title: A controlled randomized treatment study: the effects of a cognitive remediation program on adolescents with early onset psychosis The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis: I. Study rationale and design Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population. What does the PANSS mean? Pilot study investigating the effect of intercessory prayer in the treatment of child psychiatric disorders. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. Are the effects of cognitive remediation therapy (CRT) durable? Results from an exploratory trial in schizophrenia Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. Childhood-onset schizophrenia: an NIMH study in progress. A comparative pilot study of second-generation antipsychotics in children and adolescents with schizophrenia-spectrum disorders. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Obsessive-Compulsive Symptoms in a Randomized, Double-Blind Study With Olanzapine or Risperidone in Young Patients With Early Psychosis Clozapine and “High-Dose” Olanzapine in Refractory Early-Onset Schizophrenia: A 12-Week Randomized and Double-Blind Comparison A Pilot Study of Risperidone, Olanzapine, and Haloperidol in Psychotic Youth: A Double-Blind, Randomized, 8-Week Trial Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis: II. Baseline characteristics of the “prodromal” sample Antipsychotic medication for childhood-onset schizophrenia. Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. Long-term safety, tolerability, and clinical efficacy of quetiapine in adolescents: an open-label extension trial. FDG-PET in never-previously medicated psychotic adolescents treated with olanzapine or haloperidol An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome Early Psychological Intervention for Auditory Hallucinations: An Exploratory Study of Young People's Voices Groups A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Cognitive remediation therapy (CRT) for young early onset patients with schizophrenia: An exploratory randomized controlled trial Cognitive efficacy of quetiapine and olanzapine in early-onset first-episode psychosis. A trial of quetiapine compared with risperidone in the treatment of first onset psychosis among 15- to 18-year-old adolescents Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study.
abstract: Objective : To examine if a cognitive remediation program could be a positive supplement to a psychoeducational treatment program for adolescents with early onset psychosis The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome . This identifies them as being at high risk for developing psychosis in the near future . The study aims include prevention of psychosis onset and disability , as well as palliation of ongoing symptomatology . This report presents the study rationale and design . Recent studies will be review ed that have advanced our knowledge about the early course of schizophrenia and our ability to predict onset prospect ively , advances that have rendered prodromal intervention research feasible and ethical . The study design has many novel features . It tests for prevention versus delay in psychosis onset , as well as for efficacy and safety in a newly defined clinical population . This has required the development of innovative clinical research assessment instruments and a new operational definition of psychosis onset . The integration of these novel elements into an otherwise typical clinical trial design is detailed . The companion report will address sample recruitment and the clinical phenomenology at baseline of this putative " prodromal " entity Atendency to extract spurious , message-like meaning from meaningless noise was assessed as a risk factor leading to schizophrenia-spectrum disorders by assessing word length of speech illusions elicited by multispeaker babble in 43 people with prodromal symptoms . These individuals were r and omised to olanzapine v. placebo groups during year 1 followed by no pharmacological treatment for those with no disorder conversion during year 2 . A time-dependent Cox regression analysis of conversion to schizophrenia-spectrum disorder revealed a significant interaction between condition ( olanzapine v. no drug ) and length of speech illusion , with the latter strongly predicting subsequent conversion during medication-free intervals but not during olanzapine treatment 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 OBJECTIVE To investigate whether intercessory prayer had an effect on the outcomes of a group of children with psychiatric conditions , using a triple blind r and omized study design . CONCLUSION This study was unable to show any additional benefits for patients who received intercessory prayer  compared to those who received treatment as usual OBJECTIVE To assess olanzapine 's  efficacy and tolerability in adolescents with schizophrenia . METHOD One hundred seven inpatient and outpatient adolescents ( olanzapine , n = 72 , mean age 16.1 years ; placebo , n = 35 , mean age 16.3 years ) with schizophrenia participated in this r and omized ( 2:1 ) , international , multisite , industry-sponsored trial . All patients met DSM-IV-TR criteria for schizophrenia , and they were treated for up to 6 weeks with flexible doses of olanzapine ( 2.5 - 20.0 mg/day ) or placebo . Last-observation-carried-forward mean changes from baseline to endpoint on the anchored version of the Brief Psychiatric Rating Scale for Children , Clinical Global Impression Scale-Severity of Illness , and Positive and Negative Syndrome Scale ( PANSS ) were assessed . RESULTS More olanzapine-treated versus placebo-treated  patients completed the trial ( 68.1 % versus 42.9 % , p = .020 ) . Compared with placebo-treated patients , olanzapine-treated adolescents had significantly greater improvement in Brief Psychiatric Rating Scale for Children total ( p = .003 ) , Clinical Global Impressions Scale-Severity of Illness ( p = .004 ) , PANSS total ( p = .005 ) , and PANSS positive scores ( p = .002 ) . Olanzapine-treated patients gained significantly more baseline-to-endpoint weight ( 4.3 kg versus 0.1 kg , p < .001 ) . Significantly more olanzapine-treated versus placebo-treated patients gained 7 % or greater of their body weight at any time during treatment ( 45.8 % versus 14.7 % , p = .002 ) . Prolactin and triglyceride mean baseline-to-endpoint changes were significantly higher in olanzapine-treated versus placebo-treated adolescents . The incidence of treatment-emergent significant changes in fasting glucose , cholesterol , or triglycerides did not differ between the groups at endpoint , but significantly more olanzapine-treated patients had high triglycerides at any time during treatment . CONCLUSIONS Olanzapine-treated adolescents with schizophrenia experienced significant symptom improvement . Significant increases in weight , triglycerides , uric acid , most liver function tests , and prolactin were observed during olanzapine treatment . Clinical trial registration information-Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia . URL : http://www . clinical trials.gov . Unique identifier : NCT00051298 BACKGROUND This paper investigates the durability of the effects of cognitive remediation therapy ( CRT ) . In a r and omised control trial , CRT was compared with a control therapy ( intensive occupational therapy activities ) , matched for length of therapist contact . The main three cognitive outcomes , ( i ) number of categories achieved on the Wisconsin Card Sort Test , ( ii ) age-scaled score on the Digit Span subtest of the WAIS-R , and ( iii ) mean number of moves on the Tower of London test , were chosen because they are known to be problematic in schizophrenia . In addition , a wide variety of other outcomes ( symptoms , social functioning , self-esteem and cognition ) were assessed . At the end of treatment , CRT conferred a benefit to people with schizophrenia in cognition and self-esteem [ Schizophr . Bull . 25 ( 1999 ) 291 ] . This study investigates these outcomes 6 months after the therapies were withdrawn . METHOD Participants were assessed at baseline , posttreatment and 6-month follow-up ( n=17 for the CRT group ; n=16 for the control therapy group ) . In addition to the functioning measures , data on use of services and cost of therapy were collected . RESULTS The effects of CRT on cognition were still apparent at follow-up , particularly in the memory domain . When these cognitive improvements reached a criterion threshold , there were also improvements in social behaviour and symptoms . The gains made in self-esteem disappeared following the withdrawal of therapy . The economic analysis showed overall reductions in the care packages of both patient groups but there was a significant increase in day-care costs for patients who have received CRT . This additional use of day care may confer further advantages to the  CRT group , such as improved social functioning and quality of life . CONCLUSIONS The overall results of this first trial of a novel CRT approach have produced encouraging results which merit further investigation 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 An ongoing study of the phenomenology , genetics , neuropsychology , physiology ( eye tracking , autonomic responsivity ) , neuroimaging , biochemistry , and pharmacology of childhood-onset schizophrenia is described , and pilot data are presented for the first 22 subjects . Differentiation from autism " spectrum " disorders and other poorly defined , severe neurodevelopmental disorders is needed . Eye tracking and autonomic results are similar to patterns seen in later-onset schizophrenia and possibly more striking . Magnetic resonance imaging showed larger left frontal ventricular horn area for the schizophrenia subjects , larger left cau date , and lack of normal cau date asymmetry . Fluorodeoxyglucose positron emission tomography during an auditory continuous performance task revealed decreased right parietal/occipital glucose metabolic rate in the schizophrenia subjects , which may be secondary to poor attentional performance , and increased glucose metabolic rate in three left frontal regions , a left parietal region , and the right putamen . Clozapine has been effective and well tolerated in an open trial with 12 adolescents who responded poorly to typical neuroleptics ; 16 subjects have been enrolled in a double-blind comparison of haloperidol and clozapine . Longitudinal study of this narrowly defined and possibly more homogeneous group of very early-onset schizophrenia subjects will be relevant to current neurodevelopmental theories addressing the role of puberty , progression of pathology , and continuity or discontinuity with later-onset schizophrenia OBJECTIVE There is a limited evidence base to guide treatment of children and adolescents with nonaffective psychoses because few comparative studies of first-line second-generation antipsychotics ( SGAs ) have been undertaken . To plan the design of a subsequent r and omized controlled trial ( RCT ) , the authors conducted this pilot study to demonstrate the feasibility of the treatment and measurement protocol s. METHOD Thirty children and adolescents ( 20 males , 10 females ) , ages 10 - 18 years , who met unmodified Diagnostic and Statistical Manual of Mental Disorders , 4th edition ( DSM-IV ) criteria for a schizophrenia-spectrum