Short-term Placebo Research Articles

Long-term Etanercept Response for Patients with Radiographic Axial Spondyloarthritis Based on Achievement of Early, Intermediate, or Late Responses During Index Studies.

Short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that etanercept (ETN) is effective and well tolerated in patients with radiographic axial spondyloarthritis (r-axSpA) with long-term efficacy and safety continuing for up to 7years after treatment start. Short-term randomized controlled trials (RCTs) have shown the efficacy of ETN after 12-24weeks, with statistically significant improvements as early as week 2. This post hoc analysis investigated the timeframe (i.e., temporal responses) in which patients with r-axSpA achieved their first clinical response with ETN and how patients responded over a longer period according to different temporal responses in index studies. Data were analyzed from three phase 3/4 PBO- or sulfasalazine-controlled RCTs of ETN for the treatment of r-axSpA (index studies). Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses ("Early," "Intermediate," "Late," or "Non-response") in their corresponding index studies. Within each index study, patient responses differed significantly between ETN and control arms for achievement of Assessment in SpondyloArthritis international Society (ASAS) 20 and other measures of treatment response. In general, the proportion of responders in the OLE studies was high for those with "Early" and "Intermediate" responses as defined in the index studies. Despite patients being considered non-responders in the index studies, a large proportion achieved response on continued treatment in the OLE studies over the longer term, including through 48weeks. Response in the index studies was maintained in the long term, and continued treatment was warranted in a large proportion of patients despite initial non-response. Absence of an early response in index studies did not predict non-response over the long term, and early response to treatment was not always a predictor for later response. NCT00421915; NCT00247962; NCT00356356; NCT00421980; NCT00410046.

Placebo analgesia in physical and psychological interventions: Systematic review and meta-analysis of three-armed trials.

The magnitude of placebo effects from physical and psychological 'sham' is unknown but could impact efficacy trials and treatment understanding. To quantify placebo effects, this systematic review of three-armed randomised controlled trials (RCTs) of physical and psychological interventions for pain compared outcomes in 'sham' control intervention and non-exposure arms. RCTs with treatment, 'sham' control intervention, and non-exposure groups were included, enrolling adults with any pain. A protocol was pre-registered (PROSPERO: CRD42023413324), and twelve databases searched from 2008 to July 2023. Trial methods and blinding were analysed descriptively and risk of bias assessed. Meta-analysis of pain measures at short-, medium- and long-term was performed with random-effects models of standardised mean differences (SMD).Studies were sub-grouped according to control intervention type. Seventeen RCTs were included. The average short-term placebo effect was small (0.21 SMD, 0.1-0.33 95% CI, p = 0.0002, 1440 participants). It showed no heterogeneity (Tau2 = 0.1, I2 = 11%, p = 0.3), preventing meta-regression analyses of effect modifiers. However, sub-group analyses revealed larger placebo effects in manual control interventions compared to disabled devices and miscellaneous control interventions. Overall, placebo analgesia accounted for 39% of treatments' short-term effectiveness. No placebo effects were found at medium-term (7 RCTs, 381 participants) or long-term follow-up (3 RCTs, 173 participants). The observed placebo analgesia has mechanistic and methodological implications, though its clinical importance may be limited. Control intervention design affects placebo effects, highlighting the importance of considering methodology in RCT interpretation. Review limitations include a small number of long-term studies and sample heterogeneity. This systematic review directly quantifies placebo effects from physical and psychological 'sham' control interventions and compares them to treatments' overall effectiveness. By doing so, the review enhances our understanding of placebo effects, their relative contribution in clinical trials, and their susceptibly to trial design. It poses further questions regarding the influence of blinding, participant expectations, and features of the therapeutic context. Overall, the insights provided by this review carry methodological significance and are important for the interpretation and synthesis of efficacy trials in this field.

An exploratory machine learning approach to identify placebo responders in pharmacological binge eating disorder trials.

