Melissa Raven

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.

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.

Dimensions of control in bulimia and anorexia nervosa: Internal control, desire for control, or fear of losing self-control?

Abstract In a multidimensional investigation of issues of control in eating disorders, 52 women with bulimia or anorexia nervosa and 57 comparison women were surveyed regarding their perceptions of control. As predicted, the women with eating disorders reported lower internal control than comparison women but, contrary to prediction, reported lower desire for control. They also reported much higher fear of losing self-control, which emerged as the most significant predictor of eating disorder symptomology for both eating disordered and comparison women. Bulimic and anorexic women did not differ significantly from each other on any of these measures of control. Further research is recommended on the relevance of fear of losing self-control to the treatment and prevention of eating disorders.

'Prodromal' diagnosis of psychosis: ethical problems in research and clinical practice

Australian & New Zealand Journal of Psychiatry, 46(1) Ethical concerns surrounding the identification of an ‘at-risk’ state for psychosis are long-standing. Two major risks are the stigmatisation/ labelling of those identified as being at risk of progression to psychosis, and unnecessary anxiety and demoralisation about prognosis. False-positive diagnosis of ‘psychosis risk syndrome’ or ‘prodromal psychosis’ can have lifelong detrimental social and psychological consequences. An even more serious risk is unnecessary pre-emptive use of antipsychotics, with potentially serious side-effects, including weight gain, diabetes, metabolic syndrome (Foley and Morley, 2011), neurological symptoms, and brain shrinkage (Ho et al., 2011). Although weight gain emerges rapidly, many of these adverse effects only emerge in the longer term. Klosterkötter (2008) has suggested that a false-positive rate of 10% or less would be needed to justify any preventive intervention that had harmful side-effects. It is not possible to identify a genuine prodrome (as opposed to an at-risk state) prospectively. There are no reliable genetic markers for schizophrenia (Sebat et al., 2009), and the false-positive rate in high-risk groups using other markers (Stober et al., 2009) is nowhere near 10%. Consequently the use of potentially harmful preventive interventions cannot be justified. We argue that pre-emptive psychosis-related diagnoses cannot be justified either. McGorry (2011), among others, argues that the label ‘prodromal’ should not be used, but that ‘atrisk mental state’ and ‘ultra-high risk’ are appropriate. Jorm (2011), among others, argues that it is appropriate for a similar term, ‘psychosis risk syndrome’, to be used as a research diagnosis, but not as a clinical diagnosis. These cautions will reassure many. However, we argue that such diagnoses are also harmful in research, because of the consequences. The most likely studies to be undertaken are clinical trials of pre-emptive interventions, often antipsychotics with or without other treatment modalities. McGorry (2011) has acknowledged that 80% false-positive rates are common. This means that the majority of trial participants randomised to receive antipsychotics will be unnecessarily exposed to substantial risks. Furthermore, despite McGorry’s espousal of low-dose antipsychotics during first-episode psychosis (but not for the ‘at-risk’ state), he is a member of an international group that until recently was proposing to commence an industry-funded trial that would have allowed prescription of high doses (400 mg) of quetiapine (Australian New Zealand Clinical Trials Registry, 2011). Tellingly, the specified health condition in the trial – the NEURAPRO-Q (North America, EURope, Australia PROdrome) study – was ‘prodromal psychosis’. In addition, the specified follow-up period was only 6 months, the duration of the treatment. This is not long enough for some of the potential adverse effects to emerge and/or peak, nor for some cases of psychosis to emerge. Furthermore, because quetiapine reduces psychotic symptoms, it would have been symptom suppression rather than incidence of first episode psychosis – the stated primary outcome – that was measured, biasing the results in favour of quetiapine over placebo. Despite these problems, this trial was approved by an ethics committee. Such trials promote the acceptance of diagnoses such as psychosis risk syndrome. They are likely to escalate the inappropriate use of antipsychotics – in the longer term through the approval of antipsychotics for ‘treatment’ of psychosis risk, and in the shorter term through increasing off-label prescription for this purpose – with all the attendant harms and costs for both individuals and the community. Avoiding diagnoses such as ‘psychosis risk syndrome’ and ‘prodromal psychosis’ does not mean withholding treatment when it is required. However, whether in clinical practice or in research, such treatment should not be based on diagnoses that have significant social risks, increase the likelihood of potentially harmful drug prescribing, and are unsupported by evidence. ‘Prodromal’ diagnosis of psychosis: Ethical problems in research and clinical practice

Guidance offers little in the way of ethics or transparency

While noting the alleged benefits of this new guidance, the article fails to mention its weaknesses.1 The guidance uncritically endorses relationships between the drug industry and healthcare professionals, a view endorsed by 18 august bodies including various royal colleges. Despite claims of “ethics, transparency, partnership,” it takes some sleuthing to discover that the guideline is written by a multi-stakeholder group, seemingly coordinated and supported …

Health of grey nomads: On the move and under the health sector radar.

