Irinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials ...(RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC.
This meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).
Nineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82-0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80-1.03, P = 0.15).
Although the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients' condition or toxicity profiles.
Abstract 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.
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.
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 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 analysisWe 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 disseminationThis review does not require ethical approval.PROSPERO registration numberCRD42012002291.
Pharmacotherapy remains the mainstay of treatment for acute bipolar mania, but there are many choices, including mood stabilizers (MSs) and antipsychotics (APs).
To provide an up-to-date and ...comprehensive review of the efficacy, acceptability and adverse effects of MSs and APs as combination or augmentation therapy versus monotherapy with either drug class for the treatment of acute mania.
The Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, Scopus, and clinical trial databases were searched for articles published between the inception of the databases and July 1, 2014. The following keywords were used: bipolar disorder, mania, manic, mixed bipolar, schizoaffective combined with the names of MSs and APs. The reference lists of all the identified randomized controlled trials (RCTs), articles that cited the identified trials, and recent systematic reviews were also checked.
Double-blind RCTs comparing MS and AP as combination or augmentation therapy with either monotherapy during the acute phase treatment of mania were included in the present study. The electronic search yielded 6,445 potential articles in September 2013 and 264 new references in an updated search performed in July 2014. Finally, 19 RCTs were considered eligible for our meta-analyses: MS plus AP combination or augmentation therapy was compared with MS monotherapy in 14 trials (n = 3,651) and with AP monotherapy in 6 trials (n = 606) one study compared combination therapy versus both MS monotherapy and AP monotherapy.
The primary outcomes were the mean change scores on validated rating scales for mania and all-cause discontinuation at 3 weeks. The secondary outcomes included response, remission, the mean change scores for depression, dropouts due to adverse events and to inefficacy, and adverse events at 3 weeks and mean change scores on validated rating scales at 1 week. Using random-effects models, standardized mean difference (SMD), risk ratio (RR) and numbers needed to treat with their 95 % confidence intervals (CIs) were calculated.
Most patients included in trials comparing combination/augmentation therapy versus MS monotherapy had prior treatment with an MS, while more than 70 % of participants in trials comparing combination/augmentation therapy versus AP monotherapy had not been on medications or were washed out from their previous medication before randomization. MS plus AP combination/augmentation therapy was more effective than MS monotherapy in terms of change in scores on mania rating scales at 3 weeks (SMD -0.26; 95 % CI -0.36 to -0.15) and at 1 week (SMD -0.17, -0.29 to -0.04). MS plus AP combination/augmentation therapy was more effective than AP monotherapy at 3 weeks (SMD -0.31, -0.50 to -0.12), but not at 1 week (SMD -0.22, -0.84 to 0.40). No significant differences were seen between the combination/augmentation therapy and either monotherapy group in study withdrawal for any reason (MS + AP vs. MS monotherapy: RR 0.99, 0.88-1.12; MS + AP vs. AP monotherapy: RR 0.70, 0.47-1.04) or adverse events (MS + AP vs. MS monotherapy: RR 1.39, 0.97-1.99; MS + AP vs. AP monotherapy: RR 0.62, 0.27-1.40). The combination/augmentation therapy was associated with more side effects, especially with somnolence, while it did not increase treatment-emergent depression.
Combining MS and AP is more efficacious and more burdensome than, but overall as acceptable as, the continuation of MS or AP monotherapy, when either monotherapy has not been successful. There is currently no robust evidence to judge whether MS and AP combination therapy is more efficacious than MS monotherapy as the initial therapy for acutely manic patients without prior medication.
Computer-assisted treatment may reduce therapist contact and costs and promote client participation. This meta-analysis examined the efficacy and acceptability of an unguided computer-assisted ...therapy in patients with obsessive-compulsive disorder (OCD) compared with a waiting list or attention placebo.
This study aimed to evaluate the effectiveness and adherence of computer-assisted self-help treatment without human contact in patients with OCD using a systematic review and meta-analysis approach.
Randomized controlled trials with participants primarily diagnosed with OCD by health professionals with clinically significant OCD symptoms as measured with validated scales were included. The interventions included self-help treatment through the internet, computers, and smartphones. We excluded interventions that used human contact. We conducted a search on PubMed, Cochrane Central Register of Controlled Trials, EMBASE, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov, as well as the reference lists of the included studies. The risk of bias was evaluated using version 2 of the Cochrane risk-of-bias tool for randomized trials. We calculated the standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes. The primary outcomes were short-term improvement of OCD symptoms measured by validated scales and dropout for any reason.
