***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: 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 Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and /or secondary negative symptoms in schizophrenia . The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind , cross-over design trial . Outcome following mazindol supplementation was comparable to placebo supplementation ( F(1,30 ) = 0.9 ; p = .57 ) . Results for deficit and non-deficit schizophrenia subjects were similar , and were not affected by whether concurrent the antipsychotic drug treatment was clozapine , fluphenazine , or haloperidol . The efficacy hypothesis was not supported for either primary or secondary negative symptoms 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 activation and deactivation produced by amphetamine Rationale Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics ( SGAs ) is imperative . In the present study , we sought to replicate our preliminary findings , which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain . Material s and method Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this r and omized double-blind study . Reboxetine ( 4 mg/day ; 31 patients ) or placebo ( 29 patients ) was coadministered with olanzapine ( 10 mg/day ) for 6 weeks . Analysis was by intention-to-treat . Results Nine patients in each group prematurely discontinued the trial . Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight ( mean = 3.31 kg , SD = 2.73 ) than their olanzapine/placebo-treated counterparts ( mean = 4.91 kg , SD = 2.45 ) . Significantly fewer olanzapine/reboxetine-treated patients gained at least 7 % of their initial weight , the cutoff for clinical ly significant weight gain ( 6 [ 19.4 % ] of 31 patients vs 13 [ 46.4 % ] of 28 patients ) . Seven ( 22.6 % ) olanzapine/reboxetine-treated patients compared to only one patient ( 3.6 % ) in the olanzapine/placebo group revealed no weight change or even modest weight loss . Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain .  Reboxetine addition was safe and well tolerated . Conclusions The results confirm that coadministration of reboxetine promotes a clinical ly meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients . If substantiated in long-term studies , along with behavioral management and diet counseling , reboxetine may have a clinical utility in controlling SGA-induced weight gain OBJECTIVE Since increased norepinephrine availability may account for the weight-reducing effect of appetite suppressants , the authors hypothesized that the addition of the selective norepinephrine reuptake inhibitor reboxetine may prevent or attenuate olanzapine-induced  weight gain . METHOD Twenty-six patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in the study . In addition to 6 weeks of treatment with olanzapine , 10 mg/day , patients were r and omly allocated in a double-blind design to receive either reboxetine , 4 mg/day , ( N=13 ) or placebo ( N=13 ) . RESULTS Ten patients in each group completed the 6-week trial . Patients given olanzapine and reboxetine demonstrated a significantly lower increase in body weight ( mean=2.5 kg , SD=2.7 ) than those given olanzapine and placebo ( mean=5.5 kg , SD=3.1 ) . Significantly fewer patients in the olanzapine/reboxetine group ( N=2 of 10 ) than in the olanzapine/placebo group ( N=7 of 10 ) gained at least 7 % of their initial weight , the cutoff for clinical ly significant weight gain . The addition of reboxetine to olanzapine treatment was safe and well tolerated by the patients . A between-group difference in the reduction of Hamilton depression scale scores was seen that favored the olanzapine/reboxetine group ( mean difference=-3.1 , SD=1.25 ) . CONCLUSIONS The selective norepinephrine reuptake inhibitor reboxetine may reduce  olanzapine-induced  weight gain  in schizophrenia patients , and activation of the adrenergic system may attenuate weight gain induced by atypical antipsychotic agents A modification of an earlier rating scale for extrapyramidal system disturbance is described , and evidence for the validity and reliability of the scale is presented . The usefulness of the scale in studies of neuroleptic drugs is discussed . By its application it is possible to quantify extrapyramidal side effects and to separate them into four principal factors BACKGROUND In recent years , several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics .  While there has been some success , in general , results have not been compelling . Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression . Therefore , we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or  olanzapine . METHODS The study was a double-blind , placebo-controlled trial . All participants received the same psychosocial platform : a structured support and exercise group .  People with schizophrenia or schizoaffective disorder , on olanzapine or clozapine , who had gained at least 7 % of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week , r and omized , parallel group , double-blind comparison of adjunctive atomoxetine or placebo . RESULTS Thirty-seven participants ( 20 atomoxetine , 17 placebo ) were r and omized and 26 participants ( 14 atomoxetine , 12 placebo ; 70.2 % ) completed the study . There were no significant group differences in baseline BMI  ( atomoxetine : 34.5±4.9  ; placebo : 35.7±7.0 ) or weight  ( atomoxetine :  102.2±15.7 kg  ; placebo : 104.3±17.5 kg ) . Both treatment groups showed modest , not significant , trends in weight loss , averaging about 2 kg . Gender or baseline antipsychotic treatment did not modify treatment effects on weight . Secondary outcomes included neuropsychological assessment s , symptom assessment s ( BPRS , SANS ) and safety assessment s. Of these , only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine . CONCLUSIONS Atomoxetine is not effective for weight loss in this population , but both olanzapine and clozapine  participants can lose weight with structured group support and exercise BACKGROUND Currently available antipsychotic medications offer only modest , if any , effects on cognitive performance in people with schizophrenia . Treatments that would improve these impairments could lead to better functional outcomes . Atomoxetine is a nonstimulant , selective norepinephrine reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder . In animals , it has been shown to increase extracellular levels of acetylcholine and dopamine in cortical and hippocampal regions . METHOD Following a 2-week stabilization period , 32 subjects with DSM-IV-diagnosed schizophrenia or schizoaffective disorder were r and omly assigned to atomoxetine ( 80 mg daily ) or placebo for 8 weeks . All subjects were treated with antipsychotic monotherapy ( excluding clozapine , aripiprazole , and first-generation antipsychotics ) . Neuropsychological test performance was the primary outcome variable , and the neuropsychological test battery included measures of attention , motor speed , executive function , processing speed , verbal and visual memory , and working memory ( rated at baseline and end point ) . Symptom and side-effect ratings were performed every 2 weeks . The study was conducted from April 2004 through December 2006 . RESULTS There were no treatment group differences on the primary study outcome measure ( overall mean z-score : Wilcoxon chi(2 ) = 0.21 , df = 1 , p = .64 ) ; nor was there significant evidence of variation in treatment effects on z-score changes across the individual neuropsychological tests ( chi(2 ) = 8.22 , df = 8 , p = .41 ) . No between-group differences were noted in symptom changes .  Atomoxetine was well tolerated and was associated with a trend for improvement in extrapyramidal side effects relative to placebo ( p = .063 ) . CONCLUSION Our results provide further evidence that atomoxetine has limited benefit for improving cognition in people with schizophrenia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00161031 
    Output:
    
NRIs may exert an effect on depressive symptoms , and seem to be well-tolerated treatments