***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: This double-blind placebo controlled , parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia , who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication . During a baseline period of 6 weeks , patients were switched to a stable dose of haloperidol ( mean ± SD dose=13.6±8.1 mg/day ) . Patients were then r and omized to receive either lithium or placebo in addition to haloperidol for 8 weeks ( mean ± SD lithium level = 0.98±0.13 mEq/1 ) . Symptoms and side effects were assessed weekly . Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose , but not with lithium or  placebo treatment . Side effects ratings did not differ between the two groups , but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment . For these long-term , severely ill patients , combined treatment afforded no advantage over treatment with haloperidol alone OBJECTIVE The purpose of the study was to assess the relationship between plasma haloperidol and clinical response . METHOD Sixty-nine newly admitted drug-free schizophrenic men were r and omly assigned to receive haloperidol , 5 , 10 , or 20 mg daily for 4 weeks , and clinical response was measured at the end of the fixed-dose period . Haloperidol was assayed by a sensitive and specific radioimmunoassay . RESULTS The authors found a curvilinear relationship between clinical response and plasma haloperidol  during fixed-dose treatment , with an apparent optimum between 5 and 12 ng/ml . When plasma levels above 12 ng/ml were lowered to the 5 - 12 ng/ml range , all patients improved to varying degrees and no patient deteriorated . When plasma levels of nonresponders within this therapeutic window were raised above 12 ng/ml ( as in routine practice ) , they , on balance , deteriorated in that they became more dysphoric . With the 20-mg dose , half the patients had plasma levels above 12 ng/ml . CONCLUSIONS In this sample of newly admitted schizophrenic men , optimal clinical response occurred with a plasma haloperidol range of 5 - 12 ng/ml In a double-blind trial of six months ' duration , a very high dose ( VHD ) regimen of fluphenazine decanoate ( 250 mg weekly ) was compared with a st and ard dose ( SD ) regimen ( 12.5 mg weekly ) in 50 chronic schizophrenic patients . The rating scales used included the Brief Psychiatric Rating Scale and the Wing Ward Behavior Scale . Both treatment groups improved during the trial , but there was no significant difference between them . The VHD regimen , however , exerted better control of the psychosis in that it had fewer patient dropouts and fewer " additional treatments " prescribed . Some of the patients receiving st and ard doses were probably not receiving adequate antipsychotic drug dosage . No predictors of clinical response could be defined . Extrapyramidal side effects were not significantly higher in the VHD group The value of lithium carbonate as an adjunctive treatment of resistant schizophrenia was tested in a 4‐week clinical trial using a single‐blind , r and omized , consent design . Treatment and control groups were drawn from a population of detained patients in an English special ( maximum security ) hospital . The 2 groups were comparable in terms of age , sex , severity of symptoms , length of hospitalization and concurrent neuroleptic dosage . The addition of lithium carbonate to the treatment regimen did not result in symptomatic improvement in patients completing the treatment protocol . The ethical and practical difficulties raised by the trial are discussed A 6 week double-blind placebo-controlled trial of  cyproheptadine augmentation of ongoing haloperidol treatment was conducted in 40 chronic schizophrenic in- patients . Cyproheptadine augmentation , compared to administration of haloperidol with placebo , did not produce a statistically significant improvement in psychotic symptoms . Cyproheptadine augmentation caused significant reduction in the extrapyramidal symptoms , which supports the atypical profile of antipsychotics . As to the neuro-endocrinological effect , cyproheptadine augmentation did not reduce the plasma prolactin level but did induce a decrease in the plasma cortisol level- Although long-term follow-up studies are needed to confirm the results , this study suggests that cyproheptadine augmentation may be effective in treating chronic schizophrenic patients who are intolerant of extrapyramidal side effects of conventional antipsychotics BACKGROUND Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory . In this study , the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia . METHODS Twenty-one patients ( mean [ + /-SD ] age , 14.0 + /- 2.3 years ) with onset of Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study . Patients were r and omized to a 6-week double-blind parallel comparison of clozapine ( mean [ + /-SD ] final dose , 176 + /- 149 mg/d ) , or haloperidol , ( 16 + /- 8 mg/d ) . RESULTS Clozapine was superior to haloperidol on all measures of psychosis ( P = .04-.002 ) . Positive and negative symptoms of schizophrenia improved . However , neutropenia and seizures were major concerns . To date , one third of the group has discontinued using clozapine . CONCLUSIONS Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia . However , due to possibly increased toxic effects in this pediatric population , close monitoring for adverse events is essential A double blind , placebo controlled trial was carried out to examine the contribution of propranolol as an adjunct to neuroleptic medication in the treatment of chronic schizophrenic patients whose florid symptoms had not remitted with neuroleptic medication alone .  