***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: OBJECTIVE The effect of smoking on daily doses and plasma levels of neuroleptics prescribed for schizophrenic patients was studied . METHODS 90 out patients with schizophrenic disorder ( DSM-III-R ) who were on a stable regimen of psychotropic medication and showed a stable clinical state were included in a double-blind placebo-controlled trial . Data were collected and blood tests taken at the baseline interview . The plasma levels were obtained for 52 patients . RESULTS Daily neuroleptic doses converted to chlorpromazine equivalents correlated significantly ( r = 0.436 ) with the plasma levels of their unmetabolised fractions . The neuroleptic doses increased with age in smokers , while in nonsmokers they decreased . Neither sex , age nor smoking had a significant association with the neuroleptic plasma levels . CONCLUSIONS Smoking seems to lead to increased neuroleptic dosages in postmenopausal schizophrenics by increasing hepatic metabolism and renal excretion of the drugs and possibly enhancing dopamine release . It is also possible that older smoking patients form a selected group of heavy smoker and they , therefore , need exceptionally high neuroleptic doses 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 OBJECTIVE Despite the frequent use of the Positive and Negative Syndrome Scale ( PANSS ) for rating the symptoms of schizophrenia , the clinical meaning of its total score and of the cut-offs that are used to define treatment response ( e.g. at least 20 % or 50 % reduction of the baseline score ) are as yet unclear . We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions ( CGI ) . METHOD PANSS and CGI ratings at baseline ( n = 4091 ) , and after one , two , four and six weeks of treatment taken from a pooled data base of seven pivotal , multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking . RESULTS Being considered " mildly ill " according to the CGI approximately corresponded to a PANSS total score of 58 , " moderately ill " to a PANSS of 75 , " markedly ill " to a PANSS of 95 and severely ill to a PANSS of 116 . To be " minimally improved " according to the CGI score was associated with a mean percentage PANSS reduction of 19 % , 23 % , 26 % and 28 % at weeks 1 , 2 , 4 and 6 , respectively . The corresponding figures for a CGI rating " much improved " were 40 % , 45 % , 51 % and 53 % . CONCLUSIONS The results provide a better framework for underst and ing the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations . Such studies may ideally use at least a 50 % reduction from baseline cut-off to define response rather than lower thresholds . In treatment resistant population s , however , even a small improvement can be important , so that a 25 % cut-off might be appropriate The negative symptoms of schizophrenia remain a major clinical challenge . Reboxetine is an antidepressant whose major mechanism of action is as a noradrenergic reuptake inhibitor . This study was a 6-week r and omized placebo-controlled trial of reboxetine or placebo add on to haloperidol 5 mg in the treatment of 30 patients with DSM-IV schizophrenia . The trial failed to demonstrate any significant difference between the placebo and reboxetine groups on any of the outcome measures . This trial does not suggest that increased noradreneregic drive mediated by reuptake inhibition in patients taking dopamine antagonists is of therapeutic value in schizophrenia Rationale Combination treatment with reboxetine , a selective norepinephrine reuptake inhibitor , and betahistine , a histamine H1 receptor agonist/H3 antagonist , was developed to produce complementary action in CNS pathways regulating appetite and body weight . In the present placebo-controlled study , we evaluated whether a reboxetine – betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients . Method Forty-three in patients with DSM-IV schizophrenic disorder participated in a r and omized double-blind study . Reboxetine ( 4 mg/day ) with betahistine ( 48 mg/day ) ( N = 29 ) or placebo ( N = 14 ) was co-administered with olanzapine ( 10 mg/day ) for 6 weeks . Mental status was assessed at baseline and endpoint with relevant rating scales . Intention-to-treat method was used for statistical analysis . Results Seven patients in the study group and four in the placebo group discontinued the trial . At the end of the trial , patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [ 2.02 ± 2.37 and 4.77 ± 3.16 kg , respectively ; t = 2 . 89 , degrees of freedom ( df ) = 41 , p = 0.006 ] . The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone . Significantly fewer patients in the study group than in the comparison group increased their initial weight by > 7 % , the cutoff for clinical ly significant weight gain [ 3/29 ( 10.3 % ) and 6/14 ( 42.9 % ) , respectively ; χ2 = 6.03 , df = 1 , p = 0.014 ] . The reboxetine – betahistine combination was safe and well tolerated . Conclusions Reboxetine – betahistine combination produces a clinical ly meaningful attenuation  of olanzapine-induced weight gain . These results justify direct comparison between the reboxetine – betahistine combination and reboxetine alone CONTEXT Cognitive impairment in schizophrenia is frequent , involves multiple domains , and is enduring . Numerous recent clinical trials have suggested that second-generation antipsychotic