Evidence-based recommendations for monitoring safety of second-generation antipsychotics in children and youth. Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. TNF-α −308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics. Effectiveness of second-generation antipsychotics with acute-phase schizophrenia Cognitive Improvement in Schizophrenic Patients does not Require a Serotonergic Mechanism: Randomized Controlled Trial of Olanzapine vs Amisulpride Antipsychotic switching: results from a one-year prospective, observational study of patients with schizophrenia Second Generation Antipsychotics Improve Sexual Dysfunction in Schizophrenia: A Randomised Controlled Trial A randomized, double-blind, placebo-controlled study of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder. Cerebral Cortical Gray Expansion Associated with Two Second-Generation Antipsychotics
BACKGROUND The use of antipsychotics , especially second-generation antipsychotics ( SGAs ) , for children with mental health disorders in Canada has increased dramatically over the past five years . These medications have the potential to cause major metabolic and neurological complications with chronic use . OBJECTIVE To synthesize the evidence for specific metabolic and neurological side effects associated with the use of SGAs in children , and provide evidence -based recommendations for the monitoring of these side effects . METHODS A systematic review of controlled clinical trials of SGAs involving children was performed . Recommendations for monitoring SGA safety were made according to a classification scheme based on the GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) system . When there was inadequate evidence , recommendations were based on consensus and expert opinion . A multidisciplinary consensus group review ed all relevant evidence and reached consensus on the recommendations . RESULTS The present guidelines provide evidence -based recommendations for monitoring SGA safety . The strength of recommendations for specific physical examination manoeuvres and laboratory tests are provided for each SGA medication at specific time points . CONCLUSION Multiple r and omized controlled trials evaluated the efficacy of many of the SGAs in paediatric mental health disorders . These benefits , however , are not without risks - both metabolic and neurological side effects occur in children treated with SGAs . The risk of weight gain , increased body mass index and abnormal lipid levels is greatest with olanzapine , followed by clozapine and quetiapine . The risk of neurological side effects of the treatment is greatest with risperidone , olanzapine and aripiprazole . Appropriate monitoring procedures for adverse effects will improve the quality of care of children treated with these medications Until relatively recently , long-acting injectable ( LAI ) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics ( SGA ) increased . Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice , this is not seen in recent r and omized clinical trials . PROACTIVE ( Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy ) relapse prevention study incorporated efficacy and effectiveness features . At 8 US academic centers , 305 patients with schizophrenia or schizoaffective disorder were r and omly assigned to LAI risperidone ( LAI-R ) or physician 's choice oral SGAs . Patients were evaluated during the 30-month study by masked , central ized assessors using 2-way video , and monitored biweekly by on-site clinicians and assessors who knew treatment assignment . Relapse was evaluated by a masked Relapse Monitoring Board . Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant . Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group . In contrast , the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores . There were no other between-group differences in symptoms or functional improvement . Despite the advantage for psychotic symptoms , LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization . Biweekly monitoring , not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm , may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials CONTEXT Second-generation ( atypical ) antipsychotics ( SGAs ) are more expensive than first-generation ( typical ) antipsychotics ( FGAs ) but are perceived to be more effective , with fewer adverse effects , and preferable to patients . Most evidence comes from short-term efficacy trials of symptoms . OBJECTIVE To test the hypothesis that in people with schizophrenia requiring a change in treatment , SGAs other than clozapine are associated with improved quality of life across 1 year compared with FGAs . DESIGN A noncommercially funded , pragmatic , multisite , r and omized controlled trial of antipsychotic drug classes , with blind assessment s at 12 , 26 , and 56 weeks using