Item-based analysis of the effects of duloxetine in depression: a patient-level post hoc study

Abstract Oft-cited trial-level meta-analyses casting doubt on the usefulness of antidepressants have been based on re-analyses of to what extent the active drug has outperformed placebo in reducing the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) in clinical trials. Recent studies, however, suggest patient-level analyses of individual HDRS items to be more informative when assessing the efficacy of an antidepressant. To shed further light on both symptom-reducing and symptom-aggravating effects of a serotonin and noradrenaline reuptake inhibitor, duloxetine, when used for major depression in adults, we hence applied this approach to re-analyse data from 13 placebo-controlled trials. In addition, using patient-level data from 28 placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs), the response profile of duloxetine was compared to that of these drugs. Duloxetine induced a robust reduction in depressed mood that was not dependent on baseline severity and not caused by side-effects breaking the blind. A beneficial effect on depressed mood was at hand already after one week; when outcome was assessed using HDRS-17-sum as effect parameter, this early response was however masked by a concomitant deterioration with respect to adverse event-related items. No support for a suicide-provoking effect of duloxetine was obtained. The response profile of duloxetine was strikingly similar to that of the SSRIs. We conclude that the use of HDRS-17-sum as effect parameter underestimates the true efficacy and masks an early effect of duloxetine on core symptoms of depression. No support for major differences between duloxetine and SSRIs in clinical profile were obtained.

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Pharmacological Treatments for Unipolar Depression

A Guide to Treatments that Work ◽

10.1093/med:psych/9780195304145.003.0009 ◽

2007 ◽

pp. 271-288 ◽

Cited By ~ 1

Author(s):

Charles B. Nemeroff ◽

Alan F. Schatzberg

Keyword(s):

Major Depression ◽

Selective Serotonin Reuptake Inhibitors ◽

Rating Scale ◽

Antidepressant Treatment ◽

Safety Margin ◽

Antidepressant Medication ◽

Unipolar Depression ◽

Controlled Trials ◽

Adverse Side Effect ◽

Drug Induced

The treatment of unipolar major depression with antidepressant medication is well established on the basis of scores of randomized placebo-controlled trials involving thousands of patients. Tricyclic antidepressants (TCAs) were the first to be studied extensively; meta-analyses of placebo-controlled trials show them to be consistently and significantly more efficacious than a placebo. Because of a narrow safety margin and significant drug-induced adverse side effect problems, TCAs have now largely been replaced as the first-line treatment of depression by selective serotonin reuptake inhibitors (SSRIs)—fluoxetine, sertraline, paroxetine, citalopram, and escitalopram; serotonin norepinephrine reuptake inhibitors (SNRIs)—venlafaxine and duloxetine; as well as other compounds, including, for example, bupropion and mirtazapine. Each of these agents has been shown to be superior to a placebo and as effective as comparator TCAs or SSRIs in controlled trials. Clinical trials consistently show them to be better tolerated than TCAs, and they clearly have a wider margin of safety. However, there is a controversy concerning whether TCAs are more effective than SSRIs for the treatment of the most severely ill depressed patients. Monoamine oxidase inhibitors (MAOIs), while also more effective than placebo, have generally been reserved for treatment-refractory patients; however, a recently released transdermally delivered selegiline may be used in less refractory patients. It is now generally recognized that patients with recurrent major depression benefit from continued antidepressant treatment, and there is evidence that TCAs, SSRIs, SNRIs, and so forth are all effective for the long-term management of recurrent major depression. An important issue in evaluating the antidepressant literature is to distinguish between response rated as a reduction in the level of symptoms on a rating scale and response rated as true remission from illness.

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Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling

Health Technology Assessment ◽

10.3310/hta191000 ◽

2015 ◽

Vol 19 (100) ◽

pp. 1-402 ◽

Cited By ~ 12

Author(s):

Rafael Perera ◽

Emily McFadden ◽

Julie McLellan ◽

Tom Lung ◽

Philip Clarke ◽

...

