Study Confirms Efficacy of Antidepressants for Major Depressive Disorder.

[movementforthebetter]

A long post, but worthwhile for those who wish to access hard data. Moderators, please feel free to contact me if I should edit the post or break it up to better comply with standard forum guidelines. I placed this here as it's not specifically about C-PTSD, but about the treatment of Major Depressive Disorder by many different medications.

A new study, combing through vast amounts of clinical trial data,  published in The Lancet, has confirmed the effectiveness of antidepressants in treating depression.

My own opinion is that antidepressants are most effective in combination with other non-drug therapies. But much better than nothing, if medication is all that the person can access, for whatever reason. C-PTSD is more complex than major depression. I would argue that major depression is one of the symptoms of C-PTSD and other serious conditions. I am not a doctor, just someone who prefers scientific evidence in my treatment journey. I believe this information will be beneficial to many people,which is why I am sharing it here.

Brief excerpt:

"We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine."



Full text:

"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

Background
Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods
We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.

Findings
We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

Interpretation
All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

Funding
National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Research in context

Evidence before this study

Antidepressants are routinely used worldwide for the treatment of major depressive disorder, which is one of the most important global health challenges; however, in the scientific literature, there remains considerable debate about both their effectiveness as a group, and the potential differences in effectiveness and tolerability between individual drugs. With the marketing of new antidepressants and increasing numbers of trials published every year, an updated systematic review and network meta-analysis was required to synthesise the evidence in this important clinical area.

Added value of this study

This network meta-analysis represents a major update and extension of our previous study, which addressed 12 antidepressants with data for head-to-head comparisons only, and provides the best currently available evidence base to guide the choice about pharmacological treatment for adults with acute major depressive disorder. We now include a more comprehensive list of 21 antidepressants and placebo, consider three new clinical outcome measures and many potential effect modifiers, and use the most advanced statistical methodology for network meta-analysis to date.

Implications of all the available evidence

Our findings should inform clinical guidelines and assist the shared decision making process between patients, carers, and clinicians in routine practice on selecting the most appropriate antidepressant for adults with acute major depressive disorder. Future research should seek to extend network meta-analysis to combine aggregate and individual-patient data from trials in a so-called individual-patient data network meta-analysis. This analysis will allow the prediction of personalised clinical outcomes, such as early response or specific side-effects, and the estimate of comparative efficacy at multiple timepoints.

Introduction
Psychiatric disorders account for 22·8% of the global burden of diseases.1 The leading cause of this disability is depression, which has substantially increased since 1990, largely driven by population growth and ageing.2 With an estimated 350 million people affected globally, the economic burden of depressive disorders in the USA alone has been estimated to be more than US$210 billion, with approximately 45% attributable to direct costs, 5% to suicide-related costs, and 50% to workplace costs.3 This trend poses a substantial challenge for health systems in both developed and developing countries, with the need to treat patients, optimise resources, and improve overall health care in mental health.

Grouped into various classes of drugs with slightly different mechanisms of action, antidepressants are widely used treatments for major depressive disorder, which are available worldwide. However, there is a long-lasting debate and concern about their efficacy and effectiveness, because short-term benefits are, on average, modest; and because long-term balance of benefits and harms is often understudied.4 Therefore, innovation in psychopharmacology is of crucial importance, but the identification of new molecular targets is difficult, primarily because of the paucity of knowledge about how antidepressants work.5 In routine practice, clinicians have a wide choice of individual drugs and they need good evidence to make the best choice for each individual patient. Network meta-analyses of existing datasets make it possible to estimate comparative efficacy, summarise and interpret the wider picture of the evidence base, and to understand the relative merits of the multiple interventions.6 Therefore, in this study, we aimed to do a systematic review and network meta-analysis to inform clinical practice by comparing different antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods
Search strategy and selection criteria
We did a systematic review and network meta-analysis. We searched the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, AMED, the UK National Research Register, and PSYNDEX from the date of their inception to Jan 8, 2016, with no language restrictions. We used the search terms "depress*" OR "dysthymi*" OR "adjustment disorder*" OR "mood disorder*" OR "affective disorder" OR "affective symptoms" combined with a list of all included antidepressants.

