Efficacy Of Newer Antidepressants Research Articles

A Single-Day Treatment with Mifepristone Is Sufficient to Normalize Chronic Glucocorticoid Induced Suppression of Hippocampal Cell Proliferation

BackgroundChronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis.MethodsWe investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment.ResultsCorticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days.ConclusionsOur results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration.

Imipramine dose in relation to therapeutic plasma level: are clinical trials using imipramine as a positive control flawed?

Imipramine has often been used as positive control in studies investigating the efficacy of new antidepressants. Imipramine-controlled studies in general employ a fixed-dose design. It is unclear how many patients would achieve effective plasma levels with such a design. The objectives of this study were to assess the range of doses necessary to attain a therapeutic plasma level in the imipramine arms of two double-blind, fixed-plasma-level studies and to compare them with doses administered in efficacy studies with imipramine as a positive control. During two double-blind studies, imipramine doses were adjusted to a predefined fixed plasma level. Here we report an analysis of the range of doses necessary to attain that level in the imipramine arms of the studies. We also computed the cumulative percentage of patients with therapeutic plasma levels (> or = 200 ng/ml) at various imipramine doses in order to compare them with doses administered in efficacy studies with imipramine as a positive control. Target plasma levels were attained with a mean daily dose of 248 mg, with a dose range of 50-450 mg. We calculated a possible increase in efficacy of imipramine of about 20% if doses had been adjusted to therapeutic plasma levels in clinical trials using it as a positive control. The absence of significant differences in efficacy between selective serotonin re-uptake inhibitors (SSRIs) and imipramine in these trials is at least in part due to improper dosing of the latter; imipramine with therapeutic drug monitoring may be more effective than SSRIs.

Traitement des épisodes dépressifs sévères : escitalopram est plus efficace que citalopram

Escitalopram is a highly selective serotonin reuptake inhibitor (SSRI). It is the therapeutically active S-enantiomer of citalopram. It has been shown, compared with placebo, to be an effective and well-tolerated treatment for major depressive disorders (MDD) in both primary and specialist care settings. A recent meta-analysis has found that escitalopram-treated patients showed significant higher response rates and increased mean change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total scores at weeks 1 and 8 compared with citalopram-treated patients. Each of these active drugs shares similar safety profiles. Although the efficacy of newer antidepressants has been well established for the treatment of mild-to-moderate depression, there are very few studies concerning severe depression.To determine if escitalopram is more effective than citalopram in patients with severe depression.Data were pooled from three different clinical trials, each similar in design and inclusion/exclusion criteria, primary endpoints and assessment schedules. This analysis was exhaustive because it included all trials in which the maximum dose for escitalopram (20 mg) could be administered. According to the cut-off point taken to define severe depression based on the MADRS total score ( 30), 506 patients were considered as severely depressed patients and so included in this analysis. Among them, 169 received escitalopram, 171 received citalopram and 166 received the placebo. The primary efficacy parameter was the mean change from baseline to end of treatment in MADRS total score between escitalopram and citalopram groups, based on last-observation-carried-forward method. The change from baseline to endpoint of the Hamilton rating scale for Depression (HAM-D) and the Clinical Global Impression of Improvement and Severity (CGI-I and CGI-S) were also analysed as secondary criteria. Clinical response was defined by at least a 50% reduction in baseline MADRS total score or by at least a 60% reduction in baseline HAM-D score or by a score of 1 (very much improved) on the CGI scale, and remission by a MADRS total score pound 12.Results showed that the mean change from baseline in the MADRS total score was significantly higher in the escitalopram group compared with the citalopram group (- 17.3 vs - 13.8 respectively, p=0.003). This significant difference was observed as early as week 1 (p=0.01). Response rates were significantly higher for escitalopram than for citalopram (56% vs 41% respectively, p=0.007). A borderline significant difference was found for remission rate in the observed-cases analysis (43% vs 33% respectively, p=0.07). Analyses of the HAM-D, CGI-I and CGI-S scores revealed consistent results.This study shows that the new SSRI escitalopram has better efficacy in the treatment of severe depression than citalopram, its racemic parent. Mean differences between treatments groups were in favour of escitalopram for all scales. The benefits of escitalopram compared with citalopram, as demonstrated by both magnitude of effect and time of onset, are superior to the benefits of citalopram, an antidepressant drug with proven efficacy. This evidence clearly supports the use of escitalopram as a legitimate first-line treatment for MDD.

Burdens and benefits of placebos in antidepressant clinical trials: a decision and cost-effectiveness analysis.