Keyword(s):

Cost Effectiveness ◽

Primary Prevention ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Controlled Trials ◽

Patient Level Data ◽

Patient Level ◽

Monitoring Strategies ◽

Level Data ◽

Meta Analyses

BackgroundVarious lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation.ObjectiveTo determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD.Data sourcesWe searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Luke’s Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature.MethodsIn two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year.ResultsA total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I2 = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention.LimitationHeterogeneity in meta-analyses.ConclusionsWhile acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence.Study registrationThis study is registered as PROSPERO CRD42013003727.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Effect of Calcium Supplements on Risk of Myocardial Infarction and Cardiovascular Events: Meta-analysis

Journal of SAFOG with DVD ◽

10.5005/jsafog-6-1-62 ◽

2014 ◽

Vol 6 (1) ◽

pp. 62-64

Author(s):

MJ Bolland ◽

A Avenell ◽

JA Baron ◽

A Grey ◽

GS MacLennan ◽

...

Keyword(s):

Myocardial Infarction ◽

Confidence Interval ◽

Cardiovascular Events ◽

Meta Analysis ◽

Controlled Trials ◽

Patient Level Data ◽

Calcium Supplements ◽

Patient Level ◽

Level Data ◽

Meta Analyses

ABSTRACT Objective To investigate whether calcium supplements increase the risk of cardiovascular events. Design Patient level and trial level meta-analyses. Data Sources Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. Study Selection Eligible studies were randomized, placebo controlled trials of calcium supplements (. 500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than 1 year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self-reports, hospital admissions and death certificates. Results Fifteen trials were eligible for inclusion, five with patient level data (8,151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11,921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02-1.67, p = 0.035). Nonsignificant increases occurred in the incidence of stroke (1.20, 0.96-1.50, p = 0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, p = 0.057), and death (1.09, 0.96-1.23, p = 0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01-1.59, p = 0.038). Conclusion Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

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Dose escalation for insufficient response to standard-dose selective serotonin reuptake inhibitors in major depressive disorder

The British Journal of Psychiatry ◽

10.1192/bjp.bp.105.018325 ◽

2006 ◽

Vol 189 (4) ◽

pp. 309-316 ◽

Cited By ~ 46

Author(s):

Henricus G. Ruhé ◽

Jochanan Huyser ◽

Jan A. Swinkels ◽

Aart H. Schene

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Dose Escalation ◽

Randomised Controlled Trials ◽

Selective Serotonin Reuptake Inhibitors ◽

Standard Dose ◽

Controlled Trials ◽

Major Depressive ◽

Randomised Controlled ◽

Meta Analyses

BackgroundAlthough selective serotonin reuptake inhibitors (SSRIs) are frequently used for major depressive disorder, only 50–60% of patients respond to a standard dose. For non-responders, dose escalation is often applied.AimTo systematically review the evidence for dose escalation of SSRIs.MethodA systematic literature search in MEDLINE, EMBASE, CINAHL and PsycInfo was performed. Randomised controlled trials and meta-analyses investigating dose escalation of SSRIs were identified. Relevant articles were retrieved and critically appraised. Results were summarised in an evidence table. Pooling was not justified because of heterogeneity of the identified studies.ResultsEight true dose-escalation studies and three meta-analyses were identified. The available data provided no unequivocal base for dose escalation. Dose escalation before 4 weeks of treatment at a standard dose appeared to be ineffective.ConclusionsDose escalation of SSRIs is equivocally supported by evidence of randomised controlled trials; methodological difficulties in the studies may account for this lack of evidence.