Randomized, placebo-controlled trials for binge eating disorder (BED) have revealed highly variable, and often marked, rates of short-term placebo response. Several quantitative based analyses in patients with BED have inconsistently demonstrated which patient factors attribute to an increase in placebo response. The objective of this study is to utilize machine learning (ML) algorithms to identify moderators of placebo response in patients with BED. Data were pooled from 12 randomized placebo-controlled trials evaluating different treatment options for BED. The final dataset consisted of 189 adults receiving placebo with complete information of baseline variables. Placebo responders were defined as patients experiencing ≥75% reduction in binge eating frequency (BEF) at study end point. Nine patient prerandomization variables were included as predictors. Patients were divided into training and testing subsets according to an 75%:25% distribution while preserving the proportion of placebo responders. All analysis was performed in the software Pumas 2.0. Gaussian Naïve Bayes algorithm showed the best cross-validation accuracy (~64%) and was chosen as the final algorithm. Shapley analysis suggested that patients with low baseline BEF and anxiety status were strong moderators of placebo response. Upon applying the final algorithm on the test dataset, the resulting sensitivity was 88% and prediction accuracy was 72%. This is the first application of ML to identify moderators of placebo response in BED. The results of this analysis confirm previous findings of lesser baseline disease severity and adds that patients with no anxiety are more susceptible to placebo response.

Cardiometabolic Safety of Lumateperone (ITI−007): Post Hoc Analyses of Short-Term Randomized Trials and an Open-Label Long-Term Study in Schizophrenia

Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI-007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated. The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg. In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%). In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile. Intra-Cellular Therapies, Inc.

OR01-5 Leptin Acts through Altering Energy Intake and Lipolysis to Reduce Body Weight but Has No Effect on Energy Expenditure, Physical Activity, and Sympathetic Nervous System in Humans

It remains unknown whether leptin regulates body weight in humans and whether this occurs through actions centrally and/or peripherally i.e. by altering hormone and sympathetic nervous system (SNS) activity in humans as it has been suggested by experiments in rodents. We explored body weight and body composition changes in response to short and long term leptin administration to lean humans and explored potential underlying mechanisms by studying changes in energy intake, energy expenditure, lipolysis and hormonal and SNS changes in response to leptin administered in physiological and supraphysiological doses in lean subjects. We utilized the following study designs: a) open-label long-term leptin replacement study aiming at keeping circulating leptin levels within the physiological range and b) randomized, placebo-controlled, long-term leptin replacement study aiming at keeping total body weight stable by adjusting leptin doses in females with acquired hypoleptinemia. To further explore underlying mechanisms we also performed a) short-term placebo vs. leptin physiological replacement study during a three day long fasting-induced hypoleptinemia in lean subjects; and b) short-term leptin dose escalation study to supraphysiological levels in the fed i.e. normoleptinemic vs. in fasting-induced hypoleptinemic state for three days in both lean and overweight individuals. Long-term leptin replacement decreased body weight (p-value<0.001) through decreasing fat mass (p-value<0.001) and without affecting lean mass. Underlying mechanisms included decreased energy intake with leptin (caloric intake - leptin association r=-0.644, p-value<0.001), but not energy expenditure. Leptin also increased lipolysis demonstrated by elevated free fatty acids which were increased in response to leptin at time points that corresponded to fat mass loss (p-value=0.01). Long- but not short-term leptin replacement downregulated the renin-angiotensin-aldosterone axis at time points corresponding to maximum lipolytic effects (p-value=0.024 renin; p-value=0.001 aldosterone). Importantly, no changes in heart rate, blood pressure and body temperature were demonstrated with leptin. Thus, leptin administration decreases body weight in lean subjects, without changes to lean mass, by acting through decreasing body fat primarily through lipolysis and decreased caloric intake.

Efficacy and safety of short- and long-term, regular and on-demand regimens of phosphodiesterase type 5 inhibitors in treating erectile dysfunction after nerve-sparing radical prostatectomy: a systematic review and meta-analysis.