The use of placebos is a necessary, if controversial, part of determining the efficacy of new antidepressants in randomized clinical trials. Such studies need to convey accurate and useful risk-benefit information to subjects since effective treatments are withheld. The authors assessed the cost-effectiveness of entering such a trial from the perspective of potential subjects. The choice between individualized psychiatric treatment and an 8-week placebo-controlled, randomized clinical trial was modeled by using a static model. The analysis was conducted from the perspective of a potential subject who has moderate depression, is at low risk for suicide, has no comorbid conditions, and lacks adequate insurance to pay for mental health services. The trial was assumed to be free for subjects, except for indirect costs. Model outcomes included the probability of treatment response at 8 weeks and "decremental" cost-effectiveness. Data were based on reviews of published and some unpublished clinical trials of novel antidepressants that were eventually shown to be efficacious. A participant in a typical antidepressant efficacy trial has a chance of treatment response almost 25% less than that with individualized treatment. An uninsured participant can expect to save just over $164 for every 10% chance of response sacrificed by entering the placebo-controlled trial. For placebo-controlled antidepressant trials, it is possible to derive systematic and evidence-based estimates of the burdens and potential benefits to subjects. Such information may be more useful for institutional review boards and potential subjects than an unstructured enumeration of risks and benefits.

Escitalopram: A consistently effective antidepressant

La prise en charge thérapeutique des patients atteints de dépression sévère reste encore un challenge pour les médecins. Par rapport à la forme légère ou modérée, la dépression sévère se caractérise souvent par une durée plus longue, une co-morbidité supérieure, une plus faible probabilité de rémission spontanée et un taux de rechute plus important. Par ailleurs, si l’efficacité des nouveaux antidépresseurs est bien établie dans la dépression légère à modérée, beaucoup moins d’études ont été réalisées dans la dépression sévère. Probablement parce que la dépression sévère n’est pas perçue comme une entité à part, mais comme un continuum dans la clinique de cette pathologie, et aussi peut-être en raison d’une absence de consensus clair sur la définition même de cette sévérité. Après avoir utilisé les définitions basées sur la clinique et sur le mode de prise en charge, les auteurs semblent désormais privilégier l’utilisation des échelles cliniques avec un seuil spécifique pour cette définition. En utilisant l’échelle MADRS (Montgomery-Åsberg Depression Rating Scale) et la valeur seuil de 30 pour définir la sévérité de la dépression, nous avons réalisé une analyse poolée avec les données des trois essais cliniques comparant l’efficacité du escitalopram à celle du citalopram. Les résultats montrent de façon constante une meilleure efficacité du escitalopram par rapport au citalopram, dans cette indication particulière qu’est la dépression sévère.Escitalopram is a highly selective serotonin reuptake inhibitor (SSRI). It is the therapeutically active S-enantiomer of citalopram. It has been shown, compared with placebo, to be an effective and well-tolerated treatment for major depressive disorders (MDD) in both primary and specialist care settings. A recent meta-analysis has found that escitalopram-treated patients showed significant higher response rates and increased mean change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at weeks 1 and 8 compared with citalopram-treated patients. Each of these active drugs shares similar safety profiles. Although the efficacy of newer antidepressants has been well established for the treatment of mild-to-moderate depression, there are very few studies concerning severe depression.To determine if escitalopram is more effective than citalopram in patients with severe depression.Data were pooled from three different clinical trials, each similar in design and inclusion/exclusion criteria, primary endpoints and assessment schedules. This analysis was exhaustive because it included all trials in which the maximum dose for escitalopram (20 mg) could be administered. According to the cut-off point taken to define severe depression based on the MADRS total score ( 30), 506 patients were considered as severely depressed patients and so included in this analysis. Among them, 169 received escitalopram, 171 received citalopram and 166 received the placebo. The primary efficacy parameter was the mean change from baseline to end of treatment in MADRS total score between escitalopram and citalopram groups, based on last-observation-carried-forward method. The change from baseline to endpoint of the Hamilton rating scale for Depression (HAM-D) and the Clinical Global Impression of Improvement and Severity (CGI-I and CGI-S) were also analysed as secondary criteria. Clinical response was defined by at least a 50 % reduction in baseline MADRS total score or by at least a 60 % reduction in baseline HAM-D score or by a score of 1 (very much improved) on the CGI scale, and remission by a MADRS total score £ 12. Results - Results showed that the mean change from baseline in the MADRS total score was significantly higher in the escitalopram group compared with the citalopram group (− 17.3 vs − 13.8 respectively, p = 0.003). This significant difference was observed as early as week 1 (p = 0.01). Response rates were significantly higher for escitalopram than for citalopram (56 % vs 41 % respectively, p = 0.007). A borderline significant difference was found for remission rate in the observed-cases analysis (43 % vs 33 % respectively, p = 0.07). Analyses of the HAM-D, CGI-I and CGI-S scores revealed consistent results.This study shows that the new SSRI escitalopram has better efficacy in the treatment of severe depression than citalopram, its racemic parent. Mean differences between treatments groups were in favour of escitalopram for all scales. The benefits of escitalopram compared with citalopram, as demonstrated by both magnitude of effect and time of onset, are superior to the benefits of citalopram, an antidepressant drug with proven efficacy. This evidence clearly supports the use of escitalopram as a legitimate first-line treatment for MDD.

