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.     

西酞普兰治疗脑卒中后抑郁的疗效观察

目的观察西酞普兰治疗脑卒中后抑郁(PSD)患者的疗效和不良反应。方法随机将80例脑卒中后抑郁患者分为西酞普兰组40例和对照组40例,于治疗前及治疗后第4周末,对两组患者进行Hamilton抑郁量表(HAMD))评定。结果治疗后,西酞普兰组患者的HAMD评分较治疗前差异有统计学意义(P<0.01),西酞普兰组的不良反应少且轻与对照组相比差异无统计学意义。结论西酞普兰治疗脑卒中后抑郁安全、有效。     

Is There an Advantage to Venlafaxine in Comparison with Other Antidepressants?

The purpose of this article is to compare and contrast the benefits and limitations of antidepressant drugs. Several different classes of antidepressants are available for treatment of major depressive disorder, each with its own benefits and limitations as a result of its pharmacological profile. Tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors are effective in a large proportion of depressed patients, but their use is often limited by short- and long-term safety/tolerability problems. Selective serotonin reuptake inhibitors (SSRIs) exhibit comparable efficacy to TCAs in most patients, but may be less effective in certain patients. Additionally, SSRI use may by impacted by clinically significant drug interactions. Venlafaxine is a selective serotonin-noradrenaline reuptake inhibitor (SNRI) with unique pharmacological properties that may enhance its efficacy as well as its safety profile. In clinical trials, venlafaxine exhibits antidepressant activity in a broad range of patients with major depression, including those with melancholia, agitated or retarded symptoms, anxiety symptoms, and refractory or resistant depression. Venlafaxine has shown potential for an early onset of action and offers dose flexibility that may allow recruitment of additional responders at higher dosages. Because of its lack of affinity for muscarinic cholinergic, histaminergic, and alpha₁-adrenergic receptors, venlafaxine has a safety profile that is superior to that of TCAs. Venlafaxine also is devoid of the drug interactions characteristic of SSRIs. © 1997 John Wiley & Sons, Ltd.     

Citalopram in the treatment of depression and other potential uses in psychiatry.

During the past decade, treatment options for depression have increased with the introduction of new agents. Older agents, such as tricyclic antidepressants and monoamine oxidase inhibitors, increase noradrenergic and serotonergic neurotransmission. Attempts to separate antidepressant effects from adverse effects led to the development of selective serotonin reuptake inhibitors (SSRIs). Citalopram is the newest SSRI to be marketed in the United States. Of all SSRIs on the market, it is the most selective for serotonin reuptake pump. Its efficacy in treating depression was evident in both placebo-controlled and comparator trials. In addition, citalopram was studied in the treatment of other psychiatric disorders. The agent has less inhibition of cytochrome P450 enzymes than other SSRIs, possibly giving it a lower potential for drug interactions.     

Effectiveness and acceptability of sertraline and citalopram in major depressive disorder: pragmatic randomized open-label comparison

OBJECTIVE: Citalopram and sertraline are widely prescribed selective serotonin reuptake inhibitors (SSRIs). There is no conclusive evidence to show superiority of citalopram or sertraline in terms of efficacy or tolerability. Hence this study was designed to compare short term efficacy and safety of citalopram and sertraline in major depressive disorder (MDD) in Indian patients. METHODS: In an open, randomized study, 100 patients were divided into two groups. In Group A (n = 50) patients received citalopram (20-60 mg/day) for 6 weeks. In Group B (n = 50) patients received sertraline (50-150 mg/day) for 6 weeks. Patients were evaluated at baseline and then at 1, 2, 3, 4, 5, and 6 weeks. RESULTS: There was significant improvement in Hamilton depression rating scale (HDRS), Montgomery and Asberg depression rating scale (MADRS) and Amritsar depressive inventory (ADI) scores (p < 0.05) with both the drugs. However, the decrease in score was more with citalopram (p < 0.05). Onset of action of citalopram was earlier as compared to sertraline (p < 0.05). The number of responders and remitters was also more with citalopram (p < 0.05). No serious adverse event was reported in either of the groups. CONCLUSION: Citalopram had shown better efficacy, earlier onset of action and more number of responders and remitters as compared to sertraline in MDD in Indian patients.     