BackgroundWe performed a meta-analysis to evaluate the efficacy and safety of short-term (≤6 months) and long-term (>6 months), regular (OaD) and on-demand (PRN) regimens of phosphodiesterase type 5 inhibitors (PDE5-Is) in treating erectile dysfunction (ED) after nerve-sparing radical prostatectomy (NSRP).MethodsWe conducted a literature search in August 2016. Sources included PubMed, EMBASE, and MEDLINE databases. The main outcome was International Index of Erectile Function-Erectile Function (IIEF-EF) domain score, and the secondary outcome was treatment-emergent adverse events (TEAEs).ResultsEight articles involving 13 randomized controlled trials (RCTs) were used in this analysis: they suggested that PDE5-Is can improve the IIEF-EF distinctly in comparison with placebo in short and long term (mean difference [MD]: 2.26, 95% confidence interval [CI]: 1.45–3.08, P<0.00001, and MD: 4.5, 95% CI: 3.6–5.4, P<0.00001), and long-term use of PDE5-Is (>6 months) can improve the IIEF-EF distinctly in comparison with short-term use of PDE5-Is (≤6 months) (MD: 3.9, 95% CI: 3.01–4.8, P<0.00001). OaD of PDE5-Is significantly improved the IIEF-EF compared to placebo in short and long term (MD: 4.08, 95% CI: 3.2–4.97, P<0.00001, and MD: 4.74, 95% CI: 3.79–5.69, P<0.00001). No significant differences were found in IIEF-EF changes between PRN and placebo (≤6 months) (MD: 2.64, 95% CI: −0.87 to 6.14, P=0.14), and between PRN and OaD group (>6 months) (MD: −0.58, 95% CI: −9.86 to 8.74, P=0.91). There were more TEAEs in PDE5-Is group in comparison with placebo (odds ratio [OR]: 1.55, 95% CI: 1.26–1.91, P<0.0001), and TEAEs in OaD group were not significantly different from those seen in PRN group (OR: 1.05, 95% CI: 0.78–1.4, P=0.77).ConclusionOur meta-analysis suggests that PDE5-Is are efficient and safe for treatment of ED after NSRP, and we should choose the regular regimen for short term and regular or on-demand regimen for long term. Further high-quality RCTs are needed to validate this result.

Short-term placebo response in trials of patients with symptomatic osteoarthritis: differences between hip and knee

In placebo-controlled RCT of symptomatic treatment in osteoarthritis (OA) the extent of pain reduction is heterogeneous, the pooled effect size rather small. Pain reduction is typically higher in knee than in hip trials. The recommended trial duration is 3 months, but in knee OA the best treatment effect vs placebo is observed at 2weeks. We hypothesized that the placebo response differs in knee vship OA. We performed a meta-analysis to describe the time course of pain in placebo groups of trials in knee and hip OA over 3months. A systematic search of PubMed, MEDLINE and Google Scholar of placebo-controlled cox-2 inhibitor (coxib) RCT (from 1999 to 2007) of hip and knee OA was performed. Pain levels (visual analogue scale [VAS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) in the placebo groups at different measurement time points were extracted, expressed as weighted mean at weeks 2, 4, 6-8 and 12-13. Twenty-one studies included 3064 knee OA patients and 608 hip OA patients. For knee OA, pain (VAS) decreased from 15mm at week 2, to 20mm at week 6-8, and 21mm at week 12-13. For hip OA patients, pain decreased by 12mm, 14mm and 14mm, respectively. Pain decreased in both knee and hip OA patients treated with placebo at 2 weeks, but further decreases up to week 12 occurred only in knee OA, especially for pain VAS, resulting in a time dependent impact on the magnitude of treatment outcome. Primary endpoint pain should be assessed at 2-4 weeks.

The role of statins in the prevention of contrast induced nephropathy: a meta-analysis of 8 randomized trials

Contrast induced nephropathy (CIN) is a common complication of coronary angiography/angioplasty. Prevention is the key to reduce the incidence of CIN and it begins with appropriate pre-procedural management. Statins have been shown to possess pleiotropic effects (anti-oxidant, anti-inflammatory and anti-thrombotic properties) and their effects on CIN were assessed in several studies with conflicting results. Aim of this meta-analysis is to evaluate the efficacy of short-term statins for the prevention of CIN in patients undergoing coronary angiography/percutaneous interventions. We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to January 2014 of trials which compares short-term statins versus Placebo for the prevention of CIN in patients undergoing coronary angiography/angioplasty. Data regarding study design, statin dose, inclusion/exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Eight trials were included, with a total of 4734 patients. CIN occurred in 79/2,358 patients (3.3%) treated with statins versus 153/2,376 patients (6.4%) of the placebo group [OR 95% CI 0.50 (0.38-0.66), p < 0.00001; p het = 0.39]. Benefits were both observed with high-dose short-term statins [OR 95% CI 0.44 (0.30-0.65), p < 0.0001; p het = 0.16] and low-dose statins, [OR 95% CI 0.58 (0.39-0.88), p = 0.010; p het = 0.90]. By meta-regression analysis, no significant relationship was observed between benefits from statin therapy and patient's risk profile (p = 0.26), LDL cholesterol (p = 0.4), contrast volume (p = 0.94) or diabetes rate (p = 0.38). This meta-analysis showed that among patients undergoing coronary angiography/percutaneous intervention the use of short-term statins reduces the incidence of CIN, and therefore is highly recommended even in patients with low LDL-cholesterol levels.

