***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 
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    ***EXAMPLES*** 
    Input: Abstract Negative symptoms are common in schizophrenia , but often difficult to differentiate from depression . They are associated with long-term impairment and do not respond well to current treatment approaches . Even though antidepressants are commonly prescribed in schizophrenia , their beneficial effect is still under debate . In the present study , we aim ed to investigate the effect of serotonergic versus noradrenergic antidepressant add-on therapy on negative symptoms in schizophrenia . Fifty-eight patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria and with predominant negative symptoms were r and omized in a double-blind design to add-on treatment with citalopram , reboxetine , or placebo for 4 weeks . Analysis of covariance with repeated- measures design was used to compare improvement between treatment groups in scores of the Positive and Negative Syndrome Scale and the Hamilton Rating Scale for Depression . A & khgr;2 test was used to compare responder rates between treatment groups . Repeated- measures analysis of covariance revealed no differences between treatment groups over time ( treatment × time , not statistically significant ) for Positive and Negative Syndrome Scale subscales . Although a subgroup analysis in subjects fulfilling the criteria for minor depression was suggestive of higher responder rates in the citalopram group compared with reboxetine , the results did not reach significance level . Our findings do not support a beneficial effect of adjunctive antidepressant treatment on negative symptoms in schizophrenia . However , depressive symptoms are reduced in patients with minor depression by citalopram but not reboxetine , which is in line with previous findings UNLABELLED The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized . Raloxifene , a selective estrogen receptor modulator , appears to act similarly to estrogens on dopamine and serotonin brain systems . One previous trial by our team found that raloxifene was useful to improve negative , positive , and general psychopathological symptoms , without having the negative side effects of estrogens . In this study , we assess the utility of raloxifene in treating negative and other psychotic symptoms in postmenopausal women with schizophrenia exhibiting prominent negative symptoms . This was a 24-week , r and omized , parallel , double-blind , placebo-controlled study . Patients were recruited from the inpatient and outpatient departments of Parc Sanitari Sant Joan de Déu , Hospital Universitari Institut Pere Mata , and Corporació Sanitària Parc Taulí . Seventy postmenopausal women with schizophrenia ( DSM-IV ) were r and omized to either adjunctive raloxifene ( 38 women ) or adjunctive placebo ( 32 women ) . Psychopathological symptoms were assessed at baseline and at weeks 4 , 12 , and 24 with the Positive and Negative Syndrome Scale ( PANSS ) and the Scale for the Assessment of Negative Symptoms ( SANS ) . The addition of raloxifene ( 60 mg/d ) to regular antipsychotic treatment significantly reduced negative ( P = .027 ) , general ( P = .003 ) , and total symptomatology ( P = .005 ) measured with the PANSS during the 24-week trial , as compared to women receiving placebo . Also Alogia SANSS subscale improved more in the raloxifene ( P = .048 ) than the placebo group . In conclusion , raloxifene  improved negative and general psychopathological symptoms , compared with antipsychotic medication alone , in postmenopausal women with schizophrenia . These data replicate our previous results with a larger sample and a longer follow-up . TRIAL REGISTRATION NCT01573637 BACKGROUND There is currently no st and ard of care for treatment of negative symptoms of schizophrenia , although some previous results with glutamatergic agonists have been promising . METHODS Three ( SunLyte [ WN25308 ] , DayLyte [ WN25309 ] , and FlashLyte [ NN25310 ] ) phase III , multicenter , r and omized , 24-week , double-blind , parallel-group , placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics . SunLyte met the prespecified criteria for lack of efficacy and was declared futile . Key inclusion criteria were age ≥18 years , DSM-IV-TR diagnosis of schizophrenia , score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors , unaltered antipsychotic treatment , and clinical stability . Following a 4-week prospect i ve stabilization period , patients were r and omly assigned 1:1:1 to bitopertin ( 5 mg and 10 mg [ DayLyte ] and 10 mg and 20 mg [ FlashLyte ] ) or placebo once daily for 24 weeks . The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24 . RESULTS The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients , respectively . At week 24 , mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end  points . Bitopertin was well tolerated . CONCLUSIONS These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia OBJECTIVE Patients with schizophrenia frequently present with negative symptoms and cognitive impairments for which no effective treatments are known . Agents that act at the glycine site of the N-methyl-D-aspartic acid ( NMDA ) glutamatergic receptor have been suggested as promising treatments for moderate to severe negative symptoms and cognitive impairments . METHOD The Cognitive and Negative Symptoms in Schizophrenia Trial ( CONSIST ) was a 16-week double-blind , double-dummy , parallel group , r and omized clinical trial of adjunctive glycine , D-cycloserine , or placebo conducted at four sites in the United States and one site in Israel . The participants were 157 in patients and out patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder and retrospective and prospect i ve criteria for moderate to severe negative symptoms without marked positive , depressive , or extrapyramidal symptoms . The primary outcome measures were the average " rate of change " of Scale for the Assessment of Negative Symptoms ( SANS ) total scores and change in the average cognitive domain z scores . RESULTS There were no significant differences in change in the SANS total score between glycine and placebo subjects or D-cycloserine and placebo subjects . A prespecified test for the site-by-treatment-by-time interaction was significant in post hoc tests . One site had greater reduction in the SANS total score for