medications significantly enhance cognition in schizophrenia . However , none of these studies included healthy controls undergoing repeated testing to assess the possibility that improvements might reflect simple practice effects . OBJECTIVE To report the results on cognition of a r and omized comparison of 2 widely prescribed second-generation antipsychotic medications , olanzapine and risperidone , in patients with first-episode schizophrenia and a healthy control group . DESIGN R and omized clinical trial . SETTING Hospital-based research units . Patients A total of 104 participants with first-episode schizophrenia and 84 healthy controls . MAIN OUTCOME MEASURES Cognitive assessment of all study participants occurred at baseline , 6 weeks later , and 16 weeks later . Neurocognitive tests included measures of working memory and attention , speed , motor function , episodic memory , and executive function . RESULTS No differential drug effects were observed . Of 16 cognitive measures , 9 demonstrated improvement over time and only 2 demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment . The composite effect size for cognitive change was 0.33 in the healthy control group ( attributed to practice ) and 0.36 in the patients with first-episode schizophrenia . Improvements in cognition in the first-episode schizophrenia group could not be accounted for by medication dose , demographic variables , or intellectual level . CONCLUSIONS The cognitive improvements observed in the trial were consistent in magnitude with practice effects observed in healthy controls , suggesting that some of the improvements in cognition in the first-episode schizophrenia group may have been due to practice effects ( ie , exposure , familiarity , and /or procedural learning ) . Our results also indicated that differential medication effects on cognition were small . We believe that these findings have important implication s for drug discovery and the design of registration trials that attempt to demonstrate cognitive enhancement To explore the role of monoamines on cerebral function during specific prefrontal cognitive activation , we conducted a double-blind placebo- controlled crossover study of the effects of 0.25 mg/kg oral dextroamphetamine on regional cerebral blood flow ( rCBF ) as determined by 133Xe dynamic single-photon emission-computed tomography ( SPECT ) during performance of the Wisconsin Card Sorting Test ( WCST ) and a sensorimotor control task . Ten patients with chronic schizophrenia who had been stabilized for at least 6 weeks on 0.4 mg/kg haloperidol participated . Amphetamine produced a modest , nonsignificant , task- independent , global reduction in rCBF . However , the effect of amphetamine on task-dependent activation of rCBF ( i.e. , WCST minus control task ) was striking . Whereas on placebo no significant activation of rCBF was seen during the WCST compared with the control task , on amphetamine significant activation of the left dorsolateral prefrontal cortex ( DLPFC ) occurred ( p = 0.0006 ) . Both the mean number of correct responses and the mean conceptual level increased ( p less than 0.05 ) with amphetamine relative to placebo . In addition , with amphetamine , but not with placebo , a significant correlation ( p = - 0.71 ; p less than 0.05 ) emerged between activation of DLPFC rCBF and performance of the WCST task . These findings are consistent with animal models in which mesocortical catecholaminergic activity modulates and enhances the signal-to-noise ratio of evoked cortical activity The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more .  ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas Relationships between altered prefrontal cortical dopamine , norepinephrine , and some of the cognitive impairments of schizophrenia support an approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine . Atomoxetine , a selective norepinephrine reuptake inhibitor , produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine . Given this , we evaluated atomoxetine 's cognitive effects in a pilot placebo-controlled trial in patients with schizophrenia . Moreover , a functional magnetic resonance imaging investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine .  Twenty participants with schizophrenia were r and omized to treatment with placebo or atomoxetine 80 mg daily for an 8-week parallel- design ed treatment trial . Cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia . No significant cognitive improvement was associated with atomoxetine treatment . However , atomoxetine treatment was associated with significantly greater increases in working memory-related activation of the left dorsolateral prefrontal and left posterior cingulate cortices . The negative results of this study conflict with the effectiveness of amphetamine in enhancing the cognitive abilities of schizophrenic patients and may be related to the differential pattern of cortical 
    Output:
    
Our results provide tentative very low quality evidence that compared to placebo , NRIs ( specifically reboxetine ) may have a benefit on the negative  symptoms of schizophrenia .
Limited evidence also suggests that NRIs have no effect on the positive symptoms of schizophrenia  or  cognitive functioning .
NRIs appear generally well tolerated with no real differences in adverse effects such as nausea noted between NRIs and placebo .