OBJECTIVE Grey nomads - older people driving long distances recreationally and staying in caravans, tents or motor homes - are common on Australian highways. Although grey nomads report many benefits from their travels, there is anecdotal evidence that they impose a significant burden on rural/remote health services, including general practitioners, pharmacists and hospitals. There have been calls for better resourcing and service provision, but little reference to solid evidence on which to base this. This literature review is the first to integrate existing evidence for a health audience. SETTING Australia. DESIGN Narrative literature search and synthesis. RESULTS There is very little published information about the health and health service utilisation of grey nomads, and almost none in the medical literature. One key exception, a survey at a caravan park in the Kimberley region, found that, like other older Australians, many grey nomads have chronic diseases, and they have high rates of medication use. However, other studies have found that they generally view themselves as relatively healthy. There is some evidence of inadequate preparation for travelling. Issues include lack of health summaries, inadequate medication supplies and suboptimal vaccination. Some experience emergencies, sometimes resulting in hospital admissions. Overall, they place a poorly documented burden on rural/remote services. CONCLUSION There is a need for further research on the health of grey nomads, their use of self-care strategies, and their uptake of health services both on the road and at home, to inform the provision of health services and optimise their well-being and health care utilisation.

A health app developer’s guide to law and policy: a multi-sector policy analysis

BackgroundApps targeted at health and wellbeing sit in a rapidly growing industry associated with widespread optimism about their potential to deliver accessible and cost-effective healthcare. App developers might not be aware of all the regulatory requirements and best practice principles are emergent. Health apps are regulated in order to minimise their potential for harm due to, for example, loss of personal health privacy, financial costs, and health harms from delayed or unnecessary diagnosis, monitoring and treatment. We aimed to produce a comprehensive guide to assist app developers in producing health apps that are legally compliant and in keeping with high professional standards of user protection.MethodsWe conducted a case study analysis of the Australian and related international policy environment for mental health apps to identify relevant sectors, policy actors, and policy solutions.ResultsWe identified 29 policies produced by governments and non-government organisations that provide oversight of health apps. In consultation with stakeholders, we developed an interactive tool targeted at app developers, summarising key features of the policy environment and highlighting legislative, industry and professional standards around seven relevant domains: privacy, security, content, promotion and advertising, consumer finances, medical device efficacy and safety, and professional ethics. We annotated this developer guidance tool with information about: the relevance of each domain; existing legislative and non-legislative guidance; critiques of existing policy; recommendations for developers; and suggestions for other key stakeholders.ConclusionsWe anticipate that mental health apps developed in accordance with this tool will be more likely to conform to regulatory requirements, protect consumer privacy, protect consumer finances, and deliver health benefit; and less likely to attract regulatory penalties, offend consumers and communities, mislead consumers, or deliver health harms. We encourage government, industry and consumer organisations to use and publicise the tool.

Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression.

OBJECTIVE: This is an analysis of the unpublished continuation phase of Study 329, 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 objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine. METHODS: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVA testing (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics. RESULTS: Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events. CONCLUSIONS: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

Transparency and accountability in early psychosis intervention research

Australian & New Zealand Journal of Psychiatry, 47(7) Allison and colleagues (2013) are to be commended for highlighting the mental health needs of a vulnerable group of people – adolescents and young adults with chronic illness. They have drawn our attention to the parallel evolution of systems of care for young people with mental health difficulties on the one hand, and for young people with chronic medical illnesses on the other, and the risk that a large group of people with both sets of problems may not receive coordinated care. I would like to see the group go on to propose models for straddling this Cartesian divide, allowing the development of inclusive, non-stigmatising and readily disseminated services for young people with both medical and psychiatric needs. Funding

Targeted primary care-based mental health services for young Australians.

627 MJA 196 (10) · 4 June 2012 Targeted primary carebased mental health services for young Australians TO THE EDITOR: The report by Scott and colleagues on the “demographic characteristics, diagnostic category, stage of illness, as well as psychosocial and vocational impairment” of 1260 patients presenting to two Sydney headspace centres1 is problematic for several reasons. No convincing data were presented to support the authors’ conclusion that the research demonstrated that “well designed youth mental health services can directly attract large numbers of young people”. In fact, the sites studied attracted only one new patient per site per working day (1260 in 27 months= 23 per month per site). Other research found that a tiny minority of young people volunteered any knowledge of headspace as a mental health resource.2 The authors further claimed that “[s]everal characteristics of headspace centres may underpin their potential to engage young people in treatment”. However, they did not provide data about whether patients attending headspace were engaged by the service, how often the patients attended or what treatments they accepted, or patient outcomes or satisfaction levels. Furthermore, given the controversy about the recent large public investment in headspace, it would have added to the value of the paper if the authors had presented the cost per patient of the service. The article is already being cited in a way that exaggerates its questionable findings, including uncorroborated claims that the study found that young people prefer headspace to GPs.3 This adds to a pattern of misleading citation4 that distorts the psychiatric literature. It is worrying that the Journal has contributed to this process by publishing a paper with claims that are inadequately supported by its findings.