animal models which attempt to separate these three factors: the light-dark aversion test and the open-field test. Naive female CD1 mice were administered intraperitoneally (i.p.) 30 min before testing with IMI (10, 20 and 40 mg/kg) or FLU (5, 10 and 20 mg/kg) or MOC (l, 5 and 10 mg/kg) or vehicle. Results showed that IMI (10 and 20 mg/kg), FLU (10 and 20 mg/kg) and MOC (l, 5 and 10 mg/kg) significantly reduced the aversive behavior of mice for the lit area in the light/dark aversion test, suggesting an anxiolytic-like effect. In fact, vehicle controls preferred the dark box where they spent approximately 70% of their time, indicating that light serves as an anxiogenic stimulus. Importantly, the anxiolytic-like effects of these antidepressant drugs were not associated with any increase in locomotor activity. In summary, these data suggest that FLU and the new generation of RIMA, exemplified by MOC, in terms of probable efficacy and greater safety, are of interest as treatment for a broad spectrum of anxiety disorders.     

Supramolecular complex of fluoxetine with beta-cyclodextrin: an experimental and theoretical study

In this work the complex formed between beta-cyclodextrin (betaCD) and fluoxetine (FLU) was investigated by experimental and computational methods. From Horizontal Attenuated Total Reflectance (HATR) was possible to verify a strong modification in the vibrational modes of betaCD and FLU, indicating interactions between them. The Nuclear Magnetic Resonance (NMR) experiments confirm these interactions through the change in chemical shifts in (1)H spectra, reduction in longitudinal relaxation times values, and the Nuclear Ouverhauser Effect confirm the inclusion of aromatic rings of FLU into the betaCD. The structures of the proposed inclusion compounds were optimized at PM3 semiempirical level of theory. In addition, single point calculations at the Density Functional Theory (DFT) level, using the Becke, Lee, Yang, and Parr functional and 6-31G(d,p) basis set, were used to determine the interaction energy for these structures. The DFT calculations identified the aromatic ring, which contains the CF(3) group as the most stable into the betaCD by an amount of, 11.7 kcal mol(-1), in the gas phase. Polarized continuum model, at the DFT level mentioned, was used to investigate the solvent effect, and the results corroborated the gas phase analysis. A high equilibrium constant (K approximately 6921+/-316) and the stoichiometry, 1:1, were obtained by Isothermal Titration Calorimetry (ITC) experiments.     

A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder

This was a 6-week, double-blind comparison of fluoxetine, imipramine, and placebo in 89 patients with bipolar depression. Using the criteria of greater than or equal to 50% improvement in the HAMD-total score after at least 3 weeks on study drug, endpoint analysis showed 86% of the fluoxetine-treated patients improved compared with 57% of the imipramine-treated and 38% of the placebo-treated patients. Significantly fewer fluoxetine-treated patients discontinued due to adverse events than did imipramine-treated patients (7% vs. 30%, respectively).     

度洛西汀与氟西汀治疗抑郁症并发慢性疼痛的对照研究

目的:探讨比较度洛西汀与氟西汀治疗抑郁症并发慢性疼痛的有效性和安全性.方法:64例符合抑郁症并发慢性疼痛的门诊病人随机分成度洛西汀组与氟西汀组,分别给予度洛西汀(60 mg/d)及氟西汀(20 mg/d)治疗.在治疗前、第4周分别用HAMD-17、VAS量表评定疗效,用TESS量表评定不良反应及安全性.结果:两组改善抑郁症状总体疗效无显著性差异(P>0.05),但治疗疼痛症状度洛西汀总体疗效显著高于氟西汀(P<0.05).结论:度洛西汀治疗抑郁症并发慢性疼痛安全有效.     

Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens

The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24–28 days followed by 3–5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7±1.5 fmol/20 μl per 30 min, P=0.019), and moderately decreased after chronic fluoxetine (6.5±0.6, P=0.047), as compared to the vehicle controls (9.1±0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the

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-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P=0.002), but unchanged after chronic fluoxetine (P=0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337±45 fmol/180 min, P=0.005) and chronic fluoxetine (249±38, P=0.57), as compared to the vehicle controls (178±29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.     

A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression

Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 outpatients with DSM-III major depression, of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy. Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo. Both imipramine and fluoxetine were significantly superior to placebo on most measures. There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures. Fluoxetine was generally well tolerated. Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant. The results support previous studies which suggest fluoxetine's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs.     