disorder ( schizophrenia , schizoaffective , schizophreniform , psychotic disorder not otherwise specified ) were r and omized to receive 12 weeks of open-label , flexibly dosed treatment with either risperidone ( mean [ st and ard deviation , SD ] dose = 3.4 mg [ 1.5 ] ) , olanzapine ( mean [ SD ] dose = 14.0 mg [ 4.6 ] ) or quetiapine ( mean [ SD ] dose = 611 mg [ 253.4 ] ) . RESULTS Twenty one ( 70 % ) of 30 subjects completed the study . There was no overall statistically significant difference with regard to reduction in Positive and Negative Syndrome Scale ( PANSS ) total scores in treatment efficacy observed ( F((2,24 ) ) = 3.13 , p = 0.06 ) . However , the possibility of a large differential treatment effect with regard to change in PANSS total scores favoring risperidone relative to quetiapine ( risperidone vs. quetiapine , d = 1.10 [ 95 % confidence interval , CI , 0.09 - 2.01 ] ) was suggested by the point estimate . CONCLUSIONS These preliminary data , viewed together with the extant literature , suggest that a future larger RCT with only two treatment arms may be warranted to establish whether there is a clinical ly significant differential treatment effect between risperidone and quetiapine for children and adolescents with nonaffective psychoses . Additional challenges and considerations for mounting a larger RCT are explored BACKGROUND The relative effectiveness of second-generation ( atypical ) antipsychotic drugs as compared with that of older agents has been incompletely addressed , though newer agents are currently used far more commonly . We compared a first-generation antipsychotic , perphenazine , with several newer drugs in a double-blind study . METHODS A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and r and omly assigned to receive olanzapine ( 7.5 to 30 mg per day ) , perphenazine ( 8 to 32 mg per day ) , quetiapine ( 200 to 800 mg per day ) , or risperidone ( 1.5 to 6.0 mg per day ) for up to 18 months . Ziprasidone ( 40 to 160 mg per day ) was included after its approval by the Food and Drug Administration . The primary aim was to delineate differences in the overall effectiveness of these five treatments . RESULTS Overall , 74 percent of patients discontinued the study medication before 18 months ( 1061 of the 1432 patients who received at least one dose ) : 64 percent of those assigned to olanzapine , 75 percent of those assigned to perphenazine , 82 percent of those assigned to quetiapine , 74 percent of those assigned to risperidone , and 79 percent of those assigned to ziprasidone . The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine ( P<0.001 ) or risperidone ( P=0.002 ) group , but not in the perphenazine ( P=0.021 ) or ziprasidone ( P=0.028 ) group . The times to discontinuation because of intolerable side effects were similar among the groups , but the rates differed ( P=0.04 ) ; olanzapine was associated with more discontinuation for weight gain or metabolic effects , and perphenazine was associated with more discontinuation for extrapyramidal effects . CONCLUSIONS The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons . Olanzapine was the most effective in terms of the rates of discontinuation , and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine , risperidone , and ziprasidone . Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism BACKGROUND Effective treatments for adolescent schizophrenia are needed . AIMS To compare efficacy and safety of two dosing regimens of risperidone . METHOD Double-blind , 8-week study . Patients , 13 - 17 years , with an acute episode of schizophrenia , r and omised 1:1 to risperidone  1.5 - 6.0 mg/day ( regimen A ; n=125 ) or 0.15 - 0.6 mg/day ( regimen B ; n=132 ) . TRIAL REGISTRATION NUMBER NCT00034749 . RESULTS Mean total Positive and Negative Syndrome Scale ( PANSS ) score improved significantly ( P<0.001 ; effect size=0.49 ) from baseline to end-point for regimen A ( mean=96.4 ( s.d.=15.39 ) to mean=72.8 ( s.d.=22.52 ) ) compared with regimen B ( mean=93.3 ( s.d.=14.14 ) to mean=80.8 ( s.d.=24.33 ) ) . Treatment-emergent adverse events occurred in 74 % ( regimen A ) and 65 % ( regimen B ) of patients ; 4 % of patients overall discontinued for adverse events . Mean change in body weight was 3.2 kg ( s.d.=3.49 ) for regimen A and 1.7 kg ( s.d.=3.29 ) for regimen B. CONCLUSIONS Adolescent patients in the regimen A group showed greater improvement in total PANSS compared with the regimen B group . Treatment was well tolerated Background : The prevalence of obsessive-compulsive symptoms ( OCS ) in patients with schizophrenia is relatively high . Antipsychotics have been found to influence OCS . Objective : To determine whether induction or severity of OCS differs during treatment with olanzapine or risperidone in young patients with early psychosis . Methods : One hundred twenty-two patients with a Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition diagnosis of schizophrenia , schizoaffective disorder , or schizophreniform disorder were r and omized in a double-blind design to groups of 6 weeks ' treatment with olanzapine ( n = 59 ) or risperidone ( n = 63 ) , with a mean dose of 11.3 mg olanzapine and 3.0 mg risperidone at 6 weeks . Primary outcome measures were the mean baseline-to-endpoint change in total score on the Yale-Brown Obsessive-Compulsive Scale ( Y-BOCS ) . Results : Treatment with olanzapine was associated with greater decreases in Y-BOCS total score than treatment with risperidone in total group ( N = 122 : -2.2 vs -0.3 , z = -2.651 , P < 0.01 ) , in patients with baseline Y-BOCS total score greater than 0 ( n = 58 : -5.1 vs -0.4 , z = -2.717 , P < 0.01 ) , and in patients with baseline Y-BOCS