The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature

The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature

The Efficacy of Newer Antidepressants in the Treatment of Chronic Pain: A Review of Current Literature

Tricyclic antidepressants have been extensively studied and frequently used in the treatment of various chronic pain syndromes. Newer antidepressants, namely fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, trazodone, nefazodone, bupropion, mirtazapine, and venlafaxine, have also been considered for this indication, although they have been less extensively studied. This article reviews the available publications, including placebo-controlled trials, other outcome studies, and case reports, pertaining to the use of these medications for chronic pain. Although some of these newer compounds may be effective for specific types of pain, making generalizations regarding their use as analgesics is difficult, given the limitations of existing data. Additional observations based on the data are presented in the hope that they may help to guide further research and clinical use.

Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide.

Depression is a significant problem in the elderly. Because of aging-related pharmacokinetic and pharmacodynamic changes, it is not possible to automatically extrapolate findings on the efficacy or tolerability of antidepressants from younger to older populations. Venlafaxine inhibits both noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake. Analysis of data from phase II and III trials showed that venlafaxine was comparably effective in the young and in a subset of over 350 elderly patients. Venlafaxine dosage needs to be lowered in the elderly with renal impairment. As a weak cytochrome P450 (CYP) inhibitor, it is unlikely to have clinically significant drug interactions. Venlafaxine may be associated with some increase in supine diastolic blood pressure, especially at dosages above 150 mg/day. Nefazodone is a serotonin uptake inhibitor and serotonin 5-HT2A receptor antagonist. Pooled analysis of about 250 patients found nefazodone to be effective in elderly individuals with moderate or severe depressive symptoms, with or without melancholia, in both primary and recurrent episodes. Nefazodone clearance is reduced in patients with hepatic impairment, and plasma concentrations have been reported to be higher in the elderly. Nefazodone is an inhibitor of the CYP3A4 family. There does not appear to be any increase in the frequency or severity of adverse effects in the elderly. Moclobemide is a selective inhibitor of monoamine oxidase type A. Studies in the elderly have found it to be well tolerated and meta-analysis has shown it to be comparably effective in young and elderly populations, and comparable to other antidepressants in terms of efficacy. Neither age nor renal impairment necessitate dosage adjustment, but hepatic impairment does necessitate dosage reduction. Dietary restrictions are not required. Overall, there is a relative paucity of data on the tolerability and efficacy of newer antidepressants in the elderly, especially those with concomitant medical disorders. Data that are available indicate that venlafaxine, nefazodone and moclobemide have comparable efficacy in older and younger patients.

Approaches to the Management of Depression in Old Age

Depression in old age is common, underdiagnosed and undertreated. It has a high rate of recurrence and is associated with significantly increased mortality. Its mismanagement stems in large part from the misconceptions that it is an inevitable condition, that old people are too inflexible to change, and that treatment is unacceptably hazardous. There is considerable potential for prevention, improved detection and appropriate treatment. In addition, it is increasingly clear that treatment can improve prognosis. Prevention requires education, and a political agenda to address aetiological factors such as poverty, loneliness, institutionalisation and poor physical health. Treatment with antidepressant drugs and/or psychological techniques is effective. Newer drugs may well be superior in safety and real-life tolerability but require better evaluation in representative samples, against placebo and incorporating cost-benefit and quality-of-life measures. Prophylaxis with antidepressants, electroconvulsive therapy and psychotherapy groups has been shown to be effective. The prophylactic efficacy of newer antidepressants has yet to be properly evaluated.

Pharmacotherapy of depression in the medically ill: Directions for future research

A common problem facing the psychiatric consultant and the medical practitioner is evaluating depression in patients with concurrent medical illnesses. Depression is difficult to recognize in the medically ill, often presenting with “masked” symptoms and organized into unique syndromes. A primary concern of the clinician is identifying those patients who are likely to benefit from an antidepressant trial. Although antidepressants have been shown to sometimes be of benefit in medical populations, the symptoms predicting antidepressant response remain poorly defined. Important directions for future research include 1) evaluating the safety and efficacy of newer antidepressants in the medically ill and 2) identifying those depressive syndromes that may be responsive to pharmacotherapy.