intention-to-treat analysis . SETTING Fourteen community psychiatric services in the English National Health Service . PARTICIPANTS Two hundred twenty-seven people aged 18 to 65 years with DSM-IV schizophrenia and related disorders assessed for medication review because of inadequate response or adverse effects . INTERVENTIONS R and omized prescription of either FGAs or SGAs ( other than clozapine ) , with the choice of individual drug made by the managing psychiatrist . MAIN OUTCOME MEASURES Quality of Life Scale scores , symptoms , adverse effects , participant satisfaction , and costs of care . RESULTS The primary hypothesis of significant improvement in Quality of Life Scale scores during the year after commencement of SGAs vs FGAs was excluded . Participants in the FGA arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores . Participants reported no clear preference for either drug group ; costs were similar . CONCLUSIONS In people with schizophrenia whose medication is changed for clinical reasons , there is no disadvantage across 1 year in terms of quality of life , symptoms , or associated costs of care in using FGAs rather than nonclozapine SGAs . Neither inadequate power nor patterns of drug discontinuation accounted for the result There is good evidence that clozapine is more efficacious than first-generation antipsychotic drugs in resistant schizophrenia .  It is less clear if clozapine is more effective than the other second-generation antipsychotic ( SGA ) drugs . A noncommercially funded , pragmatic , open , multisite , r and omized controlled trial was conducted in the United Kingdom National Health Service ( NHS ) . Participants were 136 people aged 18 - 65 with DSM-IV schizophrenia and related disorders whose medication was being changed because of poor clinical response to 2 or more previous antipsychotic drugs . Participants were r and omly allocated to clozapine or to one of the class of other SGA drugs ( risperidone , olanzapine , quetiapine , amisulpride ) as selected by the managing clinician . Outcomes were assessed blind to treatment allocation . One-year assessment s were carried out in 87 % of the sample . The intent to treat comparison showed no statistically significant advantage for commencing clozapine in Quality of Life score ( 3.63 points ; CI : 0.46 - 7.71 ; p = .08 ) but did show an advantage in Positive and Negative Syndrome Scale ( PANSS ) total score that was statistically significant ( -4.93 points ; CI : -8.82 to -1.05 ; p = .013 ) during follow-up . Clozapine showed a trend toward having fewer total extrapyramidal side effects . At 12 weeks participants who were receiving clozapine reported that their mental health was significantly better compared with those receiving other SGA drugs . In conclusion , in people with schizophrenia with poor treatment response to 2 or more antipsychotic drugs , there is an advantage to commencing clozapine rather than other SGA drugs in terms of symptom improvement over 1 year Atypical or second-generation antipsychotics ( SGAs ) are associated with excessive body weight gain ( BWG ) and other components of metabolic syndrome . Among all SGAs , clozapine and olanzapine are known to cause the most significant weight gain , followed by risperidone and quetiapine . The genetic variant of tumor necrosis factor α ( TNF-α ) , -308 G > A polymorphism ( rs1800629 ) , has been implicated in clozapine-induced BWG in several studies . We hypothesized that TNF-α -308 G > A polymorphism has a general effect on SGA-induced BWG . The present study was conducted to examine the association between TNF-α -308 G > A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics ( SGAs ) . A total of 500 patients with schizophrenia treated with clozapine ( n=275 ) , olanzapine ( n=79 ) or risperidone ( n=146 ) for an average of 49.9 months were recruited . Subjects with an increase in weight of more than 7 % from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG . The association between TNF-α -308 G > A polymorphism and BWG was studied , and the effect of non-genetic factors such as baseline BMI , SGA treatment duration and SGA type on the association was controlled by logistic regression . The results revealed that there was no significant association between BWG and TNF-α -308 G > A polymorphism ( GG/GA/AA or GG/GA+AA ) in each separate SGA group or collectively . These findings suggest that TNF-α -308 G > A polymorphism does not play a major role in SGA-induced weight gain OBJECTIVE Second-generation antipsychotic ( SGA ) effects in youth were monitored to quantify extrapyramidal side effects ( EPS ) and to identify risk profiles for treatment-emergent EPS . METHOD Data were analyzed for the nonr and omized , prospect i ve Second-generation Antipsychotic Treatment Indications , Effectiveness and Tolerability in Youth ( SATIETY ) inception cohort study . EPS were assessed at baseline and 4 , 8 , and 12 weeks after naturalistic SGA initiation for schizophrenia , mood , disruptive behavior , and autism spectrum disorders using the Simpson-Angus Scale ( SAS ) , Barnes Akathisia Scale , Abnormal Involuntary Movement Scale ( AIMS ) , and Treatment Emergent Side Effect Scale . Drug-induced parkinsonism was defined by incident mean SAS score > 0.33 , anticholinergic initiation , or increasing total SAS score ≥2 in patients with baseline EPS . RESULTS In 342 youth aged 13.6 ± 3.5 years ( male = 58.2 % , antipsychotic-naive = 65.8 % ) , 15.2 % developed drug-induced parkinsonism .  