[Show abstract][Hide abstract] ABSTRACT: Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Design Double blind randomised placebo controlled trial.
Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998.
Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.
Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo.
Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.
Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
BMJ British medical journal 09/2015; 351. DOI:10.1136/bmj.h4320 · 16.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polypharmacy, defined as the concomitant use of two or more psychotropic drugs, has become increasingly common in the paediatric and adolescent population over the past two decades. Combining psychotropic drugs leads to possible increases in benefits, but also in risks, particularly given the potential for psychotropic drug interactions. Despite the increasing use of concomitant therapy in children and adolescents, there is very little evidence from controlled clinical trials to provide guidance for prescribers. Even while acknowledging the small evidence base, clinical practice guidelines from eminent medical organizations are either relatively silent on or tend to support the use of concomitant treatments more enthusiastically than the evidence would warrant, so that practice and guidance are running ahead of the science. Our narrative review shows that the published evidence for efficacy and safety of concomitant psychotropic drugs in children and adolescents is scanty. A comprehensive search located 37 studies published over the last decade, of which 18 were randomized controlled trials (RCTs). These focused mainly on stimulants, central sympatholytics (such as clonidine), antipsychotics and 'mood stabilizers'. While several small, often methodologically weak, RCTs demonstrated statistically significant advantages for dual pharmacotherapy over monotherapy, only adding central sympatholytics to stimulants for treating attention-deficit hyperactivity disorder (ADHD) symptoms was supported by substantial studies with an effect size large enough to suggest clinical importance. Non-randomized studies tended to have results that supported concomitant treatment, but all have design-related problems that decrease the reliability of the results. Two studies that specifically examined tolerability of combination pharmacotherapy compared with monotherapy showed significant increases in adverse effects, both subjective and objective, and other studies confirmed a statistically significant increase in adverse effects, including sedation and self-harm. Given the extent of combination therapy occurring, particularly in conditions such as ADHD, and the ambiguous evidence for benefit with clear evidence of harm, we propose that further research should be carried out as a matter of urgency. Until such a time, the attitude to combination pharmacotherapy should be conservative, and combining psychotropic medications should be considered as an 'n of 1' trial to be closely monitored.
[Show abstract][Hide abstract] ABSTRACT: Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors' Summary.
PLoS Medicine 05/2011; 8(5):e1000434. DOI:10.1371/journal.pmed.1000434 · 14.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Journals are failing in their obligation to ensure that research is fairly represented to their readers, and must act decisively to retract fraudulent publications. Recent case reports have exposed how marketing objectives usurped scientific testing and compromised the credibility of academic medicine. But scant attention has been given to the role that journals play in this process, especially when evidence of research fraud fails to elicit corrective measures. Our experience with The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) illustrates the nature of the problem. The now-infamous Study 329 of paroxetine in adolescent depression was negative for efficacy on all eight protocol-specified outcomes and positive for harm, but JAACAP published a report of this study that concluded that "paroxetine is generally well tolerated and effective for major depression in adolescents." The journal's editors not only failed to exercise critical judgment in accepting the article, but when shown evidence that the article misrepresented the science, refused either to convey this information to the medical community or to retract the article.
Accountability in Research Policies and Quality Assurance 01/2011; 18(1):45-54. DOI:10.1080/08989621.2011.542683 · 0.83 Impact Factor