patients receiving D-cycloserine relative to patients receiving placebo . A second site had greater reduction in the SANS total score for placebo patients compared with glycine patients . There were no significant differences between glycine and placebo or D-cycloserine and placebo subjects on the average cognition z score . CONCLUSIONS The study results suggest that neither glycine nor D-cycloserine is a generally effective therapeutic option for treating negative symptoms or cognitive impairments OBJECTIVE  Placebo response and the rate of failed clinical trials are increasing in schizophrenia , resembling previous experience with antidepressant clinical trials . In depression , the percent of patients r and omized to placebo was shown to be strongly associated with drug-placebo differences ( signal detection).We hypothesized that this factor would also be important in recent schizophrenia clinical trials . To test this hypothesis a data base of acute schizophrenia placebo-controlled studies conducted between 1997 and 2008 was constructed . The data base contained 27 studies , with 79 active treatment arms . As percentage of patients r and omized to placebo increased , mean placebo improvement decreased ( p = 0.047 ) and mean drug-placebo differences tended to increase ( p = 0.166 ) . The frequency of significant contrasts from studies with ≥ 25 % r and omized to placebo was 83.3 % , compared with 58.3 % in studies with < 25 % r and omized to placebo . Caveats to these findings include limited data and confounding of potentially influential factors . These limitations prevent definitive conclusions . However , results are consistent with previous findings in depression where having a higher percent of patients r and omized to placebo increased drug-placebo differences Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE Negative symptoms are core features of schizophrenia that are functionally debilitating , associated with poor outcomes , and resistant to existing pharmacotherapies . We performed a r and omized , double-blind , placebo-controlled study of modafinil , a medication approved for the treatment of excessive daytime sleepiness , to explore its efficacy as an adjunctive therapy for negative symptoms in schizophrenia . METHOD Twenty subjects with DSM-IV schizophrenia or schizoaffective disorder were r and omly assigned to double-blind treatment with modafinil or placebo for 8 weeks . The study ran from March 2002 through March 2006 . Outcome measures included the Scale for the Assessment of Negative Symptoms ( SANS ) , Brief Psychiatric Rating Scale ( BPRS ) , Clinical Global Impressions ( CGI ) scale , Quality of Life Interview , neurocognitive assessment s ( California Verbal Learning Test , De grade d Performance-Continuous Performance Test , Trail-Making Test B ) , and somatic measures ( sleep , weight , side effects ) . RESULTS Modafinil treatment was associated with a greater rate ( CGI-Improvement [ CGI-I ] score < or = 3 , 7/10 vs. 1/10 ) and degree ( mean CGI-I score , 3.2 vs. 4.1 ) of global improvement at study endpoint compared with placebo . However , modafinil did not significantly improve global negative symptoms as measured by the total SANS or SANS individual global items . Modafinil did not significantly worsen psycho-pathology ( according to the BPRS ) , compared with placebo , and was well tolerated . CONCLUSIONS Although no effect on negative symptoms was found , adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms CONTEXT Negative symptoms of schizophrenia are a prominent feature of the illness , and frequently remain refractory to treatment . Dehydroepi and rosterone ( DHEA ) , along with its sulfated form , DHEA-S , is an important circulating neurosteroid with several vital neurophysiological functions , including the regulation of neuronal excitability and function . OBJECTIVE Since the administration of DHEA has demonstrated improvement in mood , sense of well-being , interest , activity , and energy in several sub population s , we investigate the efficacy of DHEA in the management of the negative symptoms of schizophrenia . DESIGN Thirty DSM-IV-diagnosed schizophrenic patients with prominent negative symptoms ( in patients in a large referral state hospital ) were r and omized to receive either DHEA or placebo in double-blind fashion , in addition to regular antipsychotic medication , dose-stabilized prior to study entry . The DHEA was titrated up to a dose of 100 mg in divided doses during 6 weeks . RESULTS Results indicated significant improvement in negative symptoms ( P<.001 ) , as well as in depressive ( P<.05 ) and anxiety ( P<.001 ) symptoms in individuals receiving DHEA . This effect was especially noted in women . The improvement in negative symptoms was independent of improvement in depression . No differences were noted on the positive symptom subscale of the Positive and Negative Syndrome Scale ( PANSS ) or on the total PANSS score as compared with placebo . Subjects receiving DHEA demonstrated a significant increase in DHEA ( P<.05 ) and DHEA-S ( P<.01 ) plasma levels , without changes in cortisol levels . Increases in DHEA and plasma DHEA-S levels were correlated with improvement in negative symptoms ( P<.05 ) , but not with improvement in depressive and anxiety symptoms . No obvious adverse effects were experienced by participating subjects . CONCLUSIONS Our preliminary observations report for the first time in double-blind fashion the efficacy of DHEA augmentation in the management of negative , depressive , and anxiety symptoms of schizophrenia . The findings from this study raise important issues regarding the role of neurosteroids in general , and DHEA in particular , in the ongoing symptomatology and pharmacotherapy of schizophrenia OBJECTIVE The current study examined the efficacy and safety of rasagiline , a selective MAO-B inhibitor , for the treatment of persistent negative symptoms . METHODS Sixty people with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , schizophrenia or schizoaffective disorder , who met a priori criteria for persistent negative symptoms , were r and omized to receive rasagiline , 1mg/d ( n = 31 ) or placebo ( n 
    Output:
    
Multivariable meta-regression analyses showed that larger numbers of arms in the trial , larger numbers of study sites and industry sponsorship were significant moderators of placebo response in this population .