***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: In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine ( CBZ ) on the neuroleptic treatment of schizophrenic psychoses , the effects of valproate ( VPA ) were tested in a r and omly assigned double-blind , placebo-controlled study . Apart from a ( statistically nonsignificant ) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on " hostile belligerence " , no overall therapeutic effects of the combination of haloperidol ( HPD ) with VPA were observed under controlled conditions . Unlike the results with CBZ , concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group , although these differences did not attain statistical significance . In regard to use of the sedative neuroleptic chlorprothixene , there was a trend toward lower doses in the VPA group than in the placebo group . From these results , adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study . However , the trend toward lower doses of sedative medication and observed effects on " hostile belligerence " may indicate sedative and /or antimanic properties of valproate which have recently been demonstrated in several controlled studies 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 Despite the plethora of clinical drug trials in tardive dyskinesia , few consistent findings have emerged . One possible reason for this is that there have been no serious attempts to define the role of major neurotransmitter systems ( dopamine , norepinephrine , acetylcholine , serotonin , GABA ) in one specific population of tardive dyskinesia patients . This study reports a series of five controlled drug trials in a population of patients with persistent tardive dyskinesia ; each drug probed one of four neurotransmitter systems . The intra- and interpatient responses are analyzed and the implication s of the pharmacologic response profiles for the clinical management of tardive dyskinesia are discussed As a treatment for tardive dyskinesia , sodium valproate was tested in a double-blind placebo-controlled  parallel group trial , with 6-week base-line observation period followed by 6 weeks of treatment . Sodium valproate was not found to be an effective treatment for either tardive dyskinesia or drug-induced Parkinsonism , and did not affect mental state or behaviour 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 The hypothesis of a gamma-aminobutyric acid ( GABA ) involvement in the pathophysiology of schizophrenia has been recently proposed but not confirmed . As GABA has been shown to affect basal growth hormone ( GH ) secretion in humans , the assessment of plasma GH response to a GABAergic drug , such as sodium valproate ( SV ) , in schizophrenic subjects might be a tool with which to investigate central GABA activity in this illness . For this purpose , we administered orally 800 mg of SV or placebo to 13 chronic schizophrenics and to 10 normal controls , and measured plasma GH levels before and after the drug administration . SV enhanced basal GH secretion in healthy male volunteers , but not in chronic schizophrenics . These results suggest a defect of the endogenous GABA system in chronic schizophrenia . Whether the reduced responsiveness observed represents a primary defect or a secondary alteration of the GABA system in schizophrenia is as yet unknown This double-blind , r and omized , multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia . Patients ( n=249 ) who met DSM-IV criteria for schizophrenia were r and omly assigned to receive olanzapine monotherapy , risperidone monotherapy , divalproex plus olanzapine , or divalproex plus risperidone for 28 days . Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day . Olanzapine and risperidone , were , respectively , initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day . Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups , with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale ( PANSS ) total score , derived Brief Psychiatric Rating Scale ( BPRSd ) total score , as well as PANSS and BPRSd subscales . These findings were confirmed in post hoc repeated- measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total ( p=0.020 ) and PANSS positive scale scores ( p=0.002 ) . Both combination therapy and antipsychotic monotherapy were well tolerated . Treatment with divalproex in combination with an atypical antipsychotic agent result ed in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia . Further evaluation is warranted to confirm these findings Experimental and clinical data suggest that GABA-ergic drugs such as valproate may have a potential role in the treatment of schizophrenia .  The authors design ed a 21-day prospect i ve , double-blind , r and omized , placebo-controlled pilot study of divalproex sodium as add-on treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia . All patients received haloperidol 10 mg/day for 3 days and 15 mg/day for the remaining 18 days . In addition , five patients were r and omly assigned to receive divalproex augmentation and seven to receive placebo . The divalproex dose was adjusted to a target serum concentration of 75 microg/mL for 2 weeks ; placebo replaced divalproex during the third and last weeks to determine any carryover effect . Psychiatric rating scales were administered at baseline and on days 7 , 14 , and 21 . Although the placebo group improved with haloperidol treatment , the divalproex group demonstrated greater improvement . On day 21 , the divalproex group had greater improvement from baseline on the Clinical Global Impression Scale ( p < or = 0.04 ) , Brief Psychiatric Rating Scale ( p < or = 0.13 ) , and Schedule for Assessment of Negative Symptoms scores ( p < or = 0.007 ) . After divalproex withdrawal on day 15 , a carryover effect was observed during week 3 . The authors concluded that the addition of divalproex sodium to st and ard antipsychotic drugs may prove effective in relieving the symptoms of acute schizophrenia . Future studies may benefit from the design of this pilot study . However , it is premature to apply this augmentation strategy in the clinical setting just yet because of the small sample size and the likely heterogeneity of the disorder OBJECTIVE This study compared the specific antihostility effects of atypical antipsychotic monotherapy ( olanzapine or risperidone ) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode . METHODS A total of 249 in patients with schizophrenia were r and omly assigned to receive olanzapine plus placebo , olanzapine plus divalproex , risperidone plus placebo , or risperidone plus divalproex in a double-blind , 28-day multicenter trial . The target daily dose was 15 milligrams for olanzapine , 6 milligrams for risperidone , and up to 30 milligrams per kilogram ( minimum , 15 milligrams per kilogram ) for divalproex . The hostility item of the Positive and Negative Syndrome Scale ( PANSS ) was the principal outcome measure . Covariates included the PANSS items reflecting positive symptoms of schizophrenia ( delusions , suspiciousness/persecution , gr and iosity , unusual thought content , conceptual disorganization , and hallucinatory behavior ) . RESULTS Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy . Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy . This result was not seen beyond the first week of treatment , but there was a trend toward a difference in effect for the entire treatment period . The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking , a formal thought disorder , or hallucinations . CONCLUSIONS Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode The objective of this study was to compare the effects of carbamazepine ( CBZ ) and valproate ( VPA ) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders . In this controlled clinical trial , 27 patients with an ICD-10 diagnosis of schizophrenia ( N = 24 ) or schizoaffective disorder ( N = 3 ) were r and omly assigned to receive 4 weeks of treatment with either haloperidol alone , haloperidol with CBZ , or haloperidol with VPA . Whereas the haloperidol dose remained stable , the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels . Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale . The use of CBZ was associated with significantly lower  haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy . VPA had no significant effect on either plasma levels or on psychopathology . Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure . This might be a result of a pharmacokinetic interaction on the hepatic level . The concomitant use of VPA with neuroleptic therapy is not impaired by clinical ly significant drug interactions , but it is not associated with a better outcome under our conditions The effect of sodium valproate , a drug which has been demonstrated to increase gamma-aminobutyric acid levels in the CNS , on tardive dyskinesia and psychiatric symptoms was investigated in a double-blind cross-over study on 32 chronic psychiatric patients . The oro-facial 
    Output:
    
REVIEW ER 'S CONCLUSIONS Based on r and omised trial-derived evidence which is currently available , there are no data to support or to refute the use of valproate as a sole agent for schizophrenia .
There is some evidence for a more rapid improvement with valproate augmentation , but this effect vanished over time .