Effect of lurasidone on neurocognitive performance in patients with schizophrenia: A short-term placebo- and active-controlled study followed by a 6-month double-blind extension

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80mg/day and 160mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N=267), lurasidone 160mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40–160mg) group compared to the quetiapine XR (200–800mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls.

Does combination pharmacological intervention for smoking cessation prevent post-cessation weight gain? A systemic review

BackgroundMost smokers who quit smoking gain weight. There are some interventions designed to limit weight gain following smoking cessation. ObjectiveTo conduct a systematic review to evaluate if combination pharmacological therapy interventions for smoking cessation are effective in reducing post-cessation weight gain. MethodsThe following databases were researched: Medline, PubMed, PsycINFO, CENTRAL and EMBASE. Detailed inclusion and exclusion criteria were specified a priori before conducting abstract and full text screening. Included studies were required to: (1) report data on combination pharmacotherapy including at least one FDA-approved smoking cessation medication; (2) report outcome measure of weight change from baseline to the end of follow up; (3) incorporate a minimum of 2-week follow-up; (4) recruit adult smokers. Studies were excluded if they had (1) behavioral interventions; (2) sample size of <30; (3) switching medications; or (4) they were not written in English. Abstracts and the full texts were reviewed independently by two investigators. Inclusion of studies was decided by a third independent investigator in case of disagreement between the two primary investigators. ResultsOut of 1873 studies identified, 1083 studies were included for abstract screening. Finally, 12 studies met the eligibility criteria after full text screening of 242 studies. Seven studies showed that participants in the combined therapy group had less post-cessation weight gain than those in the group of individual drugs or placebo. Four studies did not report differential weight gain measures by treatment groups. Only one study showed that post-treatment weight gain in the combined therapy group was more than the monotherapy group, although the result was not statistically significant. ConclusionsSeven out of twelve studies indicated that combination smoking cessation medications had less post-cessation weight gain than monotherapy or placebo in short term. Long term weight gain was not well documented by most of the studies and future research is warranted.

Role of μ-opioid system in the formation of memory of placebo responses

The endogenous opioid system is centrally involved in short-term placebo analgesic effects, but its potential regulation of memory and learning circuits, critical for the sustainability of placebo responses, has not been explored. Here we examined the recall of analgesic effects after placebo administration as a function of its initial capacity to activate μ-opioid neurotransmission. Memories of therapeutic/adverse responses 24 hours after placebo administration were associated with differences in μ-opioid neurotransmission in the Papez circuit, VTA, amygdala and septum. These data suggests that μ-opioid neurotransmission is involved in the recall of therapeutic benefit, providing a framework to understand stimulus learning and long-term therapeutic effect associations.

Short-term walnut consumption increases circulating total adiponectin and apolipoprotein A concentrations, but does not affect markers of inflammation or vascular injury in obese humans with the metabolic syndrome: data from a double-blinded, randomized, placebo-controlled study

