Acute Treatment Of Major Depression Research Articles

Visualizing the evolution of evidence: Cumulative network meta-analyses of new generation antidepressants in the last 40 years.

It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta‐analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double‐blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all‐cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta‐Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two‐dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs.Highlights Network meta‐analysis is considered to be a proper way of demonstrating the available evidence, since it allows comparisons between multiple interventions, and has been proved to be statistically powerful.It is challenging to present the voluminous results of NMA in an efficient and comprehendible manner.Evidence evolution based on the relatively new method NMA has not been investigated yet.The results of NMA should not only include the effects but also the confidence in the evidence, which can help interpret the findings appropriately.Effective use of rapidly developing statistical analysis and presentation tools such as Shiny package in R, may facilitate and simplify the visualization of NMA output.We should stay conservative towards new drugs, as their performance was often shown to be exaggerated initially, and it took time to become stable.

No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.

In fixed-dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side-effects permit provides additional benefits is unknown. We did a systematic review of placebo-controlled randomized trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included drop-outs due to adverse effects and drop-outs for any reason. We conducted random-effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. We included 123 published and unpublished randomized controlled trials (29420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95% CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75 and 150mg over the fixed 75mg (1.30, 1.02 to 1.65). There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150mg.

Guidelines for the pharmacological acute treatment of major depression: conflicts with current evidence as demonstrated with the German S3-guidelines

Several international guidelines for the acute treatment of moderate to severe unipolar depression recommend a first-line treatment with antidepressants (AD). This is based on the assumption that AD obviously outperform placebo, at least in the case of severe depression. The efficacy of AD for severe depression can only be definitely clarified with individual patient data, but corresponding studies have only been available recently. In this paper, we point out discrepancies between the content of guidelines and the scientific evidence by taking a closer look at the German S3-guidelines for the treatment of depression. Based on recent studies and a systematic review of studies using individual patient data, it turns out that AD are marginally superior to placebo in both moderate and severe depression. The clinical significance of this small drug-placebo-difference is questionable, even in the most severe forms of depression. In addition, the modest efficacy is likely an overestimation of the true efficacy due to systematic method biases. There is no related discussion in the S3-guidelines, despite substantial empirical evidence confirming these biases. In light of recent data and with their underlying biases, the recommendations in the S3-guidelines are in contradiction with the current evidence. The risk-benefit ratio of AD for severe depression may be similar to the one estimated for mild depression and thus could be unfavorable. Downgrading of the related grade of recommendation would be a logical consequence.

Efficacy of antidepressants over placebo is similar in two-armed versus three-armed or more-armed randomized placebo-controlled trials.

Previous studies have reported that effect sizes of antidepressants were larger in two-armed than in three-armed or more-armed (multiarmed) randomized trials, where the probability of being allocated to placebo is lower. However, these studies have not taken into account the publication bias, differences among antidepressants, or covariance in multiarmed studies, or examined sponsorship bias. We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multiarmed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multivariate meta-analysis. A random-effects model was used throughout. Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multiarmed trials was 1.09 (95% confidence interval: 0.96-1.24). The ROR did not materially change between types of antidepressants, publication year, or sponsorship. The differences between two-armed versus multiarmed studies were much smaller than were suggested in previous studies and were not significant.

Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-to-head trials in acute major depression: Systematic review and meta-analysis.

A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin-reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons. We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings. In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent-improvement between TCAs and SSRIs. In addition to non-difference between drug-types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016. Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types.

Switching the Antidepressant After Nonresponse in Adults With Major Depression: A Systematic Literature Search and Meta-Analysis.

Nonresponders to antidepressant monotherapy during acute treatment of major depression are often switched to a new antidepressant. The objective of this meta-analysis was to compare the efficacy of switching to a new antidepressant with continuation of the first antidepressant. PubMed, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials (CENTRAL) databases and additional sources were systematically searched independently by 2 authors up to March 2015 without language limitations. With employment of a sensitivity-enhancing search strategy, generic terms for major depression, switching, and randomized trials were combined. Articles (3,234) were screened for trials of patients with major depression who had not responded to antidepressant monotherapy who were then randomized either to a new antidepressant or to continuation of the first antidepressant. Studies were subdivided into those not allowing for dose escalation in the continuation arm (strict analysis) and those allowing for dose escalation (broad analysis). Data were extracted and risk of bias was assessed independently by 2 authors, and data were pooled using random effects models. Four randomized controlled trials were included in the strict analysis and 8 in the broad analysis. In both analyses, switching was not superior to continuation: the standardized mean difference in the strict analysis was -0.17 (95% CI, -0.59 to 0.26; P = .45; I² = 77.8%) and in the broad analysis was 0.031 (95% CI, -0.26 to 0.32; P = .836; I² = 85.3%). All secondary outcome analyses (response and remission rates, low risk of bias studies only, leave-one-out analysis, dropouts) supported the results. There was no indication of publication bias. There is a dearth of randomized controlled trials investigating switching. There is no high-level evidence that switching the antidepressant is effective when compared to simply continuing the initial antidepressant. Since there are better treatment options than switching, physicians should be cautious to switch antidepressants.

Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies

Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics. In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression. We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk [RR] 1·00, 95% CI 0·97-1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01-1·05 for 1 more week in trial length; 1·32, 1·11-1·57 for multicentre vs single-centre trials). Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view. Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.

The Validity of the Different Versions of the Hamilton Depression Scale in Separating Remission Rates of Placebo and Antidepressants in Clinical Trials of Major Depression.

Our objective was to validate the different versions of the Hamilton Depression Scale (HAM-D) both psychometrically (scalability) and clinically in discriminating antidepressants from placebo in terms of remission rates in an 8-week clinical trial in the acute treatment of major depression. The traditional HAM-D17 version was compared with the shorter HAM-D6 and the longer HAM-D21 or HAM-D24 in a fixed-dose placebo-controlled vortioxetine study. Clinical Global Impression of Severity scores were used to establish standardized cutoff scores for remission across each scale. Using these cutoff scores, we compared the ability of each scale to separate drug-placebo remission rates, evaluated by the number needed to treat for clinical evidence. The HAM-D6 was superior to HAM-D17 in separating drug-placebo remission rates at the end point, defined as number needed to treat of less than 10. More items in the longer HAM-D versions indicated smaller discriminating validity over placebo. The HAM-D6 indicated a dose effect on remission for vortioxetine in both moderate and severe major depression. The brief HAM-D6 was thus found superior to HAM-D17, HAM-D21, and HAM-D24 both in terms of scalability and in discriminating antidepressants from placebo.

Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis

IntroductionMany antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct and indirect comparisons; however, these...

RTMS for the Treatment of Depression: a Comprehensive Review of Effective Protocols on Right DLPFC

Major depressive disorders (MDDs) are the most common and debilitating diseases worldwide. Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative or adjunctive treatment for different types of depression disorders, including drug-resistant major depressions. Despite controversial findings on the therapeutic outcomes of this technique, the general consent is developing this technique as an alternative treatment for depression disorders. Notwithstanding one protocol of rTMS has been approved by FDA for the acute treatment of major depression, studies are ongoing for finding more efficient protocols. This study aimed to comprehensively overview the effective rTMS protocols applied on left dorsolateral prefrontal cortex DLPFC for MDDs. The databases of PubMed (1985–2015), Web of Sciences (1985–2015), and Google Scholar (1980–2015) were searched using the set terms. The obtained results were screened for the relevant contents by two authors, and the appropriate studies were selected for further review. The most widely used protocols for depression are 1Hz for right and 10Hz for left DLPFC. In addition, the main parameters of these protocols and the main neurophysiological mechanisms of two common frequencies of 1 and 10 Hz are summarized. Different protocols of rTMS, particularly low versus high frequencies, result in significantly different electrophysiological and neurocognitive changes in the subject. Low frequency rTMS modulates frontal alpha power asymmetry and high frequency protocols influence more broader regions and wider electrophysiological characteristics of the brain.

Sertraline Induced Acute Hepatitis: A Case Report

Depression is a common disorder amongst the general population and frequently encountered by most physicians. Selective Serotonin Re-Uptake Inhibitors (SSRI’s) have become the most commonly prescribed antidepressants due to their superiority compared with other antidepressants in the treatment of acute major depression. Although exceedingly rare, hepatotoxicity resulting from sertraline use has been previously reported. In these case reports, the liver injury pattern was predominately hepatocellular. Unlike previous cases, we report the case of a patient presenting with markedly elevated cholestatic enzymes and painless jaundice while taking sertraline for treatment of depression.