total score greater than 10 ( n = 29 : -7.1 vs -0.6 , z = -2.138 , P = 0.032 ) . Conclusions : In this r and omized , 6-week , double-blind trial , we found a significant and clinical ly relevant difference in decrease in Y-BOCS scores favoring olanzapine compared with risperidone BACKGROUND The present study evaluated the effectiveness and safety of clozapine versus " high-dose " olanzapine in treatment-refractory adolescents with schizophrenia . METHODS Children , ages 10 - 18 years , who met DSM-IV criteria for schizophrenia and who were resistant or intolerant to at least two antipsychotic drugs were r and omized to receive 12 weeks of double-blind flexibly dosed treatment with clozapine ( n = 18 ) or " high-dose " olanzapine ( up to 30 mg/day ) ( n = 21 ) . The primary efficacy measure was response ( improvement ) , defined as a decrease of 30 % or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of " 1 " ( very much improved ) or " 2 " ( much improved ) . RESULTS Significantly more clozapine-treated adolescents met response criteria ( 66 % ) compared with olanzapine-treated subjects ( 33 % ) . Clozapine was superior to olanzapine in terms of reduction of the psychosis cluster scores and negative symptoms from baseline to end point . However , both treatments were associated with significant weight-gain and related metabolic abnormalities . CONCLUSIONS This double-blind r and omized comparison of two second-generation antipsychotic drugs for treatment-refractory adolescents with schizophrenia supports clozapine as the agent of choice . The development of interventions to limit weight gain and metabolic side effects are needed to enhance the risk-benefit profile for both study treatments This pilot study was undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population , in comparison to haloperidol , a conventional antipsychotic with established efficacy . Risperidone and olanzapine are widely used as first-line treatments to ameliorate psychotic symptoms in youth , but their abilities to specifically treat children and adolescents presenting due to psychotic symptoms have not been rigorously studied . Subjects , selected because of prominent positive psychotic symptoms , were r and omly assigned to double-blind , parallel treatment with risperidone , olanzapine , or haloperidol for 8 weeks . The primary outcome was reduction in the Brief Psychiatric Rating Scale for Children total score from baseline to termination . An exploratory , descriptive analysis was done to compare the three treatments . A total of 50 patients , 8–19 years , participated . All treatments reduced symptoms significantly with p-values ( corrected for multiple comparisons ) of 0.0018 for each of the atypical agents and 0.012 for haloperidol . In all , 88 % of subjects treated with olanzapine  , 74 % treated with  risperidone , and 53 % treated with haloperidol met response criteria . The primary side effects observed in all patients were mild to moderate sedation , extrapyramidal symptoms , and weight gain .  Risperidone and olanzapine  acutely reduced psychotic symptoms in this pediatric sample . Exploratory comparisons indicate the magnitude of the antipsychotic response with these atypical agents is comparable to that observed with haloperidol . However , youth treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appear more prevalent and severe than reported in adults 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 The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome . This identifies them as being at high risk for developing psychosis in the near future . The study aims include prevention of psychosis onset and disability , as well as palliation of ongoing symptomatology . The purpose of this report is to describe the study 's " prodromally symptomatic " sample at baseline , i.e. , at intake immediately prior to r and omization and prior to receiving study medication . Sixty treatment-seeking patients meeting prodromal inclusion criteria were recruited across four sites : New Haven , CT ( n=39 ) , Toronto , Ontario ( n=9 ) , Calgary , Alberta ( n=6 ) , and Chapel Hill , NC ( n=6 ) . The sample was young ( median age 16 ) , largely male ( 65 % ) , and came from families with high titers of serious mental illness ( 44 % ) . Most patients ( 93 % ) met criteria for the Attenuated Positive Symptom ( APS ) prodromal syndrome and presented with significant but nonpsychotic suspiciousness , perceptual aberrations , unusual thought content , and conceptual disorganization . They presented with minimal to mild affective symptoms and substance use/abuse , but they were quite functionally compromised ( mean Global Assessment of Functioning ( GAF ) score=42 ) . The prodromal sample was compared with other clinical -trial sample s of adolescent depression , adolescent mania , and first episode schizophrenia . Prodromal patients proved not to be depressed or manic . They were less severely ill than untreated first episode schizophrenia but more severely ill than treated first episode schizophrenia . While not psychotically disabled , these patients nevertheless present with a clinical syndrome . Subsequent reports will detail the effects of drug versus placebo on prodromal symptoms , neuropsychological profile , and the rate of conversion to psychosis BACKGROUND : Childhood-onset schizophrenia is schizophrenia with onset prior to the age of 13 years . Although it is rare , people who suffer from schizophrenia at an early age appear to have a clinical ly severe form of the illness with poor long-term prognosis . Antipsychotic medication is one way of managing this rare but serious mental illness . OBJECTIVES : To examine the