Resolution of sexual dysfunction during double-blind treatment of major depression with reboxetine or paroxetine

The selective noradrenaline re-uptake inhibitor reboxetine may have advantages over the selective serotonin re-uptake inhibitors fluoxetine and citalopram, in effects on sexual function and satisfaction. The effects of reboxetine and paroxetine on sexual function were compared by examining data from the UK centres in an international double-blind flexible-dose parallel-group multi-centre randomized controlled trial of acute treatment of patients with DSM-IV major depression. Patients were randomly assigned to receive reboxetine (4 mg b.d.) or paroxetine (20 mg mane) using a double-dummy technique to preserve the blind. The dosage could be increased at day 28 (to reboxetine 4 mg mane, 6 mg nocte; or paroxetine 20 mg b.d.). Antidepressant efficacy was assessed by the 21-item Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impression Scale for Severity (CGI-S) at all study visits, and the Clinical Global Impression of Improvement (CGI-I) at each visit after randomization. Sexual function and satisfaction was assessed by visual analogue scale (VAS) items of the Rush Sexual Inventory completed at baseline and days 28 and 56.There were no significant differences between groups in demographic or clinical features at baseline. There was a gradual reduction in severity of depressive symptoms (reboxetine, 14.3; paroxetine, 12.0: observed case analysis), with no significant differences between groups. There were significant differences (p 0.05), with advantages for reboxetine, at Week 4 and Week 8 on the VAS item assessing ability to become sexually excited, and non-significant trends with advantages for reboxetine, in frequency of sexual thoughts at Week 4 (p 0.05) and Week 8 (p 0.08); and in desire to initiate sexual activity at Week 4 (p 0.09). Exclusion of patients who had ever experienced sexual dysfunction with any medication prior to participation in this study (n 10) reduced the statistical significance of the findings, although there were still numerical advantages for reboxetine.Sexual function and satisfaction in depressed patients improves during double-blind acute treatment with reboxetine or paroxetine, but this improvement is greater and more rapid with reboxetine.     

Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder

Sexual side-effects due to antidepressant treatment are an important consideration when selecting a treatment regimen and can influence patient compliance. Sexual function during treatment with the selective noradrenaline reuptake inhibitor reboxetine, the selective serotonin reuptake inhibitor (SSRI) fluoxetine and placebo has been assessed in a multicentre, randomized, 8-week, double-blind study of 450 patients diagnosed with major depressive disorder. Sexual function was measured by the Rush Sexual Inventory completed by male and female patients and administered at baseline, week 4 and week 8. The results indicate that reboxetine was similar to placebo and superior to fluoxetine in its effect on overall sexual function. There was a greater degree of sexual satisfaction in the reboxetine group compared to fluoxetine (P=0.02). The percentage of female patients able to achieve orgasm increased during the study period for women who received reboxetine and placebo, but decreased for those who received fluoxetine. These results suggest that reboxetine may be of particular benefit for patients at risk for sexual dysfunction with SSRIs.     

The antidepressant efficacy of reboxetine in patients with severe depression

We examined the effectiveness of reboxetine, a norepinephrine reuptake inhibitor (NRI), compared with placebo for the treatment of patients with severe major depression (defined as a score on the 17-item Hamilton Rating Scale for Depression [HAM-D] >/=25). Data were obtained from four prospective, double-blind, randomized, placebo-controlled clinical trials of the efficacy of reboxetine (8 to 10 mg/d) over 4 to 8 weeks in patients with major depression. In three of the trials, reboxetine produced a significantly greater reduction than placebo in mean HAM-D scores from baseline to the last clinical assessment (p < 0.001). There were significantly more responders to treatment (defined as a reduction in HAM-D score >50% between baseline and the last follow-up observation) treated with reboxetine than placebo in three trials. The overall mean responder rate with reboxetine was 63% (range: 56-74%) compared with 36% (range: 20-52%) with placebo. These results demonstrate that reboxetine is significantly more effective than placebo in a subgroup of patients with severe depression.     

