***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Restless legs syndrome ( RLS ) is characterized by the desire to move the limbs associated with paresthesias of the legs , a motor restlessness , an intensification of symptoms at rest with relief by activity , and a worsening of symptoms in the evening or at night . Population -based studies are rare , and risk factors in the general population are not known . METHODS Cross-sectional survey with face-to-face interviews and physical examination among 4310 participants in the Study of Health in Pomerania in northeastern Germany . Participants were aged 20 to 79 years and were r and omly selected from population registers .  Restless legs syndrome was assessed with st and ardized , vali date d questions addressing the 4 minimal criteria for RLS as defined by the International Restless Legs Syndrome Study Group . RESULTS The overall prevalence of RLS was 10.6 % , increasing with age , and women were twice as often affected as men . While nulliparous women had prevalences similar to those among men up to age 64 years , the risk of RLS increased gradually for women with 1 child ( odds ratio , 1.98 ; 95 % confidence interval , 1.25 - 3.13 ) , 2 children ( odds ratio , 3.04 ; 95 % confidence interval , 2.11 - 4.40 ) , and 3 or more children ( odds ratio , 3.57 ; 95 % confidence interval , 2.30 - 5.55 ) . Subjects with RLS had significantly lower quality -of-life scores than those without the syndrome . CONCLUSIONS Restless legs syndrome is a common disease in the general population , affecting women more often than men . It is associated with reduced quality of life in cross-sectional analysis . Parity is a major factor in explaining the sex difference and may guide further clarification of the etiology of the disease This r and omized , double-blinded , placebo-controlled trial ( NCT00135993 ) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome ( RLS ) over a 6-month maintenance period . A total of 505 eligible participants with moderate to severe RLS ( IRLS sum score > or= 15 ) were r and omly assigned to five groups to receive either placebo or rotigotine ( 0.5 , 1 , 2 , or 3 mg/24 hr ) delivered by once-daily transdermal patch ( fixed-dose regimen ) . The two co- primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions ( CGI-1 ) score . On both primary measures , 2 and 3 mg/24 hr rotigotine was superior to placebo ( P < 0.001 ) . Adjusted treatment differences to placebo for the IRLS sum score were -4.5 ( 95 % CI : -6.9 , -2.2 ) for 2 mg/24 hr rotigotine , -5.2 ( 95 % CI : -7.5 , -2.9 ) for 3 mg/24 hr rotigotine , and for CGI item 1 -0.65 ( 95 % CI : -1.0 , -0.3 ) and -0.9 ( 95 % CI : -1.3 , -0.5 ) for the 2 and 3 mg/24 hr doses , respectively . Skin reactions ( 27 % ) and known dopaminergic side effects such as nausea ( 18.1 % ) and headache ( 11.6 % ) were mostly mild or moderate in rotigotine subjects . Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms . Treatment efficacy was maintained throughout the 6-month double-blind period Restless legs syndrome is a common and sometimes incapacitating disorder in chronic uraemic patients . While therapeutic concepts have so far been disappointing , there have been recent reports on the favourable effect of clonidine in non-uraemic patients with symptoms of restless legs syndrome . Therefore , a double-blind study was conducted in 20 patients with chronic renal failure ( 11 conservatively treated , 9 on RDT ) and symptoms of restless legs . 10 patients were treated with 0.075 mg clonidine twice daily and 10 received placebo . The patients were investigated 3 days after starting therapy . - In the clonidine-treated group complete relief of symptoms was noted in 8 out of 10 patients , a striking alleviation in one , while in one further patient the symptoms remained unchanged . In contrast , only one of 10 patients in the placebo group had a mild alleviation of symptoms . Blood pressure did not differ significantly in the two groups . The data show that low-dose clonidine administration is a very effective approach in the treatment of the restless legs syndrome in chronic uraemic patients OBJECTIVE To review factors influencing placebo response and clinical trial outcome in depression , and suggest ways to optimize trial success in mood disorders . DATA SOURCES PubMed search es were conducted by cross-referencing the terms depression , depressive with placebo , clinical trial , and clinical trials for studies published in English between 1970 and September 2013 . STUDY SELECTION Relevant abstract s were identified in PubMed , including clinical trials , quantitative studies , and qualitative research . We obtained and review ed relevant articles and utilized their information to synthesize the present review . DATA EXTRACTION Included articles were grouped in the following areas of relevance : ( 1 ) biological validity of illness , ( 2 ) baseline severity of illness , ( 3 ) chronicity of the index episode of depression , ( 4 ) age of participants , ( 5 ) medical and psychiatric comorbidity , ( 6 ) probability of receiving placebo , ( 7 ) use of prospect i ve treatment phases ( lead-in ) ( 8) dosing schedule , ( 9 ) trial duration , ( 10 ) frequency of follow-up assessment s , and ( 11 ) study outcome measure . RESULTS Several key elements emerge as critical to the ultimate success of a clinical trial , including the probability of receiving placebo , study duration , dosing schedule , visit frequency , the use of blinded lead-in phases , the use of central ized raters , illness severity and duration , and comorbid anxiety . CONCLUSIONS Our increasing underst and ing of the placebo response in clinical trials of major depressive disorder lends to a , gradually , more predictable phenomenon and , hopefully , to one that becomes lesser in magnitude and variability . Several elements have emerged that seem to play a critical role in trial success , gradually