Reboxetine: a review of efficacy and tolerability

Clinical data on the efficacy and tolerability of the novel selective noradrenergic reuptake inhibitor reboxetine are reviewed. Reboxetine appears to have almost no pharmacological activity other than potently blocking the reuptake of noradrenaline. Clinical studies show reboxetine to be highly effective for the treatment of major depression. Reboxetine is more effective than placebo and comparable in efficacy to tricyclic antidepressants and selective serotonin reuptake inhibitors. Some studies suggest that reboxetine may have slightly better efficacy than fluoxetine and imipramine. Reboxetine is effective in severely depressed patients as well as elderly depressed persons. Reboxetine is remarkably well tolerated, having very few side effects. Reboxetine appears to cause little sexual dysfunction. The most common side effects are dry mouth and constipation. The drug does not inhibit or induce hepatic cytochrome P450 enzymes and is safe in overdose. Reboxetine may prove to be as effective and better tolerated than any other antidepressant currently available.     

Efficacy and tolerability of reboxetine compared with citalopram: a double-blind study in patients with major depressive disorder

The objective of this study was to compare efficacy and tolerability of the selective noradrenaline reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram, in the treatment of major depressive disorder (MDD). In total, 357 outpatients with MDD were randomized to treatment with reboxetine 8-10 mg or citalopram 20-40 mg per day during 24 weeks. Primary end-point was change from baseline in the Hamilton Depression Rating Scale (HAM-D, 21 items). Sexual function/dysfunction was measured by the Sexual Function scale (SF). Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores: reboxetine with -21.4 and citalopram with -22.1 points (NS). LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine (-19.6 vs. -17.8; P = 0.034). The response rate was 90.3% for reboxetine and 92.7% for citalopram (NS). The most common side effect in the reboxetine group was dry mouth, and in the citalopram group sexual dysfunction. At week 24, anorgasmia was reported by 5.9% of the sexually active women in the reboxetine group vs 39% in the citalopram group. The dropout number was 91 in the reboxetine group, and 54 in the citalopram group. To summarize, both treatments gave a satisfactory antidepressant effect. The side effect profile differed between the groups, with a notably high prevalence of sexual dysfunctions in the citalopram group. The high number of dropouts in the reboxetine group, is considered as a result of the non-titration starting dose of 8 mg reboxetine per day, which gave a high incidence of early side-effects.     

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.     

Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder

The aim of this study was to compare the efficacy and tolerability of reboxetine, a uniquely selective noradrenaline reuptake inhibitor, with the selective serotonin reuptake inhibitor, fluoxetine. A double-blind, randomized, parallel-group, multicentre design was employed. One hundred and sixty-eight patients with acute major depressive episodes were randomized to receive oral reboxetine (8-10 mg/day) or oral fluoxetine (20-40 mg/day). The treatment period was 8 weeks. Reboxetine and fluoxetine were similarly effective as assessed by the mean reduction in total Hamilton Depression Rating Scale score, the percentage of responders and patients in remission, Clinical Global Impression severity of illness and global improvement scores and Montgomery-Asberg Depression Rating Scale. A sub-analysis of patients with severe depression indicated that reboxetine had superior efficacy compared with fluoxetine. Both treatments resulted in some improvement in Social Adaptation Self-evaluation Scale total scores and this was more evident for those patients treated with reboxetine who achieved remission. Both treatments were well tolerated. The results indicate that reboxetine is an effective and well tolerated antidepressant, being more effective than fluoxetine in patients with severe depression, and more effective in terms of social functioning in those patients who achieved remission.     

In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation

BackgroundAlthough several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis.MethodsThis study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine.ResultsNone of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100 μg/l, p < 0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram > sertraline > reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen.ConclusionThis study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets.     