Long-term consumption of walnuts is associated with lower cardiovascular disease risk in epidemiological studies, possibly through improvements in lipid profile and endothelial function. It remains to be elucidated how soon after initiation of walnut consumption beneficial effects on lipid profile and biomarkers of inflammation or vascular injury can be observed. Fifteen obese subjects (9 men and 6 women; age, 58 ± 2.5 years; body mass index, 36.6 ± 1.7 kg/m2) with the metabolic syndrome participated as inpatients in a randomized, double-blinded, placebo-controlled crossover study involving short-term placebo or walnut-enriched diet (48 g/d for 4 days). Apolipoproteins and markers of inflammation and vascular injury were measured before and after consumption of the experimental diets. Consumption of walnuts was associated with a statistically significant increase in serum apolipoprotein A concentrations (P = .03), but did not affect circulating levels of fetuin A, resistin, C-reactive protein, serum amyloid A, soluble intercellular adhesion molecules 1 and 3, soluble vascular cell adhesion protein 1, interleukins 6 and 8, tumor necrosis factor α, E-selectin, P-selectin, and thrombomodulin. Four days of walnut consumption (48 g/d) leads to mild increases in apolipoprotein A concentrations, changes that may precede and lead to the beneficial effects of walnuts on lipid profile in obese subjects with the metabolic syndrome.

Motivation and placebos: do different mechanisms occur in different contexts?

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.

Lurasidone: A new treatment option for schizophrenia

Lurasidone is a novel benzoisothiazol antipsychotic that has recently been approved for the treatment of schizophrenia in the U.S. Like many other second-generation antipsychotics, it has a high affinity for dopamine D(2) and serotonin 5-HT(2A) receptors as well as a high affinity for 5-HT(7) receptors. It has negligible affinity for α(1)-adrenoceptors, histamine H(1) receptors or muscarinic acetylcholine M(1) receptors. It has demonstrated efficacy in short-term trials versus placebo, two of which included an active comparator (olanzapine, quetiapine) assay arm. A short-term, head-to-head trial of lurasidone versus ziprasidone in chronic stable schizophrenia was also conducted. A long-term, 12-month risperidone-controlled study and open-label studies primarily investigated the safety and tolerability of lurasidone. Limited evidence of procognitive and antidepressant effects was seen although these need further corroboration. The incidence of extrapyramidal symptoms (excluding akathisia/restlessness) was greater with lurasidone (14.7%) than placebo (5.1%). Akathisia and somnolence were dose-related adverse events. Lurasidone appears to have relatively little effect on weight, plasma glucose or lipids to date. No evidence of QTc prolongation was seen and orthostatic hypotension was uncommon. Raised prolactin levels in short-term studies were dose-dependent, greater in females and occurred overall in 3.7 and 0.7% of lurasidone and placebo recipients, respectively.

Quality of Life in Restless Legs Syndrome

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, Psyc-INFO, 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.

When Illness Goes Public: Celebrity Patients and How We Look at Medicine (review)

