Nozomi Takeshima

Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials

BACKGROUND Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. METHODS We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40mg/d. RESULTS We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin. LIMITATIONS The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. CONCLUSIONS Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.

Which is more generalizable, powerful and interpretable in meta-analyses, mean difference or standardized mean difference?

BackgroundTo examine empirically whether the mean difference (MD) or the standardised mean difference (SMD) is more generalizable and statistically powerful in meta-analyses of continuous outcomes when the same unit is used.MethodsFrom all the Cochrane Database (March 2013), we identified systematic reviews that combined 3 or more randomised controlled trials (RCT) using the same continuous outcome. Generalizability was assessed using the I-squared (I2) and the percentage agreement. The percentage agreement was calculated by comparing the MD or SMD of each RCT with the corresponding MD or SMD from the meta-analysis of all the other RCTs. The statistical power was estimated using Z-scores. Meta-analyses were conducted using both random-effects and fixed-effect models.Results1068 meta-analyses were included. The I2 index was significantly smaller for the SMD than for the MD (P < 0.0001, sign test). For continuous outcomes, the current Cochrane reviews pooled some extremely heterogeneous results. When all these or less heterogeneous subsets of the reviews were examined, the SMD always showed a greater percentage agreement than the MD. When the I2 index was less than 30%, the percentage agreement was 55.3% for MD and 59.8% for SMD in the random-effects model and 53.0% and 59.8%, respectively, in the fixed effect model (both P < 0.0001, sign test). Although the Z-scores were larger for MD than for SMD, there were no differences in the percentage of statistical significance between MD and SMD in either model.ConclusionsThe SMD was more generalizable than the MD. The MD had a greater statistical power than the SMD but did not result in material differences.

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

BACKGROUND 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. METHODS 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. FINDINGS 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). INTERPRETATION 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. FUNDING Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.

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

Introduction Many 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 reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Methods and analysis We will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework. Ethics and dissemination This review does not require ethical approval. PROSPERO registration number CRD42012002291.

Replication and contradiction of highly cited research papers in psychiatry: 10-year follow-up

BACKGROUND Contradictions and initial overestimates are not unusual among highly cited studies. However, this issue has not been researched in psychiatry. Aims: To assess how highly cited studies in psychiatry are replicated by subsequent studies. METHOD We selected highly cited studies claiming effective psychiatric treatments in the years 2000 through 2002. For each of these studies we searched for subsequent studies with a better-controlled design, or with a similar design but a larger sample. RESULTS Among 83 articles recommending effective interventions, 40 had not been subject to any attempt at replication, 16 were contradicted, 11 were found to have substantially smaller effects and only 16 were replicated. The standardised mean differences of the initial studies were overestimated by 132%. Studies with a total sample size of 100 or more tended to produce replicable results. CONCLUSIONS Caution is needed when a study with a small sample size reports a large effect.

Adding smartphone-based cognitive-behavior therapy to pharmacotherapy for major depression (FLATT project): study protocol for a randomized controlled trial

BackgroundMajor depression is one of the most debilitating diseases in terms of quality of life. Less than half of patients suffering from depression can achieve remission after adequate antidepressant treatment. Another promising treatment option is cognitive-behavior therapy (CBT). However, the need for experienced therapists and substantive dedicated time prevent CBT from being widely disseminated.In the present study, we aim to examine the effectiveness of switching antidepressants and starting a smartphone-based CBT program at the same time, in comparison to switching antidepressants only, among patients still suffering from depression after adequate antidepressant treatment.Methods/designA multi-center randomized trial is currently being conducted since September 2014. The smartphone-based CBT program, named the “Kokoro-App,” for major depression has been developed and its feasibility has been confirmed in a previous open study. The program consists of an introduction, 6 sessions and an epilogue, and is expected to be completed within 9 weeks by patients. In the present trial, 164 patients with DSM-5 major depressive disorder and still suffering from depressive symptoms after adequate antidepressant treatment for more than 4 weeks will be allocated to the Kokoro-App plus switching antidepressant group or the switching antidepressant alone group. The participants allocated to the latter group will receive full components of the Kokoro-App after 9 weeks.The primary outcome is the change in the total score on the Patient Health Questionnaire through the 9 weeks of the program, as assessed at week 0, 1, 5 and 9 via telephone by blinded raters. The secondary outcomes include the change in the total score of the Beck Depression Inventory-II, change in side effects as assessed by the Frequency, Intensity and Burden of Side Effects Rating, and treatment satisfaction.DiscussionAn effective and reachable intervention may not only lead to healthier mental status among depressed patients, but also to reduced social burden from this illness. This paper outlines the background and methods of a trial that evaluates the possible additive value of a smartphone-based CBT program for treatment-resistant depression.Trial registrationUMIN-CTR: UMIN000013693 (registered on 1 June 2014)

