Impact of study outcome on submission and acceptance metrics for peer reviewed medical journals: six year retrospective review of all completed GlaxoSmithKline human drug research studies.

Objectives To determine whether the outcome of drug studies influenced submission and/or acceptance rates for publication in peer reviewed medical journals.Design A six year retrospective review of publication status by study outcome for all human drug research studies conducted by a single industry sponsor (GlaxoSmithKline) that completed from 1 January 2009 to 30 June 2014 and were therefore due for manuscript submission (per the sponsor's policy) to peer reviewed journals within 18 months of study completion-that is, 31 December 2015. In addition, manuscripts from studies completing after 30 June 2014 were included irrespective of outcome if they were submitted before 31 December 2015.Setting Studies conducted by a single industry sponsor (GlaxoSmithKline)Studies reviewed 1064 human drug research studies.Main outcome measures All studies were assigned a publication status at 26 February 2016 including (as applicable): study completion date, date of first primary manuscript submission, number of submissions, journal decision(s), and publication date. All studies were also classified with assessors blinded to publication status as "positive" (perceived favorable outcome for the drug under study), "negative" (perceived unfavorable outcome for the drug under study), mixed, or non-comparative based on the presence and outcome of the primary outcome measure(s) for each study. "Negative" studies included safety studies in which the primary outcome was achieved but was adverse for the drug under study. For the total cohort and each of the four study outcomes, measures included descriptive statistics for study phase, time from study completion to submission and publication, and number and outcome (accepted/rejected) of publication submissions.Results Of the 1064 studies (phase I-IV, interventional and non-interventional) included, 321 had study outcomes classified as positive, 155 as negative, 52 as mixed, and 536 as non-comparative. At the time of publication cut-off date (26 February 2016), 904 (85%) studies had been submitted for publication as full manuscripts and 751 (71%) had been successfully published or accepted, with 100 (9%) still under journal review. An additional 77 (7%) studies were conference abstracts and were not included in submission or publication rates. Submission rates by study outcome were 79% for the 321 studies with positive outcomes, 92% for the 155 with negative outcomes, 94% for the 52 with mixed outcomes, and 85% for the 536 non-comparative studies; while rates of publication at the cut-off date were 66%, 77%, 77%, and 71%, respectively. Median time from study completion to submission was 537 days (interquartile range 396-638 days) and 823 days (650-1063 days) from completion to publication, with similar times observed across study outcomes. First time acceptance rates were 56% for studies with positive outcomes and 48% for studies with negative outcomes. Over 10% of studies across all categories required three or more submissions to achieve successful publication. At the time of analysis, 83 studies had not been submitted for publication, including 49 bioequivalence studies with positive outcomes and 33 non-comparative studies. Most studies (98%, 1041/1064) had results posted to one or more public registers, including all studies subject to FDAAA (Food and Drug Administration Amendments Act) requirements for posting to www.clinicaltrials.govConclusions Over the period studied, there was no evidence of submission or publication bias: 92% of studies with negative outcomes were submitted for publication by the cut-off date versus 79% of those with positive outcomes. Publication rates were slightly higher for studies with a negative (that is, unfavorable) outcome compared with a positive outcome, despite a slightly lower rate of acceptance at first submission. Many studies required multiple submission attempts before they were accepted for publication. Analyses focusing solely on publication rates do not take into account unsuccessful efforts to publish. Sponsors and journal editors should share similar information to contribute to better understanding of issues and barriers to full transparency.

A factor analytic study in bipolar depression, and response to lamotrigine.

OBJECTIVE: There have been no previous factor analytic studies of the Hamilton Depression Rating Scale (HDRS) in samples with bipolar I depression, and no investigations of the utility of any derived factors in determining treatment response in this condition. This study aimed to identify and compare factors of a 31-item version of the HDRS (HDRS-31) in large samples of patients with bipolar depression and Major Depressive Disorder (MDD), then examine the responsiveness of such factors to lamotrigine compared with placebo in the bipolar depressed sample. METHODS: This multivariate analytical study was performed on 2 large depressed samples (one bipolar and the other MDD) that had been recruited for separate, contemporaneous, double-blind placebo-controlled trials of lamotrigine. The 2 studies had similar designs and assessment tools, the major measures being the Montgomery-Asberg Depression Rating Scale (MADRS) and HDRS-31. To identify the constructs underlying the scale, exploratory factor analyses were conducted using HDRS-31 baseline scores. Treatment responsiveness in the bipolar depressed sample-as indicated by improvement in the total MADRS and HDRS-31, as well as HDRS factors-were examined using both a mixed-effects analysis and individual time-point t-tests. RESULTS: Seven factors of the HDRS-31 were identified: I-"depressive cognitions," II-"psychomotor retardation," III-"insomnia," IV-"hypersomnia," V-"appetite and weight change," VI-"anxiety," and VII-"anergia." A significant therapeutic effect of lamotrigine in bipolar depression was found for the "depressive cognitions" factor (from week 3) and "psychomotor retardation" (from week 4). CONCLUSION: This study has identified 7 factors of the HDRS in a large sample of patients with bipolar depression. The results suggest that that the clinical benefits of lamotrigine in acute bipolar depression are primarily upon depressive cognitions and psychomotor slowing.

Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

Bupropion, a noradrenaline/dopamine reuptake inhibitor, and venlafaxine, a serotonin/noradrenaline reuptake inhibitor, are both established antidepressants with proven efficacy in randomized controlled clinical trials. The objective of this double-blind, randomized, placebo- and active-controlled, eight-week, flexible-dose study was to evaluate the efficacy and tolerability of the once-daily extended-release formulations of these two antidepressants compared with placebo. Patients with major depressive disorder were randomized to once-daily treatment with bupropion XR 150 mg (n = 204), the extended-release formulation of venlafaxine (venlafaxine XR) 75 mg (n = 198) or placebo (n = 189) during weeks 1 to 4, with the option to double the dose at week 5 if response was inadequate. In this study, bupropion XR did not demonstrate statistically significant evidence of greater improvement from baseline compared with placebo on week 8 Montgomery Asberg Depression Rating scale scores (primary endpoint) or on secondary endpoints including CGI, HAM-A and responder and remitter analyses. Descriptive statistics for venlafaxine XR indicated separation versus placebo on MADRS total scores at week 8 and other intermediate time points, and on other endpoints including CGI, HAM-A and responder and remitter analyses. Both active treatments elicited improvement on the Sheehan Disability Scale and its subscales and were generally well tolerated at the doses studied. Rates of nausea, dry mouth, dizziness, hyperhidrosis, insomnia, constipation, tremor, anorexia and male sexual dysfunction were elevated in the venlafaxine XR group, consistent with its mixed serotonergic/noradrenergic mechanism. Rates of dry mouth, insomnia and hyperhidrosis were elevated in the bupropion XR group, consistent with its catecholaminergic mechanism.

Open-label, concomitant use of lamotrigine and other medications for bipolar disorder.

OBJECTIVE: A post-hoc, descriptive analysis was undertaken to assess the tolerability of and changes in psychiatric rating scales with lamotrigine (LTG) administered concomitantly with commonly prescribed bipolar medications. METHODS: During the 8- to 16-week, open-label, preliminary phase of two large clinical trials of patients (N=1,305) with bipolar I disorder, LTG was added to each patient's existing psychotropic regimen. Medications for acute symptoms could have been added and later discontinued to achieve LTG monotherapy. Data were compared for patients taking LTG with or without concomitant valproate, lithium, any atypical antipsychotic, or any selective serotonin reuptake inhibitor. RESULTS: The percentages of patients with any reported adverse event and reported adverse events of mood symptoms or rash were comparable between those taking LTG with or without other concomitant bipolar medications. Adverse events in >10% of patients in at least one subgroup were headache, infection, nausea, rash, influenza, diarrhea, dizziness, and somnolence. Baseline scores on psychiatric rating scales improved similarly with LTG co-administered with other bipolar medications, and the pattern of results did not differ by baseline polarity of mood symptoms. CONCLUSION: LTG co-administered with valproate, lithium, an atypical antipsychotic, or a selective serotonin reuptake inhibitor in the treatment of bipolar disorder seemed to be well tolerated and was associated with clinical improvement.

Discovery and development of lamotrigine for bipolar disorder: a story of serendipity, clinical observations, risk taking, and persistence.

This paper briefly reviews and comments on the development of lamotrigine as a treatment for bipolar disorder. The events described include astute clinical observations by epileptologists, serendipitous coupling of the drug's clinical profile to unmet need of two refractory bipolar patients by a practicing psychiatrist, risk taking on the part of an industry sponsor, and persistence on the part of a few key internal and external advocates to see development through to its conclusion, taking place against a backdrop of a disease area which, at the time of the earliest events described here, had not seen the development of any new pharmacologic treatments for decades. Fortunately for patients, since that time there has been a veritable explosion of research into treatments for bipolar disorder, both old and new, so that now patients and physicians have multiple evidence-based options for the treatment of this devastating illness. The development of lamotrigine provides one example of the importance of prescience, patience and persistence in bringing a novel idea to clinical fruition.

Maintenance treatment outcomes in older patients with bipolar I disorder.

OBJECTIVE: The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains understudied. Authors retrospectively examined response to lamotrigine, lithium, and placebo in older (>or=age 55) adults with Bipolar I disorder (DSM-IV) who participated in two mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. METHODS: In all, 588 patients received double-blind lamotrigine (LTG, 100 mg-400 mg/day), lithium (Li, 0.8 mEq/L-1.1 mEq/L), or placebo (PBO); data from 98 older adults (LTG: 33, Li: 34, PBO: 31) were examined. Mean modal total daily doses were LTG 240 mg and Li 750 mg. RESULTS: LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. CONCLUSION: Lamotrigine and lithium may be effective and well-tolerated maintenance therapies for older adults with Bipolar I depression.