Involvement of serotonin neurotransmission in hippocampal neurogenesis and behavioral responses in a rat model of post-stroke depression

Ischemia-stimulated dentate gyrus (DG) neurogenesis is hypothesized to be an etiological factor of post-stroke depression (PSD) and a potential target of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in PSD. Clinical investigations have explored the strategy of augmenting SSRIs action by combination with a 5-HT1A receptor antagonist. We investigated the relative importance of the effects on ischemia-stimulated neurogenesis and depressive-like behavior of WAY-100635 versus citalopram at different dose levels in PSD animals. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Decreased sucrose consumption was indicative of the core depressive syndrome anhedonia. Proliferating cells and their fate were monitored by bromodeoxyuridine labeling protocols up to 28 days after ischemia. Expression of the 5-HT1A receptor in DG was also examined. The current findings confirmed the ability of WAY-100635 to augment SSRIs pharmacological efficacy and SSRIs-induced elevation of post-stroke DG neurogenesis. Specifically, WAY-100635 and citalopram in different dose combinations display their relative importance in ischemia-stimulated neurogenesis probably through reinforcing serotonergic neurotransmission and/or density of 5-HT1A receptor in DG. The present data extend our understanding that increase of ischemia-induced DG neurogenesis can be interpreted as a valid index, to an extent, or even a prerequisite for an efficient co-treatment strategy.     

Citalopram

Citalopram is a selective serotonin (5-HT) reuptake inhibitor (SSRI) developed by H. Lundbeck A/S in Denmark. It is the most selective serotonin antidepressant with proven efficacy, a favourable pharmacokinetic profile and a low potential for interactions with other concomitant medication. The drug has a low incidence of side effects, even when compared to the other SSRIs and good patient compliance and satisfaction is a feature of this drug. These factors make the drug a good choice for depressed patients who require continuation and long-term treatment, as well as for elderly patients. Copyright 2000 John Wiley & Sons, Ltd.     

Overview of the safety of citalopram

Citalopram is a highly selective serotonin reuptake inhibitor (SSRI) that has been prescribed to >30 million patients in >70 countries. The purpose of this focused overview is to summarize the data from well-controlled clinical trials and published literature relative to the safety of citalopram in patients with depression and depressive symptoms. This overview is based mainly on 3 sources: (1) data from clinical trials sponsored by Forest Laboratories, (2) published clinical studies, and (3) case reports. Both pharmacokinetic and pharmacodynamic interactions were scrutinized, as were data on special populations and safety concerns. The available data suggest that citalopram 20-60 mg once daily is safe for patients with depression. Few drugs appear to interact with citalopram in a clinically meaningful way. Well-designed short- and long-term trials demonstrate an overall safety/side effect profile consistent with other SSRIs. The more frequent adverse events (nausea, somnolence, dry mouth, increased sweating) are mainly transient, mostly mild to moderate in severity, and observed consistently across studies at rates similar to other SSRIs. Analysis of laboratory values, ECG, and vital signs revealed no unusual findings. Only a small, clinically unimportant reduction in heart rate was observed, similar to that seen with other SSRIs. Citalopram treatment did not increase risk of suicide, overdose, seizure, or arrhythmia. Thus, the pharmacodynamic, pharmacokinetic, and safety profiles of citalopram demonstrate that it is safe for use in adults with depression and depressive symptoms, including the elderly and patients with mild to moderate renal and hepatic disease.     

Discriminative stimulus properties of antidepressant agents: a review

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.     

抗抑郁新药西酞普兰的药代动力学

西酞普兰是已在中国上市的抗抑郁药，为一种五羟色胺冉摄取抑制剂（SSRIs），由于其疗效肯定和副作用小，而倍受关注。本文主要就西酞普兰在人体内吸收、分布、代谢、排泄的药代动力学特征；对年龄、性别、吸烟、肝肾功能损害等因素的影响及与其他药物的相互作用做一综述。     

Escitalopram

Escitalopram, a selective serotonin reuptake inhibitor (SSRI) was recently approved by the United States Food and Drug Administration (FDA) for the treatment of major depression. This chapter reviews preclinical and clinical studies with escitalopram, focusing on its therapeutic profile of action and tolerability. Escitalopram is the S-enantiomer of the racemic SSRI citalopram. It has been proposed that the S-enantiomer of citalopram is the isomer that holds antidepressant efficacy, and that the R-enantiomer is clinically inactive; preclinical and clinical data support this. Based on in vitro radioligand binding data, escitalopram is the most selective SSRI available. Hypotheses that escitalopram has a more rapid onset of action or fewer adverse effects than citalopram have not yet been fully documented in published studies, although its profile is at least comparable to citalopram. Escitalopram is more effective than placebo in the treatment of major depression and as effective as other SSRIs, including citalopram. Comparable to other SSRIs, it is well tolerated, safe in overdose and has a low incidence of adverse effects or drug interactions.     