Raw SGA-grouped drug-induced parkinsonism rates were as follows : quetiapine = 1.5 % , olanzapine = 13.8 % , risperidone = 16.1 % , ziprasidone = 20.0 % , and aripiprazole = 27.3 % . SGA type , dose , higher age , and lower baseline functioning were jointly associated with drug-induced parkinsonism ( R(2 ) = 0.18 ; p < .0001 ) . Controlling for these factors , drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine . Subjectively reported EPS ( 5 % ) , EPS-related treatment discontinuation ( 3.3 % ) , and anticholinergic initiation ( 3 % ) were infrequent . Anticholinergic initiation was most frequent with risperidone ( 10.2 % ; p = .0004 ) . Treatment-emergent dyskinesia ranged from 4.5 % ( aripiprazole ) to 15.5 % ( olanzapine ) . SGA type , younger age , white race/ethnicity , and baseline AIMS were jointly associated with treatment-emergent dyskinesia ( R(2 ) = 0.31 ; p < .0001 ) . Controlling for these factors , treatment-emergent dyskinesia rates differed among SGA subgroups , with higher rates with olanzapine and ziprasidone . At baseline , psychostimulant use was associated with dyskinesia , and number of psychotropic comedications was associated with subjective EPS . CONCLUSION In youth , SGA-related EPS rates did not generally exceed those reported in adults , with particularly low rates with quetiapine and olanzapine PURPOSE Although olanzapine may have advantages over other second-generation antipsychotics ( SGAs ) regarding longer time to treatment discontinuation among chronically ill patients , little evidence has been provided for the comparative effectiveness of SGAs in the acute phase . We aim ed to determine if any of four SGAs were more effective in treating newly admitted acute schizophrenic patients . We performed a rater-blinded , r and omized controlled trial of four SGAs in 15 psychiatric emergency sites . Eligible patients were 18 - 64 years old and met diagnostic criteria for schizophrenia , acute schizophrenia-like psychotic disorder , or schizoaffective disorder . A final total of 78 patients were r and omly assigned by means of sealed envelopes to receive risperidone ( 3 - 12 mg/day ; n=20 ) , olanzapine ( 10 - 20 mg/day ; n=17 ) , quetiapine ( 300 - 750 mg/day ; n=20 ) , or aripiprazole ( 12 - 30 mg/day ; n=21 ) , with follow-up at 8 weeks . The primary outcome measure was all-cause treatment discontinuation . RESULTS Overall , 37 % ( 29/78 ) of patients discontinued the study medication before 8 weeks : 25 % for risperidone ; 12 % for olanzapine ; 55 % for quetiapine ; and 52 % for aripiprazole .  Time to treatment discontinuation for any cause was significantly longer in the olanzapine group than in the quetiapine ( p=0.006 ) or aripiprazole ( p=0.008 ) groups , but not compared to the risperidone group ( p=0.32 ) . Time to treatment discontinuation was significantly longer in the risperidone group than in the quetiapine group ( p=0.048 ) , but not compared to the aripiprazole group ( p=0.062 ) . However , the rate of p.r.n . intramuscular haloperidol use was significantly higher in the aripiprazole group than in other groups ( p=0.029 ) . CONCLUSION Olanzapine and risperidone are superior to quetiapine and aripiprazole for the acute treatment of psychosis in hospitalized patients Combined serotonin-2A ( 5-HT2A ) and dopamine-2 ( D2 ) receptor blockade has been proposed as a c and i date mechanism by which second-generation antipsychotics ( SGAs ) improve both cognition and negative symptoms in schizophrenic patients , in contrast to antipsychotics of the first generation . The SGA amisulpride , however , only binds to D2/D3 receptors , which makes it an interesting tool to test this assumption . In a r and omized controlled trial , 52 schizophrenic patients were allocated to treatment with either olanzapine ( 10–20 mg/day ) or amisulpride ( 400–800 mg/day ) . A comprehensive neuropsychological test battery and clinical ratings were used to assess participants at inclusion and after 4 and 8 weeks . Cognitive improvements of moderate size were observed , with effect sizes similar to those obtained in previous studies on the cognitive effects of SGAs . Importantly , amisulpride was not inferior to