We included double-blind, randomised controlled trials (RCTs) comparing antidepressants with placebo or another active antidepressant as oral monotherapy for the acute treatment of adults (≥18 years old and of both sexes) with a primary diagnosis of major depressive disorder according to standard operationalised diagnostic criteria (Feighner criteria, Research Diagnostic Criteria, DSM-III, DSM-III-R, DSM-IV, DSM-5, and ICD-10). We considered only double-blind trials because we included placebo in the network meta-analysis, and because this study design increases methodological rigour by minimising performance and ascertainment biases.7 Additionally, we included all second-generation antidepressants approved by the regulatory agencies in the USA, Europe, or Japan: agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, vilazodone, and vortioxetine. To inform clinical practice globally, we selected the two tricyclics (amitriptyline and clomipramine) included in the WHO Model List of Essential Medicines). We also included trazodone and nefazodone, because of their distinct effect and tolerability profiles. Additionally, we included trials that allowed rescue medications so long as they were equally provided among the randomised groups. We included data only for drugs within the therapeutic range (appendix pp 133, 134). Finally, we excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness.

The electronic database searches were supplemented with manual searches for published, unpublished, and ongoing RCTs in international trial registers, websites of drug approval agencies, and key scientific journals in the field.8 For example, we searched ClinicalTrials.gov using the search term "major depressive disorder" combined with a list of all included antidepressants. We contacted all the pharmaceutical companies marketing antidepressants and asked for supplemental unpublished information about both premarketing and post-marketing studies, with a specific focus on second-generation antidepressants. We also contacted study authors and drug manufacturers to supplement incomplete reports of the original papers or provide data for unpublished studies.

Six pairs of investigators (ACi, TAF, LZA, SL, HGR, YO, NT, YH, EHT, HI, KS, and AT) independently selected the studies, reviewed the main reports and supplementary materials, extracted the relevant information from the included trials, and assessed the risk of bias. Any discrepancies were resolved by consensus and arbitration by a panel of investigators within the review team (ACi, TAF, LZA, EHT, and JRG).

The full protocol of this network meta-analysis has been published.8

Outcomes
Our primary outcomes were efficacy (response rate measured by the total number of patients who had a reduction of ≥50% of the total score on a standardised observer-rating scale for depression) and acceptability (treatment discontinuation measured by the proportion of patients who withdrew for any reason).8 All-cause discontinuation was used as a measure for the acceptability of treatments, because it encompasses efficacy and tolerability.9 Secondary outcomes were endpoint depression score, remission rate, and the proportion of patients who dropped out early because of adverse events. When depressive symptoms had been measured with more than one standardised rating scale, we used a predefined hierarchy, based on psychometric properties and consistency of use across included trials.8 In the absence of information or supplemental data from the authors, response rate was calculated according to a validated imputation method.10 We recorded the outcomes as close to 8 weeks as possible for all analyses.9 If information at 8 weeks was not available, we used data ranging between 4 and 12 weeks (we gave preference to the timepoint closest to 8 weeks; if equidistant, we took the longer outcome). We checked trial protocols where available and compared published with unpublished data. We extracted data following a predefined hierarchy described in our protocol and gave priority to unpublished information in case of disagreement.8

Data analysis
For studies published more than once (ie, duplicates), we included only the report with the most informative and complete data. Full details of the applied statistical approaches are provided in the protocol.8 We estimated summary odds ratios (ORs) for dichotomous outcomes and standardised mean differences (SMD, Cohen's d) for continuous outcomes using pairwise and network meta-analysis. In network meta-analysis, we used group-level data; the binomial likelihood was used for dichotomous outcomes and the normal likelihood for continuous outcomes. The study effect sizes were then synthesised using a random-effects network meta-analysis model. We accounted for the correlations induced by multi-group studies by using multivariate distributions. The variance in the random-effects distribution (heterogeneity variance) was considered to measure the extent of across-study and within-comparison variability on treatment effects. Additionally, in network meta-analysis, we assumed that the amount of heterogeneity was the same for all treatment comparisons. To assess the amount of heterogeneity, we compared the posterior distribution of the estimated heterogeneity variance with its predictive distribution.11 To rank the treatments for each outcome, we used the surface under the cumulative ranking curve (SUCRA) and the mean ranks.12 The transitivity assumption underlying network meta-analysis was evaluated by comparing the distribution of clinical and methodological variables that could act as effect modifiers across treatment comparisons.8 We did a statistical evaluation of consistency (ie, the agreement between direct and indirect evidence) using the design-by-treatment test13 and by separating direct evidence from indirect evidence.14

We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. Additionally, we assessed the certainty of evidence contributing to network estimates of the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.15