Continuation and discontinuation of benzodiazepine prescriptions: A cohort study based on a large claims database in Japan

Although benzodiazepines (BZDs) are often prescribed to treat a wide range of psychiatric and neurological conditions, they are also associated with various harms and risks including dependence. However the frequency of its continued use in the real world has not been well studied, especially at longer follow-ups. The aim of this study was to clarify the frequency of long-term BZD use among new BZD users over longer follow-ups and to identify its predictors. We conducted a cohort study to examine how frequently new BZD users became chronic users, based on a large claims database in Japan from January 2005 to June 2014. We used Cox proportional hazards models to identify potential predictors. A total 84,412 patients with new BZD prescriptions were included in our cohort. Among them, 35.8% continued to use BZD for three months, 15.2% for one year and 4.9% for eight years without ever attaining three months of no BZD prescription. The confirmed predictors for long-term BZD use were older age, psychiatrist-prescriber, regular use, high dose of BZD, and concomitant prescription of psychotropic drugs. When we consider BZD use, we have to keep in mind these figures and avoid these predictors as much as possible.

Protocol registration and selective outcome reporting in recent psychiatry trials: new antidepressants and cognitive behavioural therapies

The selective reporting of favorable outcomes has a serious influence on our evidence base. However, this problem has not yet been systematically investigated in the field of psychiatry. Our study aimed to evaluate registration and outcome reporting in randomized controlled trials (RCTs) of standard treatments for depression: cognitive behavioural therapy (CBT) or new‐generation antidepressants (ADs).

Prescription patterns following first-line new generation antidepressants for depression in Japan: A naturalistic cohort study based on a large claims database

BACKGROUND Several studies have described real-world prescription patterns of first-line antidepressants for depression but little is known about their fate in terms of duration, intensity and changes. METHODS An inception cohort of new onset non-psychotic depression initiating antidepressant treatment with a new generation antidpressive agent was identified in a large health insurance claims database in Japan between 2009 and 2010. The duration and intensity of first-line antidepressants, the timing and kind of second-line antidepressants and the total duration of antidepressant treatment were examined. RESULTS We identified 1592 patients. The starting dose and the maximum dose attained with the first-line agent appeared to be largely in line with the guideline recommendations although the latter tended toward the minimum of the recommended range. The continuity of the first-line antidepressant was far below the guideline recommendations, with 28% never returning after the initial prescription and 55% dropping out within 3 months. Of all the first-line antidepressants, 14% were subsequently augmented by another psychotropic agent while 17% were switched to another antidepressant after a median of 3 or 2 months, respectively. The choice of the second-line agents varied extremely widely. The total duration of antidepressant therapy was as short as a median of 4 months, with 68% stopping treatment by 6 months. LIMITATIONS The diagnosis of non-psychotic unipolar depression in the claims database analyses remains approximate. CONCLUSIONS The current guidelines are grossly out of touch with the clinical realities. On the one hand, guidelines need to reflect the real-world practices; on the other hand clinicians should limit their treatment options and allow evidence-based comparative effectiveness research among them so that patients shall no longer be given less effective and more effective treatments without being able to distinguish among them.

Antidepressants might work for people with major depression: where do we go from here?

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