We included 11 randomized controlled trials with a total of 983 participants. The results indicated that unguided computer-assisted self-help therapy was significantly more effective than a waiting list or psychological placebo (standard mean difference -0.47, 95% CI -0.73 to -0.22). Unguided computer-assisted self-help therapy had more dropouts for any reason than waiting list or psychological placebo (risk ratio 1.98, 95% CI 1.21 to 3.23). However, the quality of evidence was very low because of the risk of bias and inconsistent results among the included studies. The subgroup analysis showed that exposure response and prevention and an intervention duration of more than 4 weeks strengthen the efficacy without worsening acceptability. Only a few studies have examined the interaction between participants and systems, and no study has used gamification. Most researchers only used text-based interventions, and no study has used a mobile device. The overall risk of bias of the included studies was high and the heterogeneity of results was moderate to considerable.
Unguided computer-assisted self-help therapy for OCD is effective compared with waiting lists or psychological placebo. An exposure response and prevention component and intervention duration of more than 4 weeks may strengthen the efficacy without worsening the acceptability of the therapy.
PROSPERO (International Prospective Register of Systematic Reviews) CRD42021264644; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=264644.
For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve ...remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished.
This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates.
Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects.
In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine.
ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.
Abstracts of scientific reports are sometimes criticized for exaggerating significant results when compared to the corresponding full texts. Such abstracts can mislead the readers. We aimed to ...conduct a systematic review of overstatements in abstract conclusions in psychiatry trials.
We searched for randomized controlled trials published in 2014 that explicitly claimed effectiveness of any intervention for mental disorders in their abstract conclusion, using the Cochrane Register of Controlled Trials. Claims of effectiveness in abstract conclusion were categorized into three types: superiority (stating superiority of intervention to control), limited superiority (intervention has limited superiority), and equal efficactiveness (claiming equal effectiveness of intervention with standard treatment control), and full text results into three types: significant (all primary outcomes were statistically significant in favor of the intervention), mixed (primary outcomes included both significant and non-significant results), or all results non-significant. By comparing these classifications, we assessed whether each abstract was overstated. Our primary outcome was the proportion of overstated abstract conclusions.
We identified and included 60 relevant trials. 20 out of 60 studies (33.3%) showed overstatements. Nine reports reported only significant results although none of their primary outcomes were significant. Large sample size (>300) and publication in high impact factor (IF>10) journals were associated with low occurrence of overstatements.
We found that one in three psychiatry studies claiming effectiveness in their abstract conclusion, either superior to control or equal to standard treatment, for any mental disorders were overstated in comparison with the full text results. Readers of the psychiatry literature are advised to scrutinize the full text results regardless of the claims in the abstract.
University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000018668).
ObjectivesResearchers have identified cases in which newspaper stories have exaggerated the results of medical studies reported in original articles. Moreover, the exaggeration sometimes begins with ...journal articles. We examined what proportion of the studies quoted in newspaper stories were confirmed.MethodsWe identified newspaper stories from 2000 that mentioned the effectiveness of certain treatments or preventions based on original studies from 40 main medical journals. We searched for subsequent studies until June 2022 with the same topic and stronger research design than each original study. The results of the original studies were verified by comparison with those of subsequent studies.ResultsWe identified 164 original articles from 1298 newspaper stories and randomly selected 100 of them. Four studies were not found to be effective in terms of the primary outcome, and 18 had no subsequent studies. Of the remaining studies, the proportion of confirmed studies was 68.6% (95% CI 58.1% to 77.5%). Among the 59 confirmed studies, 13 of 16 studies were considered to have been replicated in terms of effect size. However, the results of the remaining 43 studies were not comparable.DiscussionIn the dichotomous judgement of effectiveness, about two-thirds of the results were nominally confirmed by subsequent studies. However, for most confirmed results, it was impossible to determine whether the effect sizes were stable.ConclusionsNewspaper readers should be aware that some claims made by high-quality newspapers based on high-profile journal articles may be overturned by subsequent studies within the next 20 years.
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