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Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression

The British Journal of Psychiatry ◽

10.1192/bjp.2017.24 ◽

2018 ◽

Vol 212 (3) ◽

pp. 148-154 ◽

Cited By ~ 6

Author(s):

Jakob Näslund ◽

Fredrik Hieronymus ◽

Alexander Lisinski ◽

Staffan Nilsson ◽

Elias Eriksson

Keyword(s):

Young Adults ◽

Serotonin Reuptake ◽

Selective Serotonin Reuptake Inhibitors ◽

Rating Scale ◽

Serotonin Reuptake Inhibitors ◽

Selective Serotonin ◽

Patient Level ◽

Advisory Boards ◽

Hamilton Rating Scale ◽

Ssri Treatment

BackgroundSelective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation.AimsTo explore the effect of SSRIs on the suicidality item of the Hamilton Rating Scale for Depression (HRSD).MethodWe undertook a patient-level mega-analysis of adults with depression participating in industry-sponsored studies of sertraline, paroxetine or citalopram, comparing patients on an SSRI (n = 5681) with those on placebo (n = 2581) with respect to HRSD-rated suicidality. Separate analyses were conducted for young adults (age 18–24; n = 537) and adults (age ≥25; n = 7725).ResultsAmong adults, the reduction in mean rating of suicidality was larger and the risk for aggravation of suicidality lower in patients receiving an SSRI from week 1 and onwards. In young adults, SSRI treatment neither reduced nor increased suicidality ratings relative to placebo at the end-point.ConclusionsThe net effect of SSRIs on suicidality appears beneficial in people above the age of 24 and neutral in those aged 18–24.Declaration of interestF.H. has received speaker's fees from Servier. E.E. has previously been on the advisory boards and/or received speaker's honoraria and/or research grants from Eli Lilly, GlaxoSmithKline, Servier and Lundbeck.

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Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials

10.31219/osf.io/3tuzy ◽

2019 ◽

Author(s):

Michael P. Hengartner ◽

Janus Christian Jakobsen ◽

Anders Sorensen ◽

Martin Plöderl

Keyword(s):

Effect Size ◽

Gold Standard ◽

Treatment Effects ◽

Rating Scale ◽

Meta Analysis ◽

Standard Procedure ◽

Controlled Trials ◽

Summary Estimate ◽

Minimal Improvement ◽

Meta Analyses

Background: It has been claimed that efficacy estimates based in the Hamilton Depression Rating-Scale (HDRS) underestimate antidepressants true treatment effects due to the instrument’s poor psychometric properties. The aim of this study is to compare efficacy estimates based on the HDRS with the gold standard procedure, the Montgomery-Asberg Depression Rating-Scale (MADRS).Methods and findings: We conducted a meta-analysis based on the comprehensive dataset of acute antidepressant trials provided by Cipriani et al. We included all placebo-controlled trials that reported continuous outcomes based on either the HDRS 17-item version or the MADRS. We computed standardised mean difference effect size estimates and raw score drug-placebo differences to evaluate thresholds for clinician-rated minimal improvements (clinical significance). We selected 109 trials (n=32,399) that assessed the HDRS-17 and 28 trials (n=11,705) that assessed the MADRS. The summary estimate (effect size) for the HDRS-17 was 0.27 (0.23 to 0.30) compared to 0.30 (0.22 to 0.38) for the MADRS. The difference between HDRS-17 and MADRS was not statistically significant according to both subgroup analysis (p=0.47) and meta-regression (p=0.44). Drug-placebo raw score difference was 2.07 (1.76 to 2.37) points on the HDRS-17 (threshold for minimal improvement: 7 points) and 2.99 (2.24-3.74) points on the MADRS (threshold for minimal improvement: 8 points). Conclusions: Overall there was no difference between the HDRS-17 and the MADRS. These findings suggest that previous meta-analyses that were mostly based on the HDRS did not underestimate the drugs’ true treatment effect as assessed with MADRS, the preferred outcome rating scale. Moreover, the drug-placebo differences in raw scores suggest that treatment effects are indeed marginally small and with questionable importance for the average patient.