Role of Lithium Augmentation in the Management of Major Depressive Disorder

The high rate of non-responders to initial treatment with antidepressants requires subsequent treatment strategies such as augmentation of antidepressants. Clinical guidelines recommend lithium augmentation as a first-line treatment strategy for non-responding depressed patients. The objectives of this review were to discuss the current place of lithium augmentation in the management of treatment-resistant depression and to review novel findings concerning lithium's mechanisms of action. We conducted a comprehensive and critical review of randomized, placebo-controlled trials, controlled and naturalistic comparator studies, and continuation-phase and discontinuation studies of lithium augmentation in major depression. The outcomes of interest were efficacy, factors allowing outcome prediction and results from preclinical studies investigating molecular mechanisms of lithium action. Substantial efficacy of lithium augmentation in the acute treatment of major depression has been demonstrated in more than 30 open-label studies and 10 placebo-controlled trials. In a meta-analysis addressing the efficacy of lithium in 10 randomized, controlled trials, it had a significant positive effect versus placebo, with an odds ratio of 3.11 corresponding to a number-needed-to-treat (NNT) of 5 and a mean response rate of 41.2% (versus 14.4% in the placebo group). The main limitations of these studies were the relatively small numbers of study participants and the fact that most studies included augmentation of tricyclic antidepressants, which are not in widespread use anymore. Evidence from continuation-phase studies is sparse but suggests that lithium augmentation should be maintained in the lithium-antidepressant combination for at least 1 year to prevent early relapses. Concerning outcome prediction, single studies have reported associations of better outcome rates with more severe depressive symptomatology, significant weight loss, psychomotor retardation, a history of more than three major depressive episodes and a family history of major depression. Additionally, one study suggested a predictive role of the -50T/C single nucleotide polymorphism of the glycogen synthase kinase 3 beta (GSK3B) gene in the probability of response to lithium augmentation. With regard to novel mechanisms of action, GABAergic, neurotrophic and genetic effects might explain the effects of lithium augmentation. In conclusion, augmentation of antidepressants with lithium remains a first-line, evidence-based management option for patients with major depression who have not responded adequately to antidepressants. While the mechanisms of action are currently widely studied, further clinical research on the role of lithium potentiation of the current generation of antidepressants is warranted to reinforce its role as a gold-standard treatment for patients who respond inadequately to antidepressants.

Homeopathy for Depression: A Randomized, Partially Double-Blind, Placebo-Controlled, Four-Armed Study (DEP-HOM)

BackgroundThe specific clinical benefit of the homeopathic consultation and of homeopathic remedies in patients with depression has not yet been investigated.AimsTo investigate the 1) specific effect of individualized homeopathic Q-potencies compared to placebo and 2) the effect of an extensive homeopathic case taking (case history I) compared to a shorter, rather conventional one (case history II) in the treatment of acute major depression (moderate episode) after six weeks.MethodsA randomized, partially double-blind, placebo-controlled, four-armed trial using a 2×2 factorial design with a six-week study duration per patient was performed.ResultsA total of 44 from 228 planned patients were randomized (2∶1∶2∶1 randomization: 16 homeopathic Q-potencies/case history I, 7 placebo/case history I, 14 homeopathic Q-potencies/case history II, 7 placebo/case history II). Because of recruitment problems, the study was terminated prior to full recruitment, and was underpowered for the preplanned confirmatory hypothesis testing. Exploratory data analyses showed heterogeneous and inconclusive results with large variance in the sample. The mean difference for the Hamilton-D after 6 weeks was 2.0 (95%CI −1.2;5.2) for Q-potencies vs. placebo and −3.1 (−5.9;−0.2) for case history I vs. case history II. Overall, no consistent or clinically relevant results across all outcomes between homeopathic Q-potencies versus placebo and homeopathic versus conventional case taking were observed. The frequency of adverse events was comparable for all groups.ConclusionsAlthough our results are inconclusive, given that recruitment into this trial was very difficult and we had to terminate early, we cannot recommend undertaking a further trial addressing this question in a similar setting.Prof. Dr. Claudia Witt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Trial registrationclinicaltrials.gov identifier NCT01178255. Protocol publication: http://www.trialsjournal.com/content/12/1/43

Adrenergic Receptor Gene Variation and Selective Norepinephrine Reuptake Inhibitors

Adrenergic Receptor Gene Variation and Selective Norepinephrine Reuptake Inhibitors

Review: reboxetine is ineffective and potentially harmful for acute treatment of major depression

Question: How clinically effective and safe is reboxetine for acute treatment of major depression and what is the effect of publication bias on reported effect measures? Outcomes: Remission, response, adverse events and withdrawals due to adverse events compared with selective serotonin reuptake inhibitors (SSRIs) or placebo. Design: Systematic review with meta-analysis. Data sources: Medline, Embase, PsycINFO, BIOSIS, Cochrane Library, clinical trial registries, trial results databases and regulatory authority websites were searched up until February 2009. Unpublished data were obtained from the manufacturer (Pfizer, Berlin, Germany), and reference lists of primary and secondary publications were hand searched for additional references. Study selection and analysis: Double blinded randomised controlled trials comparing reboxetine versus placebo or SSRIs for the acute treatment of adults with a primary diagnosis of DSM-IV major depressive disorder were included. Trials had to last at least 6 weeks for inclusion. Selected trials had at least one prespecified outcome and were published in English, French or German (or any other language providing that relevance could be ascertained from the English title or abstract). Response and remission were defined according to the primary studies. All of the studies used the …