Reviewed by: When Illness Goes Public: Celebrity Patients and How We Look at Medicine Fahmida Hussain, DMD (bio) When Illness Goes Public: Celebrity Patients and How We Look at Medicine, by Barron H. Lerner. Baltimore: Johns Hopkins University Press, November 2006. 362 pp. When Illness Goes Public: Celebrity Patients and How We Look at Medicine is a well-crafted book by Barron H. Lerner, MD, PhD of Columbia University’s Mailman School of Public Health and the Center for the Study of Society and Medicine. It combines historical perspectives with enduring narratives of 13 celebrity patients. It shows how the issues of consumerism in medicine, patient rights, patient advocacy, research funding, fundraising, ethical principles and the role of media evolved. Lerner’s 2001 book, The Breast Cancer Wars: Hope, Fear and the Pursuit of a Cure in Twentieth-Century America, published by Oxford University Press, received the William H. Welch Medal of the American Association for the History of Medicine, the Washington Irving Book Award from the Westchester Library Association and was named one of the 26 most notable books of 2001 by the American Library Association. Funded by grant money, Lerner worked tirelessly with historians, librarians, archivists, and friends and family of the celebrity patients he discusses for five years. Intriguingly, the author reports sometimes finding it hard to distinguish between facts and myth when working on the story of a cultural icon’s illness. Highlighted Stories The man Lerner calls “the first modern patient,” the Yankee baseball superstar Lou Gehrig, did not receive quality care on time due to lack of public awareness about amyotrophic lateral sclerosis (ALS), the motor neuron disease now often referred to as Lou Gehrig disease. Gehrig’s illness was wrongly diagnosed as polio; additionally, Lerner reports, physicians who were less knowledgeable themselves acted paternalistically towards the Yankee slugger. The media, the public, and often his teammates proved their ignorance time and again. Through it all, Gehrig and his wife Eleanor functioned as symbols of hope for everyday people, maintaining “cautious optimism” to minimize false dreams of a full recovery. Lerner argues that through Gehrig’s public ordeal, two hot button topics—namely patients’ right to know and authenticity of research design— emerged as part of the national discourse on health. Lerner recounts the history of another baseball player, Boston Red Sox centerfielder Jimmy Piersall (born in 1929), arguing that he was the first celebrity who used the media to his. Piersall became best known for his struggles with bipolar disorder, which were the subject of a 1957 movie Fear Strikes Out, also the title of Piersall’s book about his own life. Until that point mental diseases were never discussed in any detail in public. The 1950s and 1960s saw the transformation of the field of psychiatry through debates [End Page 1146] over treatment modalities. The role of biographies and the distinction between actual events and movie adaptations became evident. Unlike Gehrig, Piersall contradicted public images of his disease and of himself. For the first time people got the opportunity to hear the patient’s voice. Interestingly, Piersall also introduced celebrity endorsement and promotion for pay. Photographer Margaret Bourke White embraced controversial, less publicized surgical procedure to treat Parkinson’s disease. Bourke White pushed for full disclosure, in an effort to fight the paternalism of physicians. Prefiguring modern chat forums, she was communicated with other patients through her photography and writings, sharing information, comparing symptoms, and predicting the outcome of her illness. She felt greatly optimistic about medical sciences, and therefore subjected herself to risky procedures. Ultimately, Lerner concludes, Bourke White’s story was inspirational but at the same time misleading. In her case, surgery and physical therapy for Parkinson’s disease proved to have created only a short-term placebo effect. John Foster Dulles, Secretary of State under President Dwight D. Eisenhower from 1953 until shortly before his death from cancer in 1959, pushed for transparency in the government. In keeping with this approach, Dulles informed the public of his illness and publicly discussed state-of-the-art technologies. True investigative reporting took place with medical experts explicitly discussing prognosis and cure of cancer; religion and faith in medicine came to play...

The evaluation of efficacy and tolerability of Hylan G-F 20 in bilateral thumb base osteoarthritis: 6 months follow-up

The aims of this randomized controlled trial were to evaluate the efficacy of intra-articular Hylan G-F 20 on the pain, pinch strength, and functional status in patients with thumb base osteoarthritis (OA). Sixty-six hands of 33 female patients (mean age, 62.6 +/- 6.4 years) with bilateral clinical and radiological thumb base OA were included into this study. Hands of the same patient were divided to Hylan G-F 20 and saline-injection groups. VAS pain 100 mm, pinch strength (key, tripod and pulp to pulp pinch) and functionality (Dreiser functional index) were assessed at baseline, at sixth and 24th weeks. Statistically significant improvements were detected in function (p = 0.001), VAS pain (p = 0.002), and pinch strength (p = 0.004) at the 24th week in the Hylan G-F 20 group. However, only VAS pain scores decreased temporarily in control hands at the 6th week (p = 0.02). Although short-term placebo analgesic effect could not be ignored, intra-articular hylan was effective on pain, pinch strength, and function at the 24th week.