effects of antipsychotic medication for childhood-onset schizophrenia . SEARCH STRATEGY : We search ed the Cochrane Schizophrenia Group Trials Register ( November 2006 and February 2007 ) , inspected references of all identified studies for further trials and contacted relevant pharmaceutical companies and authors of trials for additional information . SELECTION CRITERIA : We included all r and omised clinical trials involving children and young people with a diagnosis of childhood onset schizophrenia ( i.e. with a diagnosis of schizophrenia before the age of 13 ) comparing any antipsychotic drug with another antipsychotic or placebo . DATA COLLECTION AND ANALYSIS : We reliably selected , quality assessed and extracted data from trials . We excluded data where more than 50 % of participants in any group were lost to follow up . For homogenous dichotomous data we calculated r and om effects , relative risk ( RR ) and its 95 % confidence interval ( CI ) and , where appropriate , number needed to treat ( NNT ) on an intention-to-treat basis . For normal continuous data we calculated the weighted mean difference ( WMD ) . MAIN RESULTS : From a total of 2062 citations , we identified six relevant trials . We categorised trials into three comparisons : atypical versus typical , atypical versus atypical and typical versus typical antipsychotic drugs . The only comparison to find any differences between treatment groups was atypical versus typical antipsychotic drugs . A few results from one study favoured the atypical antipsychotic clozapine over haloperidol in treating treatment resistant childhood-onset schizophrenia ( n=21 , WMD CGAS 17.00 CI 7.74 to 26.26 ; n=21 , WMD Bunney-Hamburg Psychosis Rating Scale -3.60 CI -6.64 to -0.56 ) . Participants on clozapine , however , were three times more likely to have drowsiness ( 1 RCT , n=21 , RR 3.30 CI 1.23 to 8.85 , NNH 2 CI 2 to 17 ) and half of the children receiving clozapine had neutropenia ( 1 RCT , n=21 , RR 12 , CI 0.75 to 192.86 ) . AUTHORS ' CONCLUSIONS : There are few relevant trials and , presently , there is little conclusive evidence regarding the effects of antipsychotic medication for those with early onset schizophrenia . Some benefits were identified in using the atypical antipsychotic clozapine compared with haloperidol but the benefits were offset by an increased risk of serious adverse effects . Larger , more robust , trials are required OBJECTIVE This study characterizes the tolerability of ziprasidone in children and adolescents with bipolar mania , schizophrenia , or schizoaffective disorder . METHOD Sixty-three subjects ( aged 10 - 17 years ) entered an open-label study consisting of a 3-week fixed-dose period ( Period 1 ) and a subsequent 24-week flexible-dose period ( Period 2 ) . In Period 1 , subjects received ziprasidone 80 or 160 mg/d in two divided doses , titrated over 10 days . In Period 2 , subjects received flexible doses ( 20 - 160 mg/d ) . Tolerability was evaluated using movement rating scales , laboratory tests , and electrocardiograms . Clinical response was assessed using the Young Mania Rating Scale , the Brief Psychiatric Rating Scale-Anchored Version , and the Clinical Global Impressions-Severity scale . RESULTS Adverse events ( AEs ) occurred mostly during dose titration and in the high-dose ( 160 mg/d ) group . The most common AEs during Period 1 were sedation ( 32 % ) , somnolence ( 30 % ) , and nausea ( 25 % ) and during Period 2 were sedation ( 30 % ) , somnolence ( 30 % ) , and headache ( 25 % ) . The incidence of movement disorder AEs was 22 % and 16 % during Periods 1 and 2 , respectively . Six percent of study participants discontinued study participation due to AEs during Period 1 and 20 % discontinued in Period 2 . Thirty-three percent of subjects gained > or=7 % of their baseline weight . No Fridericia-corrected QT ( QTcF ) intervals of > 450 ms were observed during Period 1 and only one occurred during Period 2 . No QTcF increase > or=60 ms from baseline was observed . Symptom reductions were observed in all patient groups . CONCLUSIONS No unexpected tolerability findings were observed in this prospect i ve trial of ziprasidone in children and adolescents with bipolar mania , schizophrenia , or schizoaffective disorder . On the basis of the results , a starting dose of 20 mg/d titrated to between 80 and 160 mg/d over 1 - 2 weeks appears optimal for most patients Quetiapine is a novel , atypical antipsychotic agent that has been shown to provide long-term efficacy without serious adverse effects in adults . This is the first study of the extended use of quetiapine in adolescents . Five boys and 5 girls , ages 12.3 to 15.9 years , with diagnoses of schizoaffective disorder ( n = 7 ) or bipolar disorder with psychotic features ( n = 3 ) were eligible for entry into this single-site , 88-week , open-label trial . Subjects had completed a pharmacokinetic study over 23 days , during which the dosage of quetiapine was increased sequentially from 25 mg bid to a maximum of 400 mg bid ( 800 mg/day ) ( McConville et al. 2000 ) . In the open-label extension of this trial , which followed directly after this trial , a physician 's choice design allowed for flexible dose titration of quetiapine by the study physician to an optimal dose for each patient , with ending doses ranging from 300 mg/day to 800 mg/day . Concomitant medications , especially for anxiety and /or manic symptoms , were allowed as deemed necessary . Tolerability and safety were assessed using clinical laboratory tests , physical examinations , measurements of vital signs , interviews for selective symptomatology , and electrocardiograms . Psychiatric measurements included