Invited editorial presents an accurate summary of the results of two randomised placebo-controlled trials of vertebroplasty

Our recent editorial in the Journal presents an accurate summary of our two randomised trials of vertebroplasty, which found no benefit of vertebroplasty over placebo.

Participants in both trials are representative of patients seen in clinical practice and who would qualify for government-subsidised funding of vertebroplasty in Australia.

Clinical experience and previous published literature are likely to have overestimated the treatment benefit of vertebroplasty for many reasons.

This is why randomised placebo-controlled trials are required to determine the efficacy of treatment interventions, particularly when the condition being treated is self-limiting and the primary end point is improvement of symptoms.

Based on the best evidence currently available, the routine use of vertebroplasty outside of the research setting for painful osteoporotic vertebral fractures appears unjustified.

Reporting of the ACT heroin trials

The aim of this research is to analyse the reports of the proposed heroin maintenance trials in the Australian Capital Territory (A.C.T.), in Melbourne print media during 1997. The proposal for trials of heroin-prescription to long-term users in the A.C.T. was based on extensive scientific research. The rejection of this proposal by Prime Minister Howard raised many questions. This study was designed to help understand what discourses and rhetorical devices were used in the reporting of heroin issues in the media and what part some sections of the media played in the government’s decision. Discourse analysis was conducted of newspaper articles from two major Melbourne newspapers, The Age and the Herald-Sun for the year 1997. All articles relating to heroin and drug-policy from the newspapers were included for analysis. Those in favour of the trials used predominantly health and social discourses. Those opposed used moral discourses supported with stereotypes, metaphors, emotive practices and ‘inaccuracies’. There were considerable differences in discourses presented by The Age and the Herald-Sun. This study demonstrates that opposition to the heroin trials relied on rhetorical strategies and sensationalistic arguments, rather than meaningful debate of scientific and social issues. Researchers should act to identify the stereotypes and metaphors used in the discourses surrounding an issue and act to disarm them.

Randomized placebo controlled trials of n-acetyl cysteine as adjunct therapy for schizophrenia and bipolar disorder

Glutathione is the principal antioxidant of the brain. There is evidence of oxidative stress, lowered brain glutathione and genetic linkage involve glutathione metabolic genes in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a safe, orally bioavailable, precursor of glutathione. NAC has been shown to reverse animal models of oxidative stress, and raises brain glutathione levels.

Qualitative methods in early-phase drug trials : data and methods from a trial of N-acetylcysteine in schizophrenia

Objective: The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application, with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis-driven, quantitative research methodology is exclusively used in early-phase trials, unexpected but important phenomena may escape detection. In this context, this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early-phase drug trials. To our knowledge, this mixed methodology has not previously been applied to blinded psychopharmacologic trials.

Method: We undertook qualitative data analysis of clinical observations on the dataset of a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) in patients with DSM-IV-TR–diagnosed schizophrenia (N = 140). Textual data on all participants, deliberately collected for this purpose, were coded using NVivo 2, and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005.

Results: The principal findings of the published trial could be replicated using a qualitative methodology. In addition, significant differences between NAC- and placebo-treated participants emerged for positive and affective symptoms, which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder.

Conclusions: The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals, thereby maximizing the findings of early-phase clinical trial research.

Do we need to flick the switch? The need for a broader conceptualization of iatrogenic course aggravation in clinical trials of bipolar disorder?

The term ‘switching’ is often used in bipolar disorder when describing polarity changes in bipolar disorder, but this term is ambiguous and imprecise, and is sometimes used interchangeably with the term ‘cycling’. Furthermore, polarity changes in bipolar disorder can be understood in different ways, because their clinical manifestations range from the emergence of subthreshold symptoms to a full episode of the opposite pole. Besides the need to tighten the meaning of the term ‘switching’, this paper also argues that switching does not adequately describe the complex phenomena that occur with course aggravation of bipolar disorder, such as alteration in episode frequency or amplitude. A more-fine grained approach to course aggravation in bipolar disorder is proposed, which incorporates trans-polar switching, index polarity aggravation, as well as alterations in episodic amplitude, episodic duration, and interepisode length. This approach has the potential to capture a broader, more fine-grained and clinically relevant picture of the process of aggravation of the bipolar cycle.