Effects of reboxetine on Hamilton Depression Rating Scale factors from randomized, placebo-controlled trials in major depression

Reboxetine is the first selective norepinephrine reuptake inhibitor (NRI) approved for the treatment of major depressive disorder (MDD). Although reboxetine has demonstrated efficacy for the treatment of depression, its effects on specific depressive symptoms have not been reported. We evaluated the effects of reboxetine on four Hamilton Depression Rating Scale (HAM-D) factors: psychomotor retardation, anxiety, cognitive disturbance and insomnia. Data were obtained from four short-term (4-8-week), randomized, placebo-controlled trials of reboxetine for the treatment of MDD. For each study, mean changes in HAM-D symptom factor scores from randomization to the study endpoint were compared between reboxetine and placebo. In addition, data from all four studies were pooled to determine the proportions of patients who either improved or worsened with treatment were compared between placebo (n = 353) and reboxetine (n = 350) treatment groups. Compared to placebo, reboxetine significantly improved psychomotor retardation in all four trials. Cognitive disturbance and anxiety were improved in three of four trials, and insomnia was improved in one trial with a positive trend in the second trial. Reboxetine, a selective NRI, improves symptoms of psychomotor retardation, anxiety and cognitive disturbance during treatment of MDD.     

Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors.

To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor (SSRI), we analyzed data from a placebo-controlled trial designed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone. At baseline, all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or placebo was added to the SSRI for 4 weeks; the mean daily dose of buspirone at endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a structured interview. Before starting medication with buspirone or placebo, 40% (47 of 117) reported at least one kind of sexual dysfunction (decreased libido, ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment, approximately 58% of subjects treated with buspirone reported an improvement with respect to sexual function; in the placebo group, the response rate was 30%. The difference between placebo and active drug treatment was more pronounced in women than in men. The response was obvious during the first week, with no further improvement during the course of the study. It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug.     

Comparison of efficacy and tolerability of reboxetine and venlafaxine XR in major depression and major depression with anxiety features: an open label study

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of reboxetine in the treatment of major depressive disorder (MDD) and MDD with anxiety features to venlafaxine XR. METHOD: Patients with MDD, aging 18 between 65 years, were randomly allocated to two groups receiving either open-label venlafaxine XR capsules (n = 50) or reboxetine tablets (n = 43). Subjects were administered Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) at baseline and 2, 4, 7, 10 weeks after the baseline visit. RESULTS: Response rates to antidepressant treatment were significantly higher in the venlafaxine XR group at 10th week. When patients having anxious depression were analysed separately; response rate for anxiety of reboxetine group was significantly higher at 7th week only. Mean number of side effects were significantly higher in reboxetine group. Only one subject in each group was dropped out due to side effect. CONCLUSION: We may suggest that reboxetine is as effective and tolerable as venlafaxine XR in the treatment of MDD and MDD with anxiety features, and it may be considered a treatment option to venlafaxine XR.     

Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder

The efficacy and tolerability of reboxetine, a unique selective noradrenaline reuptake inhibitor, were compared with those of placebo in a 6-week, randomized, double-blind study of hospitalized patients with a DSM-III-R diagnosis of major depressive disorder. Fifty-two patients (25 in the placebo group, 27 in the reboxetine group) were included in the efficacy analysis. Sixteen (64%) of those in the placebo group and four (15%) in the reboxetine group were withdrawn during the study because of lack of efficacy. Improvement in the mean Hamilton Rating Scale for Depression (HAM-D) total score at last assessment was significantly greater in the reboxetine group than in the placebo group (p < 0.001). Similarly, the response rate to treatment, defined as > or =50% reduction in HAM-D total score, was 74% for patients who received reboxetine compared with 20% for those who received placebo (p < 0.001). A significantly greater response with reboxetine than with placebo was seen as early as day 10 of treatment (p = 0.006). The therapeutic efficacy of reboxetine was substantiated by improvement in mean scores on the Zung Self-Rating Scale and on the Clinical Global Impression Severity of Illness and Global Improvement scales. Reboxetine was well tolerated, and only one patient in each group withdrew because of adverse events. Dry mouth, insomnia, blurred vision, sweating, and constipation were recorded more frequently in the reboxetine group than in the placebo group. There was a tendency toward orthostatic changes in the systolic blood pressure, but this was not clinically significant. This study demonstrated that reboxetine is significantly more effective than placebo in the treatment of hospitalized patients with severe major depressive disorder and is well tolerated.     

Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients

Impaired cognitive functioning is often associated with major depressive disorder (MDD). Moreover, a number of agents used to treat MDD are known to have negative effects on cognitive functioning. We report an assessment of the effects of the selective norepinephrine reuptake inhibitor reboxetine, the selective serotonin reuptake inhibitor paroxetine, and placebo on a variety of measures of cognitive functioning in patients with MDD. Cognitive functioning in 74 adult patients (aged 18-65 years) with a confirmed diagnosis of MDD (DSM-IV) was assessed as part of two identical, randomized, double-blind, placebo- and active-treatment-controlled, fixed/flexible dose comparisons of 8 weeks of treatment with reboxetine (8-10 mg/day), paroxetine (20-40 mg/day) and placebo. Cognitive function was assessed at baseline, day 14 and day 56 using a selection of tasks from the Cognitive Drug Research computerized assessment system, including Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working Memory, Word Recognition and Critical Flicker Frequency. The results in the 74 patients (reboxetine n = 25, paroxetine n = 23, placebo n = 26) showed that reboxetine significantly improved the ability to sustain attention at day 56 compared with baseline (P = 0.023). In addition, patients who received reboxetine experienced significant improvements in their speed of cognitive functioning when tested at day 56 compared to baseline (P = 0.024). No significant changes or trends in this direction were seen among patients who received either placebo or paroxetine. The results of the present study provide objective data to support the possibility that reboxetine favourably affects cognitive processes in depressed patients.     

Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor

Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a score > or =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total score < or =31 and >31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores < or =31 or >31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total score < or =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the >31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score >31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.     

Does baseline fatigue influence treatment response to reboxetine or citalopram in depression? An open label randomized controlled trial

It has been suggested that antidepressants that increase noradrenergic transmission should be better than serotonergic antidepressants at treating fatigue in depression. We conducted a secondary analysis of an RCT in which patients with depression were randomly assigned to reboxetine (a noradrenaline reuptake inhibitor [NARI]) or citalopram (a selective serotonin reuptake inhibitor [SSRI]). We investigated the difference between citalopram and reboxetine in treating the symptom of fatigue in depression, and also in treating depression with high levels of baseline fatigue. We found no difference between citalopram and reboxetine in terms of improvement in fatigue at six weeks (0.11, 95% confidence interval (-0.28, 0.49); p = 0.59:), or at 12 weeks. Using the Beck Depression Inventory at 12 weeks as the outcome measure, we found some evidence in support of our hypothesis that reboxetine is more effective than citalopram in treating depression in those with high baseline fatigue (interaction term: -2.87, 95% confidence interval (-5.15, -0.60); p = 0.01). We conclude that there is no evidence of any difference between reboxetine and citalopram in their efficacy in treating fatigue as a symptom of depression, but that reboxetine may be more effective in treating depression with high levels of fatigue. Fatigue might be useful in the prediction of response to NARIs or SSRIs.     

Reboxetine,a new noradrenaline selective antidepressant,is at least as effective as fluoxetine in the treatment of depression

The clinical profile of reboxetine, a selective noradrenaline reuptake inhibitor, was compared with that of the selective serotonin reuptake inhibitor fluoxetine and placebo in a double-blind, multicenter, parallel-group clinical trial of patients with major depression. Among the 381 patients treated with reboxetine 8 to 10 mg/day, fluoxetine 20 to 40 mg/day, or placebo for up to 8 weeks, a statistically significant greater reduction in the mean Hamilton Rating Scale for Depression (21-item HAM-D) total score (the primary efficacy variable) was seen for both active treatment groups compared with placebo (p < 0.024). A significantly greater proportion of patients treated with either reboxetine or fluoxetine also achieved a response (>or=50% reduction in HAM-D) or remission (HAM-D 相似文献   

Reboxetine and citalopram in panic disorder: a single-blind,cross-over,flexible-dose pilot study

Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder. The advent of selective serotonin (5-HT) reuptake inhibitors (SSRIs) (e.g. citalopram) and, more recently, selective noradrenergic (NA) reuptake inhibitors (NRIs) (e.g. reboxetine) has provided potentially important avenues of treatment for the disorder. To date, the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved. Nineteen patients with panic disorder were randomized in a single-blind, cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug. At week 18, seven of 13 patients (54%) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram (82%). Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy. However, citalopram demonstrated superior efficacy in treating depressive symptoms. One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram. Although SSRIs are viewed as a first-line treatment for panic disorder, these results suggest that a NA agent such as reboxetine may also have a role. These data also suggest an advantage for citalopram in treating comorbid depressive symptoms, although some patients may respond preferentially to an SSRI and other patients to an NRI.     