the 18-item Brief Psychiatric Rating Scale ( BPRS ) , the Clinical Global Impression ( CGI ) scale , and the modified Scale for the Assessment of Negative Symptoms ( SANS ) . Neurologic symptom ratings included the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale . Mean BPRS , CGI , and SANS scores improved significantly during the trial ( p < 0.05 ) . No extrapyramidal symptoms or evidence of tardive dyskinesia was seen . Clinical ly , there was a nonsignificant increase in mean weight and body mass index at week 64 . This long-term study suggests that quetiapine is a well-tolerated antipsychotic agent that is efficacious for the treatment of symptoms of selected psychotic disorders in adolescents We acquired Positron emission tomography with 18-F-deoxyglucose ( FDG-PET ) and anatomical MRI in 30 never-previously medicated psychotic adolescents ( ages 13 - 20 ) .  ( FDG-PET ) was obtained at baseline and after 8 - 9 weeks of a r and omized double-blind trial of either olanzapine or haloperidol .  Neuropsychological tests of executive function were also obtained . Patients carried out the  serial verbal learning task , a modification of the California Verbal Learning Test , during the uptake of the FDG . PET scans were coregistered with spoiled gradient MRI ( TR=24 , TE=5 , flip angle 40 degrees , slice thickness 1.2 mm , field of view 230 mm ) for accurate anatomical identification of regions of interest traced on the MRI . Twenty-two of the thirty patients completed the second PET and clinical evaluation . Individuals treated with olanzapine  increased relative metabolic rates in the frontal lobe more than the occipital lobe while patients treated with haloperidol failed to increase frontal metabolic rates and did not show an anteroposterior gradient in medication response .  Haloperidol  increased striatal metabolic rate more than olanzapine . Both drugs increased thalamic metabolic rates and this increase was significantly larger in younger ( age 13 - 15 ) than older ( 16 - 21 ) patients OBJECTIVE To review the response of 11 adolescents with childhood-onset schizophrenia to a 6-week open clozapine trial . METHOD Eleven children meeting DSM-III-R criteria for schizophrenia had a 6-week open trial of clozapine ( mean sixth week daily dose 370 mg ) . Behavioral ratings included the Brief Psychiatric Rating Scale and Children 's Global Assessment Scale . RESULTS More than half showed marked improvement in Brief Psychiatric Rating Scale ratings by 6 weeks of clozapine therapy compared to admission drug rating and compared to a systematic 6-week trial of haloperidol . CONCLUSIONS This open trial indicates that clozapine may be a promising treatment for children and adolescents with schizophrenia who do not respond well to typical neuroleptics . A double-blind placebo-controlled study is ongoing BACKGROUND The prodromal phase of schizophrenic disorders has been described prospect ively . The present study aim ed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo . METHODS This was a double-blind , r and omized , parallel-groups , placebo-controlled trial with fixed-flexible dosing conducted at four sites . Sixty patients met prodromal diagnostic criteria , including attenuated psychotic symptoms , as determined by structured interviews .  Olanzapine 5 - 15 mg daily or placebo was prescribed for 8 weeks . RESULTS In the mixed-effects , repeated- measures analysis , the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant , and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8 . Ratings of extrapyramidal symptoms remained low in each group and were not significantly different .  Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients ( p<.001 ) . CONCLUSIONS This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients . Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo . Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment Twenty to fifty percent of people with a diagnosis of schizophrenia continue to hear voices despite taking neuroleptic medication . Trials of group cognitive behavioral therapy for adults with auditory hallucinations  have shown promising results . Auditory hallucinations may be most amenable to psychological intervention during a 3-year critical period after symptom onset . This study evaluates the effectiveness of group cognitive behavioral therapy ( CBT ) for young people with recent-onset auditory hallucinations ( N = 22 ) , using a waiting list control . Outcome measures were administered at four separate time points . Significant reductions in auditory hallucinations occurred over the total treatment phase , but not over the waiting period . Further investigations in the form of r and omized controlled trials are warranted 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 Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia . METHOD Eleven patients ( 9 boys , 2 girls ; mean age = 14.1 + /- 2.1 years ) received a 6-week blinded or open trial of clozapine . Five patients also received 6 weeks of blinded or open haloperidol . Doses were increased on an individual basis to a mean 6-week dose of 5.99 + /- 2.6 mg/kg/day for clozapine and 0.24 + /- 0.20 mg/kg/day for haloperidol . The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject . Weekly blood sample s were obtained during therapy and assayed by high performance liquid chromatography . RESULTS The mean  clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6  haloperidol level was 23.0 ng/mL ( range , 6.2 - 44.3 ng/mL ) . The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77 % and 18 % , respectively , of those of the parent compound . The mean ratio of haloperidol/reduced haloperidol  was 4.48 ( range , 0.76 - 8.76 ) .  Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients ( correlation range , 0.26 - 0.96 ) . Conversely , poor and inconsistent correlations between  haloperidol concentrations and clinical effects were observed . No relationships were noted between  clozapine or haloperidol dose and clinical effects . CONCLUSION Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults . Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement BACKGROUND A recent review suggested an association between using unpublished scales in clinical trials and finding significant results . AIMS To determine whether such an association existed in schizophrenia trials . METHOD Three hundred trials were r and omly selected from the Cochrane Schizophrenia Group 's Register . All comparisons between treatment groups and control groups using rating scales  were identified . The publication status of each scale was determined and cl aims of a significant treatment effect were recorded . RESULTS Trials were more likely to report that a treatment was superior to control when an unpublished scale was used to make the comparison ( relative risk 1.37 ( 95 % CI 1.12 - 1.68 ) ) . This effect increased when a ' gold-st and ard ' definition of treatment superiority was applied ( RR 1.94 ( 95 % CI 1.35 - 2.79 ) ) . In non-pharmacological trials , one-third of ' gold-st and ard ' cl aims of treatment superiority would not have been made if published scales had been used . CONCLUSIONS Unpublished scales are a source of bias in schizophrenia trials OBJECTIVE Aripiprazole is a dopamine partial agonist approved for use in adults for short- and long-term treatment of schizophrenia and bipolar disorder . This study was design ed to examine the acute efficacy , safety , and tolerability of aripiprazole for adolescents with schizophrenia . METHOD This was a 6-week multicenter , double-blind , r and omized , placebo-controlled trial . Subjects 13 to 17 years old with a DSM-IV diagnosis of schizophrenia and a Positive and Negative Syndrome Scale ( PANSS ) total score of 70 or more were r and omly assigned ( 1:1:1 ratio ) to placebo or 10 or 30 mg/day of aripiprazole . The primary endpoint was mean change from baseline to endpoint ( last observation carried forward ) in PANSS total score . Assessment s of safety and tolerability included spontaneously reported adverse events , extrapyramidal symptom scores , serum prolactin concentration , body weight , and metabolic measures . RESULTS Of 302 patients , 85 % completed the 6-week study . The mean baseline PANSS score was 94.1 . At the end of the study , both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS total score . Adverse events occurring in more than 5 % of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder , somnolence , and tremor . Mean changes in prolactin were -8.45 , -11.93 , and -15.14 ng/ml for placebo and 10 mg and 30 mg of aripirazole , respectively . Mean body weight changes were -0.8 , 0.0 , and 0.2 kg for placebo and 10 mg and 30 mg of aripiprazole , respectively . CONCLUSION Both 10- and 30-mg/day doses of aripiprazole were superior to placebo in the acute treatment of adolescents with schizophrenia .  Aripiprazole was generally well tolerated BACKGROUND Schizophrenia with an onset in adolescence is known to be associated with a poorer outcome and cognitive difficulties . These impairments have an impact on quality of life and represent treatment targets . Cognitive remediation therapy ( CRT ) attempts to improve cognitive deficits by teaching information processing strategies through guided mental exercises . The objective of this study is to evaluate the efficacy of CRT in alleviating cognitive deficits compared to treatment as usual and explore the mediating and moderating effects of cognitive improvement . METHOD Single-blind r and omized controlled trial with two groups , one receiving CRT ( N21 ) and the other st and ard care ( N19 ) assessed at baseline , 3 months ( post therapy ) and follow-up ( 3 months post therapy ) . Participants were recruited from specialist inpatient and community mental health services and were young patients with recent onset schizophrenia ( average age of 18 ) and evidence of cognitive and social behavioural difficulties . The intervention was individual cognitive remediation therapy delivered over a period of 3 months with at least three sessions per week . The main outcome measures were cognition ( memory , cognitive flexibility and planning ) and secondary outcomes ( symptoms , social contacts and self-esteem ) . RESULTS Compared to st and ard care , CRT produced significant additional improvements in cognitive flexibility as measured by the Wisconsin Card Sort Test ( WCST ) . Therapy moderated the effects of improved planning ability on symptoms such that improvements only had a beneficial effect when they were achieved in the context of CRT .  