Quality of life in restless legs syndrome: A systematic review of clinical trials and a critical review of instruments

Restless legs syndrome (RLS) is a neurological movement disorder characterized by sensory symptoms and motor disturbances. While the underlying cause remains unknown, it is suggested that 20–25% of people with RLS are affected seriously enough to require pharmacological treatment. Dopamine agonists (DAs) are the most common treatment and act by increasing the low levels of dopamine to which RLS is often attributed. A growing literature highlights the debilitating and distressing nature of this condition from the patient's perspective. While sleep problems are most commonly reported, the impact of RLS on quality of life (QOL) is wide ranging, affecting relationships with partners, sex life, family life, social life, leisure activities, friendships, everyday activities, concentration, travel, career/work, sleep, and health.

We conducted a systematic review of clinical trials in which DAs have been evaluated in terms of RLS-specific QOL, i.e. their impact on the QOL of people with RLS, and critically reviewed the development history and measurement properties of RLS-specific QOL instruments.

A systematic search using terms synonymous with RLS, DAs and QOL was conducted using Scopus software, which includes MEDLINE, PsycINFO, EMBASE, and CINAHL. Our search covered publications from 2000 (prior to which RLS-specific QOL measures did not exist) to August 2009. Trials were included in our review if they evaluated DAs for the treatment of adults with RLS and reported evaluation using an RLS-specific QOL measure. We also ran citation searches to identify papers reporting the development history and measurement properties of the identified RLS-specific QOL instruments.

Three measures of RLS-specific QOL have been developed in recent years and are reviewed here: the Restless Legs Syndrome Quality of Life (RLSQOL) questionnaire, the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI), and the Quality of Life Restless Legs Syndrome (QOL-RLS) measure. Critical review indicates that each has limitations (particularly in terms of published developmental history and content validity). Eleven trials of DAs were identified that included assessment of RLS-specific QOL (nine using the RLSQOL and two using the QOL-RLS). In all studies, significant improvements in RLS-specific QOL were observed, although these were mostly short term (12 weeks) and large placebo effects were also noted.

In people with RLS, the use of DAs has been shown to improve RLS-specific QOL. Longer-term, large-scale studies may be needed to confirm these findings and demonstrate statistically significant improvements in RLS-specific QOL at lower doses. Further development of the RLS-specific QOL measures is needed to ensure that the full impact of RLS (and the full benefit of new treatments) on aspects of life identified as important to individuals is captured in future studies.

The suitability of polycystic ovary syndrome-specific questionnaires for measuring the impact of PCOS on quality of life in clinical trials

Objectives: Generic patient-reported outcome (PRO) measures underestimate the impact of polycystic ovary syndrome (PCOS) on quality of life (QoL). The aim of this review was to identify PCOS-specific QoL measures and establish whether their development history and measurement properties support their use in clinical trials.

Methods: A systematic search was conducted using terms synonymous with “PCOS” and “QoL.” Following identification of measures, further searches were undertaken using the questionnaire name and abbreviation to explore its use, development history, and demonstrated measurement properties.

Results: Of 56 abstracts screened, 21 reported using PRO measures. One PCOS-specific QoL measure was identified: the PolyCystic Ovary Syndrome Questionnaire (PCOSQ). Nine papers show that the PCOSQ’s development history is somewhat incomplete, and that it does not have good content validity. The PCOSQ subscales demonstrate acceptable levels of reliability (0.70–0.97) and partial known-groups validity as well as convergent/divergent validity with other PRO instruments. Responsiveness
to change is variable and minimally important differences have not been established.

Conclusions: The PCOSQ is the only condition-specific measure of the impact of PCOS on QoL. Additional research is required to ensure its comprehensiveness, sensitivity, and to guide interpretation prior to including in clinical trials.