Successful treatment of reboxetine-induced urinary hesitancy with tamsulosin.

Urinary hesitancy can be an uncomfortable side effect during antidepressant treatment. Clinicians often use the selective alpha(1A)-adrenoceptor antagonist, tamsulosin, to treat urinary hesitancy associated with prostate enlargement. We report here a series of case studies in which tamsulosin has been successfully used in the management of urinary hesitancy during therapy with the selective noradrenaline reuptake inhibitor reboxetine for major depressive disorder (MDD). Eight male adults (aged 43-64 years; DSM-IV diagnosis of MDD) who were receiving treatment with reboxetine (4-8 mg/day) were considered candidates for concomitant tamsulosin (0.4 mg/day) therapy. Tamsulosin was administered either as prophylaxis (n=4) or as treatment (n=4) for emergent urinary hesitancy. All patients experienced relief of urinary hesitancy within 20 min of tamsulosin therapy and this effect was sustained. Concomitant treatment with tamsulosin should be considered for those patients in whom urinary hesitancy may lead to withdrawal from reboxetine therapy.     

Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment

Sexual dysfunction is a frequently reported side effect of many antidepressants, including serotonin reuptake inhibitors. Bupropion, an antidepressant of the aminoketone class, is relatively free of adverse sexual effects. In a randomized, double-blind, multicenter trial, sustained-release bupropion (bupropion SR) and sertraline, a selective serotonin reuptake inhibitor, were found to be similarly efficacious in the treatment of outpatients with moderate to severe depression. This report describes the results of a double-blind comparison of the sexual side effect profiles of bupropion SR and sertraline. Two hundred forty-eight patients who had received a diagnosis of moderate to severe major depression were randomly assigned to receive treatment with bupropion SR (100-300 mg/day) or sertraline (50-200 mg/day) for 16 weeks. Eligible patients were required to be in a stable relationship and to have normal sexual functioning. Sexual functioning was assessed by the investigator at each clinic visit using investigator-rated structured interviews. A significantly greater percentage of sertraline-treated patients (63% and 41% of men and women, respectively) developed sexual dysfunction compared with bupropion SR-treated patients (15% and 7%, respectively). Sexual dysfunction was noted as early as day 7 in sertraline-treated patients at a dose of 50 mg/day and persisted until the end of the 16-week treatment phase. Four patients, all of whom were treated with sertraline, discontinued from the study prematurely because of sexual dysfunction. Given the similar efficacy of the two drugs in treating depression, bupropion SR may be a more appropriate antidepressant choice than sertraline in patients for whom sexual dysfunction is a concern.     

Switching to tianeptine in patients with antidepressant-induced sexual dysfunction

Sexual side effects are frequent and are recently being considered as effects of antidepressant treatment. One method to improve the sexual dysfunction associated with the use of antidepressants is to change to another antidepressant. In the present work, the consequences of switching to tianeptine in patients with antidepressant-induced sexual dysfunction were studied. The study group comprised 23 patients with major depressive disorder who experienced antidepressant-induced sexual dysfunction. These antidepressants were stopped and switched to tianeptine (12.5mg x 3/day). All patients were screened by using the clinical global impression-improvement scale (CGI-I), the Hamilton depression rating scale (HAM-D) and the Arizona sexual experience scale (ASEX) at the beginning of the study, and at weeks 4 and 8. No patient failed to tolerate 37.5mg of tianeptine or to complete the study except for one patient becoming pregnant. Paired t-tests revealed a significant difference between baseline and week 4 or week 8 in scores on both the HAM-D and ASEX. At 8 weeks, six patients were rated as very much improved (CGI-I=1) and ten patients were rated as much improved (CGI-I=2). Thus, with a CGI-I score of 2 or less used to indicate a positive response, 72.7% of the patients were responders. The results suggest that switching to tianeptine appears to be useful for alleviating sexual dysfunction caused by other antidepressants.     

Effect of combined treatment with noradrenaline and serotonin reuptake inhibitors on conditioned freezing

To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment.     

