Jon Jureidini

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

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.

Psychiatric assessment of children and families in immigration detention – clinical, administrative and ethical issues

Objective: This paper reports the clinical, practical and ethical issues arising in the assessment of 10 consecutive referrals from a remote Immigration Reception and Processing Centre to a child and adolescent mental health service (CAMHS) between February and August 2002.

Overuse of Antidepressant Drugs for the Treatment of Depression

The problem of under-diagnosis and under-treatment of depression has been identified as a major public health issue and measures have been taken to increase the recognition of depression and its treatment with antidepressants. The possibility of harm from the overuse of antidepressants has attracted far less attention. This review sets out evidence to show that inappropriate use of antidepressants (i.e. outside clinical indications, in excessive doses and for prolonged periods) constitutes a concerning public health problem. Antidepressant prescribing increased by between 4- and 10-fold in various age groups and countries in the last decade of the 20th century. The population of severely depressed patients (in whom antidepressants are accepted to be an effective treatment) who are not receiving antidepressants is probably much smaller than the population receiving these drugs inappropriately. We sound a note of caution for depression awareness campaigns. These apparently well-reasoned responses to the perceived under-recognition of depression can exacerbate over-prescribing. Unless prescribing patterns change, any benefits from increasing access to antidepressants for those with severe depression will be accompanied by significant harms due to inappropriate prescribing in conditions, such as mild depression, where antidepressants are not indicated

Industry-Sponsored Ghostwriting in Clinical Trial Reporting: A Case Study

In this case study from litigation, we show how ghostwriting of clinical trial results can contribute to the manipulation of data to favor the study medication. Study 329 for paroxetine pediatric use was negative for efficacy and positive for harm. Yet the ghostwritten publication from this study concluded that paroxetine provided evidence of efficacy and safety and continues to be influential. Despite the role of named authors in revisions of the manuscript, the sponsor company remained in control of the message.

The increased use of antidepressants has contributed to the worldwide reduction in suicide rates

Numerous ecological studies have shown an inverse association between antidepressant use and suicide rates and a smaller number of individual-based studies have shown an association between current antidepressant use and reduced suicide risk. Such evidence is often cited in support of the notion that antidepressants prevent suicide. However, more recently, the premises underlying this proposition, namely that suicide is caused by depression and that antidepressants relieve depression, have been challenged and the potential harm caused by antidepressants has been highlighted. In this article, Goran Isacsson and Charles Rich debate with Jon Jureidini and Melissa Raven the motion that the increased use of antidepressants has contributed to the worldwide reduction in suicide rates.

Restrained rehabilitation: an approach to children and adolescents with unexplained signs and symptoms

The validation of treatment approaches for children and adolescents diagnosed with unexplained signs and symptoms is made difficult by the variety of clinical presentations and the different developmental levels of different patients. There is little evidence about what combination of approaches is most successful. This article uses what evidence is available to develop a coordinated multidisciplinary rehabilitation package that ensures consistency and can be evaluated. The package is organised around a psychologically informed physical rehabilitation programme. The need for coordination and a common approach between medical, allied health and psychological staff, and family is formally addressed. The approach is illustrated with a case study.

Educating Health Professionals about Drug and Device Promotion: Advocates' Recommendations

Mansfield and colleagues outline the recommendations from four advocacy groups for improving the education of health professionals on promotion of drugs and devices.

Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature

A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.

Concerns about research and prevention strategies in Munchausen Syndrome by Proxy (MSBP) abuse

There would seem to be three motives for research into Munchausen Syndrome by Proxy (MSBP) abuse; first to enhance treatment; second to enhance our understanding of the psychopathology of those who carry out the abuse; and third to find interventions to prevent its occurrence. We will argue that only the first justification is valid. The second and third should be questioned for several reasons including: MSBP abuse is the wrong kind of event to think of in terms of categorical diagnosis; rare events are inherently difficult to predict; and better research targets are available. We propose that research energy would be more productively directed towards furthering our understanding of somatization and certain problematic aspects of modern pediatric practice. We offer suggestions as to appropriate areas for research.

Key Opinion Leaders and Paediatric Antidepressant Overprescribing

Perhaps the most influential efficacy study of antidepressants in children has been the TADS study [11–13] . The main methodological criticism of the TADS study is that it included an unblinded comparison between cognitive behavioural therapy (CBT) alone and fluoxetine plus CBT. This was carried out in parallel to a doubleblind comparison between fluoxetine and placebo. The lack of patient blinding for medication status and placebo control for one half of the study is likely to have exaggerated the benefit seen in the fluoxetine plus CBT group who knew that they were not receiving placebo. The decision not to include a placebo in the CBT group was based on the belief that it was ‘both too expensive and too artificial to have clinical relevance’ [14] . This, however, is not a plausible explanation for why the CBT-only group could not have been converted into a CBT plus placebo group. In any case, the lack of placebo control for half the patients means that comparing results between parts of the trial, with and without a placebo control, is not valid. Yet The lingering controversy about the usefulness and safety of antidepressants for children and adolescents is likely to leave clinicians in a state of confusion. Some papers report that there is little evidence for efficacy and raise concerns about harm [1–3] ; others state that antidepressants are not only safe and effective, but also prevent suicides [4–7] . This journal has previously noted the influence on decision-making of irrational habits and misplaced trust in data submitted by the pharmaceutical industry [8, 9] . In this editorial we address the manipulation of outcomes that result from academics’ alliance with industry. We explain how industry and key opinion leaders have distorted the clinician’s perception of the safety and usefulness of antidepressants for the treatment of depression in children and adolescents through publication bias, poor methodology, and selective reporting.