Improvements in cognition in all domains had a direct effect on social functioning and improvements in WCST had a direct effect on overall symptom improvement . CONCLUSIONS Cognitive remediation therapy can contribute to the improvement in WCST even in adolescents . The changes in cognitive outcomes also contributed to improvements in functioning either directly or solely in the context of CRT . Evidence of the mediator and moderator effects of cognitive changes should lead to more effective therapy development The primary purpose of this study was to compare changes in cognition in early-onset psychosis after 6-months treatment with quetiapine or olanzapine . This is a r and omized , single-blind , 6-month study in 50 adolescents with a diagnosis of early-onset psychosis . Patients were r and omized to quetiapine ( n = 24 ) or olanzapine ( n = 26 ) . A thorough neuropsychological battery was administered at baseline and after 6-month treatment . Out of the total sample included in the study , 32 patients completed at least 6-months treatment with the assigned medication ( quetiapine , n = 16 ; olanzapine , n = 16 ) . No changes were observed in cognitive performance after 6-month treatment with quetiapine or olanzapine . Although some trends toward cognitive improvement were observed for the olanzapine group after 6-month treatment , neither group showed statistically significant gains . Furthermore , there was no evidence of any differential efficacy of  olanzapine  or quetiapine on cognitive improvement in this sample of adolescents with psychosis The objective of this study was to evaluate the efficacy and tolerability of quetiapine in the treatment of first onset psychosis in older adolescents using risperidone as a comparator . Twenty-two patients with first onset psychosis were r and omized to receive quetiapine ( up to 800 mg/day ) or risperidone ( up to 6 mg/day ) for 6 weeks . Raters blind to treatment assignment performed outcome symptom ratings . No statistical differences emerged in terms of efficacy or tolerability between the two drugs . However , there were some clinical ly notable differences that seem to favour the efficacy of risperidone over quetiapine . Patients taking quetiapine , although improved , showed less clinical improvement on scores for total positive and negative symptoms , clinical global severity and depression at 6 weeks than patients taking risperidone . Although both treatments were associated with weight gain and sedation , more patients on quetiapine experienced over 10 % weight gain . However , fewer patients who were taking quetiapine required anticholinergic medication or experienced extrapyramidal side effects than patients taking risperidone . Risperidone was significantly more likely to be associated with elevation in serum prolactin levels in this population . In conclusion , the results in this small trial show that adolescent patients may benefit more from treatment with risperidone than quetiapine . However , those susceptible to side effects , particularly hyperprolactinaemia , may be more suitable for treatment with quetiapine OBJECTIVE Atypical ( second-generation ) antipsychotics are considered st and ard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder . However , the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated . This study compared the efficacy and safety of two second-generation antipsychotics ( olanzapine and risperidone ) with a first-generation antipsychotic ( molindone ) in the treatment of early-onset schizophrenia and schizoaffective disorder . METHOD This double-blind multisite trial r and omly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine ( 2.5 - 20 mg/day ) , risperidone ( 0.5 - 6 mg/day ) , or molindone ( 10 - 140 mg/day , plus 1 mg/day of benztropine ) for 8 weeks . The primary outcome was response to treatment , defined as a Clinical Global Impression ( CGI ) improvement score of 1 or 2 and > or=20 % reduction in Positive and Negative Syndrome Scale ( PANSS ) total score after 8 weeks of treatment . RESULTS In total , 119 youth were r and omly assigned to treatment . Of these subjects , 116 received at least one dose of treatment and thus were available for analysis . No significant differences were found among treatment groups in response rates  ( molindone : 50 % ; olanzapine : 34 % ; risperidone : 46 % ) or magnitude of symptom reduction . Olanzapine and risperidone were associated with significantly greater weight gain . Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol , low density lipoprotein , insulin , and liver transaminase levels . Molindone led to more self-reports of akathisia . CONCLUSIONS Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder . Adverse effects were frequent but differed among medications . The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder . The safety findings related to weight gain and metabolic problems raise important public health concerns , given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders
target: No convincing evidence suggests that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis .
  However , atypical antipsychotic medications may be more acceptable to young people because fewer symptomatic adverse effects are seen in the short term .
  Little evidence is available to support the superiority of one atypical antipsychotic medication over another , but side effect profiles are different for different medications .
  Treatment with olanzapine , risperidone and clozapine is often associated with weight gain .
  Aripiprazole is not associated with increased prolactin or with dyslipidaemia .
  Adolescents may respond better to st and ard-dose as opposed to lower-dose risperidone , but for aripiprazole and ziprasidone , lower doses may be equally effective .
background: BACKGROUND Schizophrenia often presents in adolescence , but current treatment guidelines are based largely on studies of adults with psychosis .
  Over the past decade , the number of studies on treatment of adolescent-onset psychosis has increased .
  The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis .
  OBJECTIVES To investigate the effects of atypical antipsychotic medications in adolescents with psychosis .
  We review ed in separate analyses various comparisons of atypical antipsychotic medications with placebo or a typical antipsychotic medication or another atypical antipsychotic medication or the same atypical antipsychotic medication but at a lower dose .