Sertraline Induced Hepatotoxicity: A Case Report and Review of Literature

Introduction:Depression is a common disorder amongst the general population and frequently encountered by most physicians (1). Selective Serotonin Re-Uptake Inhibitors (SSRI’s) have become the most commonly prescribed antidepressants due to their superiority compared to other antidepressants in the treatment of acute major depression (2). Although exceedingly rare, hepatotoxicity resulting from Sertraline use has been previously reported (3-7). In these case reports, the liver injury pattern was predominately hepatocellular. Unlike previous cases, we report the case of a patient presenting with markedly elevated cholestatic enzymes and painless jaundice while taking Sertraline for treatment of depression. Case Presentation:A 61-year-old Caucasian female presented with a history of fatigue, malaise, anorexia, and painless jaundice. She had taken Sertraline 100 mg daily for one year for management of her depression. However, due to a suboptimal therapeutic response, her dose was increased to 200 mg daily three weeks prior to presentation. She was also taking hormone replacement therapy (Premarin 0.625mg daily and Prometrium 100mg daily) to control menopausal symptoms. Liver enzymes obtained at the time of admission showed an ALT of 207 U/L, AST 161 U/L, Total Bilirubin 164 umol/L, Direct Bilirubin 135 umol/L, ALP 915 U/L, and GGT 4412 U/L. Laboratory and radiological investigations were inconclusive and a liver biopsy was consistent with a drug-induced hepatitis. Our patient’s symptoms and liver biochemistry improved following cessation of Sertraline therapy. Conclusion:Heightened awareness amongst prescribing physicians is warranted for patients taking Sertraline in the treatment of depression for the development of hepatotoxicity. These effects may be compounded by patients also on hormone replacement therapy.

Publishing negative clinical trials results: the case of reboxetine

The recent publication of a systematic review and meta-analysis of published and unpublished data from controlled trials on the effects of reboxetine in the acute treatment of major depression (Eyding et al, 2010) has reignited the debate surrounding the publication of negative trials by pharmaceutical companies.

Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials

Objectives To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential...

Plasma levels and cerebrospinal fluid penetration by duloxetine in a patient with a non-fatal overdose during a suicide attempt

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake (Wong et al. 1993). Daily doses of 60 mg are effective in the acute treatment of major depression. Duloxetine is extensively metabolized by cytochrome P450 isoenzymes (CYP) 1A2 and to a lesser extent 2D6 (Lobo et al. 2008) to numerous non-active metabolites. Maximum plasma concentration occurs after 6 h, steady-state within 3 d and the mean terminal half-life is 12 h. Fatal outcomes have been reported for acute overdoses as low as 1000 mg, and symptoms of duloxetine overdose are well described. However, information about plasma levels of duloxetine and corresponding cerebrospinal fluid (CSF) levels providing information about its CSF penetration is lacking. We therefore report …

Agomelatine: The evidence for its place in the treatment of depression.

Depressive disorders are among the main causes of disability due to disease. In spite of recent progress in the pharmacotherapy of depression, there is still a high nonresponse rate of approximately 30% to the first antidepressant treatment. Furthermore, the latency of several weeks until sufficient clinical improvement and the risk of side effects remain unresolved problems. Therefore, there is still further need for the development of new antidepressants. In the last years a variety of melatonin receptor agonists have been synthesized and evaluated for the treatment of sleep disorders. Animal studies suggested that agomelatine (S-20098), a synthetic melatonergic MT(1) and MT(2) receptor agonist with serotonin receptor antagonistic properties, may have additional activating properties and may represent a new approach in the treatment of depression. Clinical trials that have demonstrated efficacy and safety of agomelatine for the treatment of depression are reviewed. In clinical trials, including phase III studies, superior efficacy compared to placebo and good efficacy compared to standard antidepressants was shown for agomelatine for the acute treatment of major depression. In all studies published so far agomelatine was safe and the overall tolerability profile was superior to selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors. Agomelatine may represent a novel perspective in the treatment of acute depression. The improvement of sleep disturbances, the tolerability in terms of sexual side effects, and the lack of withdrawal symptoms after abrupt discontinuation of treatment may represent important clinical benefits compared to established antidepressants.