Propranolol was shown to have a more beneficial effect than placebo , but the results were much less dramatic than those which have been described in previous studies . Recent work has shown that there may be a pharmacokinetic interaction between propranolol and neuroleptics , and this should be considered as one possible explanation of our findings Double blind controlled study on fifty treatment-resistant schizophrenic in patients showed a statistically significant improvement in favour of the high dose group In a double blind chlorpromazine-controlled trial , high dosage haloperidol ( 100 mg daily ) given for three months , appreciably improved the mental state of male chronic ' drug resistant ' schizophrenic in patients in the rehabilitation/long-stay unit of one psychiatric hospital . The results of a three-month follow-up suggested that the improvement could be maintained in some patients on lower doses of the drug . Serious extrapyramidal side effects were not seen at high doses . However , the majority of patients on haloperidol showed a deterioration in ward behaviour , possibly related to drowsiness , and developed raised serum alkaline phosphatase levels . These side effects disappeared in the follow-up period when either the drug was discontinued or the dose of haloperidol reduced OBJECTIVE The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients . METHOD In a controlled double-blind , multicenter study , 86 in patients with chronic schizophrenia ( DSM-III-R ) , who were resistant to or intolerant of conventional neuroleptics , were r and omly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period . After a 1-week dose-titration phase , doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient 's response . The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine . Treatment efficacy and safety were evaluated with several well-known rating scales . RESULTS Both risperidone and clozapine significantly reduced the severity of psychotic symptoms ( scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale ) from baseline , with no significant between-group differences . At endpoint , 67 % of the risperidone group and 65 % of the clozapine group were clinical ly improved ( reduction of 20 % or more in total Positive and Negative Syndrome Scale score ) . Risperidone appeared to have a faster onset of action . In both groups extrapyramidal symptoms and other adverse events were few , and their severity was generally mild . Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness . CONCLUSIONS Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics In a double-blind trial , female ' drug-resistant ' chronic schizophrenic in- patients were given high dose or st and ard dose flupenthixol decanoate for 13 weeks . Plasma flupenthixol levels showed a five-fold interindividual variation , but were consistently higher with the high dose . Analysis of final scores showed no statistically significant differences between groups with regards to mental state , ward behaviour and extrapyramidal side-effects . When compared with pre-trial scores , the extrapyramidal side-effects worsened significantly in the high dose patients and social withdrawal decreased in the st and ard dose patients . The mental state of a sub-group of patients , possibly drug resistant for pharmacokinetic reasons , improved significantly on the high dose over the 13 weeks A controlled investigation was design ed to determine the relative values of a new drug thiopropazate dihydrochloride , chlorpromazine hydrochloride and occupational therapy on overactive and aggressive chronic schizophrenics . Fifty-four patients were r and omly allotted to six groups of nine . Three groups attended O.T. and three did not . The pharmacist allocated the two active drugs and similar placebos to paired groups from the O.T. and non-O.T. groups . This information he did not release until the end of the trial . The patients were rated on their behaviour in the ward by the two charge nurses , and for symptoms by any two physicians not directly in charge of the patient . Practice ratings were made on a similar category of patient beforeh and . The ratings were made before the treatments started , after 2 weeks and again after 8 weeks of treatment . Results : 1 . Behaviour in the ward was significantly improved by thiopropazate at the end of 2 weeks and 8 weeks . O.T. significantly improved ward behaviour in the first 2 weeks , but by 8 weeks the other patients had improved sufficiently to make the difference non-significant . Interaction between drugs and O.T. showed that at the end of 8 weeks both chlorpromazine and , to a lesser extent , thiopropazate exerted a significant inhibitory effect on the improvement due to O.T. 2 . In the course of the trial , all groups of patients showed improvement in their symptoms , regardless of the combinations of treatment they received . This emphasized the importance of proper control groups in investigations on the effects of treatment . 3 . For the P group of symptoms ( apathy , mannerisms , hallucinations , etc . ) the only significant result was that at 8 weeks patients on O.T. did not improve as much as the others . For the N group of symptoms ( hostility , persecutory and other delusions ) all groups of patients improved , but differences between groups were not significant at 8 weeks . At 2 weeks , the patients on O.T. were significantly better than the others , and the patients on placebo were significantly better than those on active drugs . These differences were temporary and had fallen below statistical significance by the end of 8 weeks . For the total of all symptoms , neither O.T. nor drugs made any significant contribution to improvement . Factors which may have influenced the results are considered . There is evidence to suggest that in a rehabilitation programme for overactive , aggressive , chronic schizophrenics the maximum value of tranquillizing drugs may be obtained from their use at the start of the programme . There was no evidence of any soporific effect from these drugs given in the doses of : thiopropazate 10 mg . t.d.s . and chlorpromazine 100 mg . t.d.s . At the dosage level stated one patient receiving chlorpromazine developed , temporarily , symptoms of Parkinsonism but no patient receiving thiopropazate showed side-effects We evaluated ceruletide , a cholecystokininlike peptide , in a double-blind , placebo-controlled study of 20 male chronic schizophrenic patients . After baseline investigations , 10 patients received 0.3 microgram/kg body weight ceruletide , and 10 patients received placebo ( normal saline ) intramuscularly once weekly for 3 consecutive weeks . Psychopathology was rated on the Brief Psychiatric Rating Scale and the Nurses ' Observation Scale for Inpatient Evaluation . Blood was drawn on the same days for estimation of norepinephrine , epinephrine , beta-endorphin , cortisol , and prolactin . There were no significant changes in biochemical parameters . With regard to psychopathology , no significant differences in behavior 
    Output:
    
On the basis of the method ologically sound studies included , we conclude that only clozapine has proved to be clinical ly effective in the treatment of refractory schizophrenia .
In single inconclusive trials , olanzapine and risperidone have been found as effective as clozapine .