We evaluated whether treatment effects for the two primary outcomes were robust in subgroup analyses and network meta-regression using study year, sponsorship, depressive severity at baseline, dosing schedule, study precision (ie, small study effect), and novelty effect.16 The appendix (pp 133–36) summarises the definition of covariates. The sensitivity of our conclusions was evaluated by analysing the dataset with the following restrictions: studies with reported response rate, studies using accepted doses in all groups, studies with unpublished data, multi-centre studies, and head-to-head studies. We used comparison-adjusted funnel plots to investigate whether results in imprecise trials differ from those in more precise trials.17

We fitted all models in OpenBUGS (version 3.2.2)18 using the binomial likelihood for dichotomous outcomes, uninformative prior distributions for the treatment effects, and a minimally informative prior distribution for the common heterogeneity SD. We assumed uninformative priors—ie, N(0,1000)—for all meta-regression coefficients. Convergence of models was ensured by visual inspection of three chains and after considering the Brooks–Gelman–Rubin diagnostic. The codes of analyses, statistical details of the meta-analysis, and meta-regression models are presented in the appendix (pp 182, 183). Statistical evaluation of inconsistency and production of network graphs and result figures were done using the network and network graphs packages in Stata (version 14.2).19 Network meta-analyses of the primary outcomes were duplicated using the netmeta 0.9-6 package in R (version 3.4.0).20 The appendix (p 289) lists the changes to the original protocol. The study was done from March 12, 2012, to June 4, 2016, and data analysis was done from June 5, 2016, to Sept 18, 2017.

This study is registered with PROSPERO, number CRD42012002291.

Data sharing
With the publication of this Article, the full dataset will be freely available online in Mendeley Data, a secure online repository for research data, which allows archiving of any file type and assigns a permanent and unique digital object identifier (DOI) so that the files can be easily referenced (DOI:10.17632/83rthbp8ys.2).

Role of the funding source
The funder of this study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. ACi, TAF, GS, ACh, LZA, and YO had full access to all the data, and ACi was responsible for the decision to submit for publication.

Results
28 552 citations were identified by the search and 680 potentially eligible articles were retrieved in full text (figure 1). We included 421 trials from the database search, 86 unpublished studies from trial registries and pharmaceutical company websites, and 15 from personal communication or hand-searching other review articles. Overall, 522 double-blind, parallel, RCTs (comprising 116 477 patients) done between 1979 and 2016, and comparing 21 antidepressants or placebo were included in the analysis (appendix pp 6–64). The appendix (pp 65–114) summarises the characteristics of included studies. The mean study sample size was 224 participants (SD 186). In total, 87 052 participants were randomly assigned to an active drug and 29 425 were randomly assigned to placebo. The mean age was 44 years (SD 9) for both men and women; 38 404 (62·3%) of 61 681 of the sample population were women. The median duration of the acute treatment was 8 weeks (IQR 6–8). 243 (47%) of 522 studies randomly assigned participants to three or more groups, and 304 (58%) of 522 were placebo-controlled trials. 391 (83%) of 472 were multi-centre studies and 335 (77%) of 437 studies recruited outpatients only. 252 (48%) of 522 trials recruited patients from North America, 37 (7%) from Asia, and 140 (27%) from Europe (59 [11%] trials were cross-continental and the remaining 34 [7%] were either from other regions or did not specify). The great majority of patients had moderate-to-severe major depressive disorder, with a mean reported baseline severity score on the Hamilton Depression Rating Scale 17-item of 25·7 (SD 3·97) among 464 (89%) of 522 studies. Response rate was imputed in 20 608 (17·7%) of 116 447 cases. Rescue medications (typically benzodiazepines or other sedative hypnotics) were allowed in 187 (36%) of 522 studies. 409 (78%) of 522 studies were funded by pharmaceutical companies. We retrieved unpublished information for 274 (52%) of the included trials. Consistent with the study protocol, the primary analysis was based on the 474 studies (comprising 106 966 patients) that used drugs within the licensed dose range (ie, the dosage approved by the regulatory agencies in the USA and Europe; appendix pp 133, 134)


Figure 1 [viewable at source website]
Study selection process

RCTs=randomised controlled trials. *Industry websites, contact with authors, and trial registries. The total number of unpublished records is the total number of results for each drug and on each unpublished database source. †522 RCTs corresponded to 814 treatment groups."

Source: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/abstract

[Rainagain]

Saw your post, it reminded me that I've been diagnosed with major depressive disorder, I'd forgotten.

Need to keep that in mind and not totally focus on cptsd.

[Three Roses]

Wow, great info, mftb, thanks!