reshaping the design of clinical , translational , as well as mechanistic studies in depression The Unified Parkinson 's Disease Rating Scale ( UPDRS ) is primarily composed of an investigator-derived objective rating of motor function and a patient-derived assessment of activities of daily living ( ADL ) . Using a stringent definition of placebo effect , we examined the frequency , temporal development , and stability of improvements during placebo treatment over 6 months in a large placebo-controlled trial of deprenyl and tocopherol in early Parkinson 's disease ( DATA TOP ) . One hundred ninety-nine subjects received placebo treatment in the r and omized , multicenter , placebo-controlled DATA TOP study . We compared the baseline UPDRS motor section scores with follow-up scores at 4 , 13 , and 26 weeks . Placebo-associated improvement was defined as an improvement over baseline score in motor UPDRS of at least 50 % or a change in at least two motor items at any one visit by two or more points . Seventeen percent of the 185 subjects who qualified for analysis met the placebo response criteria . The group prevalence of response was steady ( 7 % to 10 % ) at any one visit without a marked predominance of an early study effect . Older subjects with more motor impairment at baseline were most likely to show a placebo-associated improvement . ADL scores were low throughout the study , and ADL improvements did not identify the subjects with objective ly defined placebo-associated improvement . Prominent improvements in investigator-derived objective measures of Parkinson 's disease motor impairment occur during clinical trials , including one that was not aim ed at showing improved short-term efficacy . Although the notion of placebo effect often implies patient-based perceptions , we found subjective changes to be infrequent in placebo-treated patients , suggesting that either : ( 1 ) the placebo effect was rater-driven ; ( 2 ) the ADL question naire is insensitive to transient but objective ly demonstrable motor changes ; or ( 3 ) that the objective changes , albeit major , are within the realm of natural variation in the UPDRS motor scale from visit to visit BACKGROUND Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome . Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome . METHODS In this r and omised , double-blind , placebo-controlled trial , 458 patients with moderate-to-severe idiopathic restless legs syndrome ( average baseline International Restless Legs Syndrome Study Group severity rating scale [ IRLS ] sum score of 28.1 ) were r and omly assigned to receive transdermal rotigotine 1 mg over 24 h ( n=115 ) , 2 mg over 24 h ( n=112 ) , or 3 mg over 24 h ( n=114 ) , or to receive placebo ( n=117 ) . Study medication was delivered via patches , applied once a day for 6 months . R and omisation was done with a computer-generated r and omisation list , stratified by centre . Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions ( CGI ) item 1 score , assessed by analysis of covariance in the intention-to-treat population . This trial is registered with Clinical Trials.gov , number NCT00136045 . FINDINGS Efficacy analyses were done on 112 patients in the 1 mg group , 109 in the 2 mg group , 112 in the 3 mg group , and 114 in the placebo group . Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 ( SE 0.9 ) in the 1 mg group , -16.2 ( 0.9 ) in the 2 mg group , -16.8 ( 0.9 ) in the 3 mg group , and -8.6 ( 0.9 ) in the placebo group ( p<0.0001 for treatment difference vs placebo with each dose ) . Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 ( 0.14 ) in the 1 mg group , -2.41 ( 0.14 ) in the 2 mg group , -2.55 ( 0.14 ) in the 3 mg group , and -1.34 ( 0.14 ) in the placebo group ( p<0.0001 for treatment difference vs placebo with each dose ) . Skin reactions , mostly mild or moderate , were seen in 145 ( 43 % ) of 341 patients who received rotigotine and in two ( 2 % ) of 117 who received placebo .  Ten patients had serious adverse event that were deemed to be related to rotigotine :  elevation of liver enzymes ( one patient ) , worsening of tinnitus ( one patient ) , non-response to anticoagulation ( one patient ) , electrocardiogram changes ( one patient ) , and application-site reactions ( six patients ) . No admissions to hospital were needed for the application-site reactions , and they all resolved within a short time of patch removal without any other therapeutic intervention . The rate of typical dopaminergic side-effects in patients who received rotigotine was low ; no signs of augmentation were noted . INTERPRETATION 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome . FUNDING Schwarz Biosciences In a r and omized , controlled and double-blind cross-over trial with L-Dopa and placebo we evaluated the effects of a single bedtime dose of L-Dopa 100 to 200 mg on sleep quality and frequency of periodic leg movements ( PLM ) in 17 patients with idiopathic and in 11 patients with uremic restless legs syndrome ( RLS ) by polysomnography , actigraphy , and subjective ratings . Treatment with L-Dopa showed significant reduction of the number of periodic leg movements and the PLM-index most pronounced during the first 4 hours of bedtime . Subjective evaluation confirmed improvement of sleep quality .  L-Dopa proved to be effective in idiopathic and uremic RLS without any severe side effects 
    Output:
    
The placebo and nocebo responses were greater in trials with longer duration , evaluating pharmacologic interventions and idiopathic RLS , and in industry-funded and unpublished studies .
The placebo response was considerably smaller in objective as compared to subjective outcomes .
In addition , the nocebo response increases proportionally with the placebo response , and has the same predictors .
Conclusions : The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference , and the frequency of adverse events is also considerable .