Citalopram: new indication. No advantage

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.     

小剂量米氮平联合西酞普兰治疗脑卒中后抑郁症的疗效分析

目的探讨小剂量米氮平联合西酞普兰治疗脑卒中后抑郁症（PSD）的临床疗效及安全性。方法将我院收治的114例脑卒中后抑郁症患者,将其随机分为对照组和观察组,每组57例。对照组给予西酞普兰,观察组在此基础上给予小剂量的米氮平。治疗6周,观察并比较两组患者的临床疗效。治疗前后采用汉密尔顿抑郁量表（H｜删D）、日常生活能力Barthel指数（BI）量表、临床神经功能缺损评分（SSS）以及不良反应症状量表（TESS）评定疗效及治疗出现的不良反应。结果6周后,两组治疗PSD均有效,观察组的基本治愈率为29．82％,对照组的基本治愈率为21．05％,两组患者间的基本治愈率的差异具有统计学意义（P〈0．05）,观察组总有效率（92．98％）明显高于对照组（80．71％）,差异有显著性（P〈0．01）。观察组HADM和SSS评分明显低于对照组（P〈0．05）,BI评分明显高于对照组（P〈0．05）,两组患者的TESS评分无显著性差异,但观察组在失眠及头痛或头晕方面明显低于对照组（P〈0．01）。结论西酞普兰联合小剂量米氮平治疗脑卒中后抑郁症的疗效显著,安全性好,利于神经功能康复,能提高患者的生活质量。     

Neuropharmacology of antidepressants that modify central noradrenergic and serotonergic function: a short review

The first generation of antidepressants largely act as ‘dual’ action drugs in that they facilitate both noradrenergic and serotonergic activity either by blocking the reuptake of noradrenaline and serotonin (tricyclic antidepressants) or by inhibiting the catabolism of these amines (monoamine oxidase inhibitors). Largely as a consequence of their unacceptable side effects, these drugs have been partly replaced by the second generation drugs that showed selectivity of either the noradrenaline (viloxazine, maprotiline, reboxetine) or serotonin (fluoxetine, sertraline, etc.) transporter. While these second generation drugs have undoubted advantages in terms of their safety and tolerability, there is growing evidence that the efficacy of some of these selective uptake inhibitors (e.g. SSRIs) in the treatment of the more severe forms of depression is less than that of the TCAs. This has led to the view that ‘dual action’ antidepressants may offer superiority in the treatment of severe depression. Two groups of novel antidepressants have been developed to meet the need of combining increased efficacy with safety. These include the mixed amine reuptake inhibitors such as lofepramine, venlafaxine and milnacipran and the novel tetracyclic antidepressant mirtazepine that facilitates the functional activity of both noradrenaline and serotonin without affecting the reuptake sites. Copyright © 1999 John Wiley & Sons, Ltd.     

Are SNRIs more effective than SSRIs? A review of the current state of the controversy

The selective serotonin reuptake inhibitors (SSRI) are widely considered to be the first choice for antidepressant therapy. There is evidence from inpatient studies dating to 1986, however, suggesting that the tricyclic antidepressant clomipramine, which inhibits reuptake of both serotonin and norepinephrine, may have greater efficacy than some SSRIs for severe depression. There is controversy whether the newer, better tolerated, and safer serotonin norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and-in some countries-milnacipran and desvenlafaxine) are more efficacious than SSRIs. In addressing this controversy, this article first focuses on the limitations of randomized controlled trials (RCTs), including the factors that limit their sensitivity to detect differences between active antidepressants, and meta-analysis to examine results of large sets of RCTs. Next, the results of RCTs and meta-analyses are reviewed. Although few individual studies report significant differences, meta-analyses consistently suggest that venlafaxine may have greater efficacy than the SSRIs as a class. The magnitude of this advantage is modest (i.e., differences in remission rates of 5-10%) and no advantage has been demonstrated versus escitalopram. The advantage for duloxetine versus selected SSRIs is limited to patients with more severe depression and the RCTs are flawed by use of minimum therapeutic doses of SSRIs. No evidence of an advantage is found in RCTs of milnacipran versus SSRIs. Even a modest difference in antidepressant efficacy-if sustained-may have important public health implications for the common, disabling condition of depression. Nevertheless, differences in tolerability and cost also must be considered when choosing therapies.