Reboxetine in the treatment of bulimia nervosa: a report of seven cases

Controlled trials in patients with bulimia nervosa have demonstrated efficacy of antidepressant medications with serotonergic function (e.g. fluoxetine) as well as noradrenergic function (e.g. desipramine). Seven outpatients with bulimia nervosa according to DSM-IV criteria were treated openly with 8 mg of reboxetine, a selective noradrenaline reuptake inhibitor (NRI) over a 12-week period. The patients were assessed with the Structured Clinical Interview for DSM, Clinical Global Impression, 17-item Hamilton Depression Rating scale (HAM-D), Eating Disorder Inventory, Eating Disorders Questionnaire, daily self-ratings of eating behaviour, and the UKU side-effect rating scale. Three patients dropped out prematurely, one after 6 weeks and two after 4 weeks of reboxetine treatment. The reasons for premature attrition were rapid remission in one patient after 2 weeks and constipation, which led to an increase in episodes of laxative intake in two patients. In the total group, the monthly binge eating frequency showed a reduction of 73% and the frequency of vomiting episodes per month decreased by 67%. Furthermore, there was a concomitant decrease of depression ratings (HAM-D: from 12.2-6.1). Reboxetine seems to be an option for the treatment of bulimia nervosa.     

Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats

RATIONALE: Although drug discrimination procedures have proven difficult to apply to antidepressant agents, we recently characterized discriminative stimulus properties of the selective serotonin (5-HT) reuptake inhibitor, citalopram, in rats. However, discriminative stimulus properties of selective norepinephrine (NE) reuptake inhibitors remain to be evaluated. OBJECTIVE: We determined the potential discriminative stimulus properties of the highly selective NE reuptake inhibitor and antidepressant, reboxetine. METHODS: Employing a two-lever discrimination procedure, rats were trained to discriminate reboxetine (2.5 mg/kg, IP) from saline. In parallel, the influence of reboxetine (2.5 mg/kg) upon dialysate levels of monoamines in frontal cortex and dorsal hippocampus of freely moving rats was determined. RESULTS: After 54+/-10 training sessions, reboxetine elicited robust stimulus recognition, fully generalizing to itself with an ED50 of 1.2 mg/kg. Two further NE reuptake inhibitors, desipramine (5.3) and maprotiline (1.8), as well as the 5-HT/NE reuptake inhibitor, venlafaxine (1.0), likewise generalized. In contrast, the 5-HT reuptake inhibitors, paroxetine, citalopram and sertraline, and the DA reuptake inhibitors, GBR12935 and bupropion, did not show significant generalization. Reboxetine markedly increased dialysate levels of NE, but not 5-HT, in frontal cortex and hippocampus. Dopamine (DA) levels were also (though less markedly) enhanced in frontal cortex. CONCLUSION: In parallel with an elevation in extracellular levels of NE, the selective NE reuptake inhibitor, reboxetine, elicits a specific discriminative stimulus in rats.     

Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.     

Effects of reboxetine on anxiety,agitation, and insomnia: results of a pooled evaluation of randomized clinical trials

Several recent clinical trials have established that reboxetine, a new selective norepinephrine reuptake inhibitor (selective NRI), is effective and safe for the treatment of major depression. However, the effects of reboxetine on specific symptoms of anxiety, agitation, and insomnia have not been reported. Data were obtained from nine short-term, double-blind, randomized clinical trials in patients with major depression. After initial titration, patients received reboxetine 8 to 10 mg per day. The effects on specific HAM-D symptoms of agitation, anxiety, and insomnia were compared between reboxetine-and placebo-treated patients. In addition, the incidence of treatment-emergent agitation, anxiety, and insomnia side effects with reboxetine were examined. Compared with placebo, the proportion of patients with improvement on the HAM-D agitation item and the HAM-D anxiety and insomnia factors from baseline was significantly greater with reboxetine at most assessment intervals. In general, the incidence of agitation-or anxiety-related side effects was comparable with reboxetine and placebo. Although reboxetine was associated with a significant (p < 0.05) increase in treatment-emergent insomnia reported as an adverse effect during the first week of treatment, very few reports of insomnia were made at subsequent evaluations. The incidence of treatment-emergent agitation or anxiety was comparable between treatment groups.