Issues in Psychopharmacology

Although pharmacologic treatment remains a critical element in the short- and long-term management of schizophrenia, the past decade has been a challenging time in terms of real progress. Despite the introduction of several new medications as well as the conduct of larger and more diverse clinical trials, there remains considerable debate as to how far we have progressed in addressing some of the fundamental unmet needs in treating this disorder. A theme in this issue of Schizophrenia Bulletin addresses a number of topics in this context. Although the notion of careful, systematic, and critical summaries of all relevant randomized controlled trials is not a new one, the Cochrane Schizophrenia Group is relatively young. Clive Adams, one of its founders, and colleagues provide the rationale and history of the group as well as reviewing its methods and contributions. The Bulletin also carries a “Cochrane Corner” in each issue to alert the field to schizophrenia-related reviews. Systematic meta-analyses are playing an increasingly important role in informing both the research agenda and clinical practice. The work of the Cochrane collaboration has been enormously valuable in this process. In recent years, the field of schizophrenia research has benefited from the application of various clinical trial methodologies to enhance the study of treatment outcomes and determine generalizability. Large effectiveness trials have provided data to expand our knowledge base beyond that which is provided by traditional efficacy trials. Stroup and Geddes provide examples of each type of trial to illustrate their relative advantages and disadvantages. Within the context of different trial designs, Leucht et al provide an overview addressing critical aspects of trial design, potential population sampling bias, endpoint choices and definitions, quality of assessments, data analysis and reporting, as well as, other potential sources of bias or confounds relevant to the interpretation of clinical trials data in schizophrenia. One of the most difficult challenges in the design, conduct, analysis, and interpretation of clinical trials is the problem of dropouts—those individuals who do not complete the trial, often for unknown reasons. A variety of statistical techniques have been developed and applied in order to address this issue; however, none is entirely satisfactory. Rabinowitz and Davidov discuss the association of dropout and outcome in trials of antipsychotic medication and its implications for strategies to address missing data. Another strategy to minimize dropouts in acute treatment trials would be to shorten the length of the trial, particularly when placebo control groups are included. Addressing this issue and drawing on recent meta-analysis suggesting that a substantial proportion of antipsychotic drug response occurs within the first 2 weeks, McMahon and colleagues present an exploratory analysis from short-term placebo controlled clinical trial data suggesting the potential feasibility of reducing the duration of such trials. Much more work needs to be done to determine the benefits and risks of such an approach, but this is a very valuable first step. In the final article, we provide a review of unanswered questions in the pharmacologic treatment of schizophrenia. Despite numerous trials being conducted with antipsychotic medication, there are many clinical decisions that must be made on a day-to-day basis for which sufficient data are not available to provide an adequate evidence base. We hope that these articles will provide a snapshot of current challenges and opportunities for further progress in the design, conduct, and interpretation of psychopharmacologic trials in schizophrenia.

A controlled trial of methylphenidate in adults with attention deficit/hyperactivity disorder and substance use disorders

Attention deficit/hyperactivity disorder (ADHD) is common among adult patients with substance use disorders. The benefits of treating ADHD in these patients are uncertain and the prescription of psychostimulants is disputed, because of the risk of abuse. This study examined the short-term effectiveness of methylphenidate treatment for ADHD in adults with substance use disorders. Double-blind, placebo-controlled, multiple cross-over (A-B-A-B design) comparative trial of methylphenidate versus placebo. In-patient addiction treatment facility. Twenty-five patients with ADHD who were receiving in-patient treatment for various substance use disorders. During the course of 8 weeks, each participant completed two phases of placebo and two phases of active medication treatment, in a fixed low-dosage schedule (up to 0.6 mg/kg/day). Abstinence was maintained during the study. The outcome measure was ADHD symptomatology, as measured with the ADHD rating scale-IV. The results were compared using MANOVA repeated measures. Nineteen of the 25 patients completed the trial. A significant reduction in ADHD symptoms was observed in the first week in both conditions. The positive response to active treatment (nine patients; 36%) was not significantly higher than that to placebo (five patients; 20%). In this small pilot study, the effect of low-dose methylphenidate in adult ADHD patients with concomitant substance use disorders is limited. ADHD symptoms in adults were susceptible to a distinct short-term placebo response.

Focus on trial endpoints of clinical relevance and the use of almotriptan for the acute treatment of migraine

Almotriptan is a 5-HT(1B/1D) receptor agonist, or triptan, indicated for the acute treatment of migraine. It has been shown to be effective and well tolerated for the treatment of acute migraine in approximately 5000 patients enrolled in short-term placebo- and active-controlled trials and long-term open-label trials. A recent meta-analysis reported that almotriptan has the highest sustained pain-free (SPF) rate and lowest adverse-event (AE) rate of all oral triptans. Sustained pain free is a composite endpoint of pain freedom at 2 h, no recurrence of moderate-to-severe headache and no use of rescue medication from 2 to 24 h after dosing. Patient surveys have indicated that migraine sufferers consider complete pain relief, no recurrence, rapid onset and no side-effects to be the most important attributes of their acute treatment. Composite endpoints such as SPF and SPF with no AEs (SNAE) contain the attributes that migraine sufferers express as being the most important elements of an acute migraine therapy, and their use in future clinical trials should aid in the selection of agents that can offer patients the highest likelihood of consistent treatment success.