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Kaleidoscope

The British Journal of Psychiatry ◽

10.1192/bjp.207.2.183 ◽

2015 ◽

Vol 207 (2) ◽

pp. 183-184

Author(s):

Derek K. Tracy ◽

Dan W. Joyce ◽

Sukhwinder S. Shergill

Keyword(s):

Selective Serotonin Reuptake Inhibitors ◽

Active Drug ◽

Rating Scale ◽

Illness Burden ◽

Baseline Severity ◽

Patient Level ◽

Post Hoc ◽

Hamilton Rating Scale ◽

Pooled Sample ◽

Diagnostic Importance

Antidepressant effectiveness is a topic seldom out of the scientific or popular press, with claim and counter-claim about the disclosure, reporting, and interpretation of data. Hieronymus and colleagues1 have thrown their hats into the ring: noting that about half of company-sponsored trials failed to show any superiority over placebo, they challenge that most studies evaluated changes in total scores on the 17-point Hamilton Rating Scale for Depression (HRSD-17), but that this might mask improvement in important subcomponents. Not all items equally correlate with illness burden, so they undertook patient-level post hoc analyses focusing on the four-point depressed mood subcomponent in 18 placebo-controlled industry trials of various selective serotonin reuptake inhibitors (n = 6669). The choice of this question was based on its diagnostic importance and the fact it had the highest baseline severity in the pooled sample. The result was that 91% of comparisons showed superiority of the active drug over placebo, compared with 46% where the summed scale was used (P<0.001). The authors argue that the summed scale is insensitive, and clouds current views on medications. The end of the debate? We think not …

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Meta-analyses of the efficacy of asenapine vs placebo in bipolar I disorder as monotherapy and adjunct therapy compared with other atypical antipsychotics

European Psychiatry ◽

10.1016/s0924-9338(11)71961-7 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 251-251

Author(s):

H. Fennema ◽

B. Slaap ◽

C. Karson ◽

A. Szegedi

Keyword(s):

Treatment Effect ◽

Adjunctive Therapy ◽

Atypical Antipsychotics ◽

Rating Scale ◽

Adjunctive Treatment ◽

Controlled Trials ◽

Random Effects Model ◽

Young Mania ◽

Bipolar Mania ◽

Meta Analyses

IntroductionSuperiority of asenapine vs placebo, as monotherapy or adjunctive therapy to lithium or valproate, for acute bipolar mania has previously been reported.ObjectivePresent meta-analyses of asenapine compared with atypical antipsychotics based on placebo-controlled trials.AimFurther demonstrate the efficacy of asenapine for acute bipolar mania.MethodsThe primary endpoint was change from baseline vs placebo on Young Mania Rating Scale (YMRS) total score at treatment week 3. Data for asenapine (5 or 10 mg BID) and comparators were obtained from all monotherapy (n = 20) or adjunctive treatment trials in patients showing incomplete response to lithium or valproate monotherapy (n = 10) published at the time of the analysis. Meta-analyses used a random-effects model described by DerSimonian and Laird (Control Clin Trials 1986;7:177–188).ResultsTreatment effects varied substantially across agents and for individual agents across trials. For monotherapy, the change from baseline in YMRS total score with asenapine exceeded placebo by 4.5 points (95% CI, 2.5–6.4; p < 0.0001); this was comparable to the treatment effect of all comparators vs placebo (4.9 points; 95% CI, 3.8–6.0). The treatment effect for adjunctive asenapine exceeded placebo by 2.4 points (95% CI, 0.5–4.3); this was also comparable to the overall treatment effect for the combined comparators (2.7 points; 95% CI, 2.0–3.3).DiscussionThese meta-analyses demonstrate statistical superiority of asenapine over placebo, as monotherapy or adjunctive therapy, for acute bipolar mania. Further, they reveal that the efficacy of asenapine is similar to that of other atypical antipsychotics used as monotherapy or adjunctive therapy.

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Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials

British Journal Of Nutrition ◽

10.1017/s0007114513001050 ◽

2013 ◽

Vol 110 (8) ◽

pp. 1384-1393 ◽

Cited By ~ 49

Author(s):

Sarah M. Bristow ◽

Mark J. Bolland ◽

Graeme S. MacLennan ◽

Alison Avenell ◽

Andrew Grey ◽

...