Increase of therapeutic activity of doxorubicin by long circulating liposomes in combination with curcumin

In this study, doxorubicin (DOX)-loaded long circulating liposomes combined with curcumin (CUR) (DOX-CUR-LCLs) were successfully prepared as a novel formulation for cancer treatment. The particle size and distribution, zeta potential, drug loading capacity, and entrapment efficiency (EE) of the preparation were characterized. The in vitro anti-tumor activities of DOX-CUR-LCLs and DOX-LCLs against A549 cells were then evaluated and compared with that of free DOX. Cytotoxicity evaluation showed that DOX-CUR-LCLs had a significantly higher antitumor activity than other DOX preparations. These results suggest that novel DOX-CUR-LCLs, combination of DOX and CUR administered in long-circulating liposomes, could improve antitumor activity.     

Evaluation of the nitric oxide radical scavenging activity of manganese complexes of curcumin and its derivative

Curcumin manganese complex (CpCpx) and diacetylcurcumin manganese complex (AcylCpCpx) were determined as to their effect on the nitric oxide (NO) radical scavenging in vitro method using a sodium nitroprusside generating NO system compared with their parent compound and astaxanthin, an extreme antioxidant. All compounds effectively reduced the generation of NO radicals in a dose dependent manner. They exhibited strong NO radical scavenging activity with low IC(50) values. The IC(50) values of curcumin, diacetylcurcumin, CpCpx and AcylCpCpx obtained are 20.39+/-4.10 microM, 28.76+/-1.48 microM, 9.79+/-1.50 microM and 8.09+/-0.99 microM, respectively. CpCpx and AcylCpCpx show greater NO radical scavenging than their parent compounds, curcumin and acetylcurcumin, respectively. However, the IC(50) values of curcumin and related compounds were found to be less than astaxanthin, an extreme antioxidant, with the lower IC(50) value of 3.42+/-0.50 microM.     

Toxicological evaluation of imipramine in combination with adriamycin and strophanthin

Chronic oral administration of imipramine to rats caused characteristic changes of the electrocardiogram (ECG), i.e. prolongation of the PR interval, widening of the QRS complex, and increase in T-wave voltage. The cardiotoxic anthracycline antibiotic adriamycin induced dose-dependent widening of the QRS complex. This effect on intraventricular conduction was not enhanced in rats receiving both drugs. The high adriamycin dose (5 x 4 mg/kg) abolished imipramine-induced prolongation of the PR interval and T-wave elevation. This was not seen with the low adriamycin dose (20 x 1 mg/kg). Imipramine prolonged survival time of rats treated with toxic doses of adriamycin, but enhanced growth retardation in animals receiving the low adriamycin dose. Chronic treatment with increasing doses of strophanthin induced significant flattening of the T wave in rats with and without imipramine therapy, but did not influence the changes of the ECG or body weight gain caused by imipramine. It is concluded that the combined use of imipramine and adriamycin or strophanthin did not lead to a serious enhancement of the toxicity of the tricyclic antidepressant.     

Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism

Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John’s wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. In addition, hypericum extracts, as well as standard antidepressants such as the tricyclic, impramine, and the selective serotonin reuptake inhibitor, fluoxetine, have been reported to be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients. It was the aim of the present study to compare the effects of hypericum extracts with those of imipramine and fluoxetine in the rat forced swimming test (RFST), a model of depression, as well as in cAA rats, a genetic model of alcoholism. In the RFST, triple i.p. administration of imipramine (3–30 mg/kg) and fluoxetine (3–30 mg/kg) induced a dose-dependent reduction in immobility; the minimal effective dose (MED) being 30 and 10 mg/kg, and the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. In this test, the hypericum extracts Ze 117 (Remotiv^®) and LI 160 (Jarsin^®) also induced a statistically significant reduction of immobility when administered under the same application schedule (5–40 mg/kg, i.p., triple application). In the case of the hypericum extracts the dose–response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively. Interestingly, the anti-immobility effects tended to be more pronounced after subacute (1 week, B.I.D.) treatment with 10 mg/kg of imipramine, fluoxetine, or Ze 117, as compared with acute treatment. This phenomenon is in accordance with clinical experience and suggests that repeated treatment is required for full development of antidepressive effects. In the alcohol-preferring cAA rats, acute i.p. administration of imipramine (3–30 mg/kg), fluoxetine (1–10 mg/kg) and Ze 117 (10–40 mg/kg) dose-dependently reduced alcohol intake in a 12-h limited access two-bottle [ethanol 10% (v/v) versus water] choice procedure; with MED values of 30, 5 and 20 mg/kg, respectively. The anti-alcohol effects of fluoxetine and Ze 117 appeared to be specific, as reductions in alcohol intake coincided with reductions in alcohol preference. The present study suggests that hypericum extracts have antidepressant-like properties which resemble those of clinically established antidepressants, and that Remotiv^® may be an interesting adjunct for the treatment of alcoholism.