Keyword(s):

Vitamin D ◽

Relative Risk ◽

Cancer Risk ◽

Meta Analysis ◽

Controlled Trials ◽

Patient Level Data ◽

Patient Level ◽

Level Data ◽

Total Cancer ◽

Meta Analyses

Some evidence suggests that Ca and vitamin D supplements affect cancer risk; however, it is uncertain whether the effects are due to Ca, vitamin D or the combination. We investigated the effect of Ca supplements without co-administered vitamin D on cancer risk. Medline, Embase and the Cochrane Central Register of Controlled Trials, reference lists of meta-analyses and two clinical trial registries were searched for randomised, placebo-controlled trials of Ca supplements ( ≥ 500 mg/d), with ≥ 100 participants and duration >1 year. The lead authors of eligible trials supplied data on cancer outcomes. Trial-level data were analysed using random-effects meta-analyses and patient-level data using Cox proportional hazards models. A total of sixteen trials were eligible, six had no data available, ten provided trial-level data (n 10 496, mean duration 3·9 years), and of these, four provided patient-level data (n 7221, median duration 3·5 years). In the meta-analysis of trial-level data, allocation to Ca did not alter the risk of total cancer (relative risk 0·95, 95 % CI 0·76, 1·18, P= 0·63), colorectal cancer (relative risk 1·38, 95 % CI 0·89, 2·15, P= 0·15), breast cancer (relative risk 1·01, 95 % CI 0·64, 1·59, P= 0·97) or cancer-related mortality (relative risk 0·96, 95 % CI 0·74, 1·24, P= 0·75), but reduced the risk of prostate cancer (relative risk 0·54, 95 % CI 0·30, 0·96, P= 0·03), although there were few events. The meta-analysis of patient-level data showed similar results, with no effect of Ca on the risk of total cancer (hazard ratio 1·07, 95 % CI 0·89, 1·28, P= 0·50). Ca supplements without co-administered vitamin D did not alter total cancer risk over 4 years, although the meta-analysis lacked power to detect very small effects, or those with a longer latency.

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Treatment of Obsessive-Compulsive Disorder

CNS Spectrums ◽

10.1017/s1092852900002480 ◽

2007 ◽

Vol 12 (S3) ◽

pp. 28-35 ◽

Cited By ~ 16

Author(s):

Dan J. Stein ◽

Jonathan C. Ipser ◽

David S. Baldwin ◽

Borwin Bandelow

Keyword(s):

Obsessive Compulsive Disorder ◽

Selective Serotonin Reuptake Inhibitors ◽

Rating Scale ◽

Good Evidence ◽

Functional Improvement ◽

Future Research ◽

Consensus Guidelines ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Meta Analyses

AbstractBackground: Many randomized controlled trials of the pharmacotherapy and psychotherapy of obsessive-compulsive disorder (OCD) have been undertaken. Several meta-analyses of these trials, and a number of expert consensus guidelines, have been published. This article summarizes these works, and suggests future research directions.Methods: Meta-analyses of OCD were assessed with the QUORUM statement and the Oxman and Guyatt rating scale, and consensus guidelines on the treatment of OCD were assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument. Current principles in the treatment of OCD, and gaps in our knowledge, were reviewed.Results: Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy are currently viewed as the first-line treatments of choice for adult and pediatric OCD.There is also good evidence for the efficacy of atypical antipsychotics in the augmentation of patients refractory to SSRIs. Important questions remain for the field.Conclusions: There have been significant advances in both the pharmacotherapy and psychotherapy of OCD. Nevertheless, there is a paucity of longer-term trials, data on symptom remission and functional improvement, and data on treatment effectiveness in wider clinical practice. It is hoped that improved understanding of the mechanisms underlying OCD will lead to future advances.

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