olanzapine for any cognitive domain . Combined 5-HT2A/D2 receptor blockade is probably not necessary for cognitive improvement by SGAs ABSTRACT Objective : The Health Outcomes of a Canadian Community Cohort ( HOCCC ) study is a 1-year prospect i ve observational study of out patients with schizophrenia or related psychotic disorders . The purpose of the study was to compare effectiveness of antipsychotic treatment as measured by 1-year treatment completion rates . Design and methods : Patients ( N = 929 ) were enrolled if in the course of usual clinical practice they switched to a second-generation antipsychotic ( SGA ) . Observational data were collected for up to 1 year . The primary analysis compared 1-year treatment-completion rates for the olanzapine cohort with the other SGA cohort ( quetiapine , risperidone , clozapine ) , using a chi-squared test . Results : Of 929 patients enrolled , 64.8 % ( 516/796 ) of evaluable patients completed 1 year of treatment . There was no statistically significant difference in the proportion of treatment completers between the olanzapine cohort ( 67.4 % , 256/380 ) and the other SGA cohort ( 62.5 % , 260/416 ) . Treatment-completion rates were risperidone 62.0 % ( 127/205 ) , quetiapine 63.7 % ( 123/193 ) and clozapine 55.6 % ( 10/18 ) . Antipsychotic polypharmacy was common . Patients treated with olanzapine or risperidone had significantly higher increases in BMI than quetiapine-treated patients . There were no major differences between olanzapine monotherapy and pooled other SGA monotherapy groups in status of extrapyramidal symptoms from baseline to endpoint . Conclusions : Olanzapine and other SGAs exhibited similar rates of 1-year treatment completion . Further study of medication combinations is needed , given their perceived clinical value , and the high frequency of antipsychotic polypharmacy in clinical practice . Limitations : As most patients received several psychotropics and power was reduced in monotherapy analyses , comparisons between cohorts must be interpreted cautiously . Comparisons between individual antipsychotics were post hoc and not powered a priori . Accuracy and completeness of adverse event information for drugs other than olanzapine is limited The impact of antipsychotic drug treatment on sexual function was investigated during a r and omised trial comparing first generation antipsychotics ( FGAs ) to ( nonclozapine ) second generation antipsychotics ( SGAs ) .  Sexual function and quality of life were ( rater-blind ) assessed in 42 patients with DSM-IV schizophrenia ( aged 18–65 ) using the self-report version of the Derogatis Interview for Sexual Function ( DISF-SR ) and the Heinrichs Quality of Life Scale ( QLS ) , prior to , and 12 weeks following , a change in medication from an FGA drug to either an FGA or SGA drug . SGAs significantly improved sexual function compared to FGAs . Change in sexual function was associated with change in quality of life . Where impaired sexual functioning is a distressing adverse effect of treatment with an FGA agent , consideration should be given to switching to an SGA OBJECTIVE Bipolar disorder often co-occurs with anxiety disorders . Evidence suggests that second-generation antipsychotics ( SGAs ) may be useful in treating both conditions . This study examined the efficacy of ziprasidone in the treatment of these disorders . METHOD This 3-site , r and omized , double-blind , placebo-controlled , parallel group , 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder ( with or without agoraphobia ) or generalized anxiety disorder ( GAD ) experiencing moderately severe anxiety symptoms at entrance into the study . Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria . Patients were screened and r and omized from June 25 , 2010 , through August 23 , 2011 . Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale ( CGI-21 Anxiety ) and the Sheehan Disability Scale ( SDS ) , with secondary measures monitoring anxiety and mood symptoms . RESULTS Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety ( F1 = 0.34 ; P = .564 ) or SDS ( F1 = 0.26 ; P = .611 ) . Secondary analysis using hierarchical linear modeling found similar results ( CGI-21 Anxiety : F1 = 1.82 ; P = .178 ; and SDS : F1 = 0.70 ; P = .408 ) . Regardless of group , time in the study was associated with significant decrease in anxiety ( F1 = 11.08 ; P = .001 ) and total disability ( F1 = 26.16 ; P < .001 ) . Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement , and 81.8 % ( n = 9 ) of the subjects who withdrew from the study due to adverse events , serious adverse events , or side effects were in the ziprasidone group . CONCLUSIONS Results suggest that ziprasidone monotherapy was not associated with a clinical ly significant improvement in anxiety symptoms or improved function for patients with bipolar disorder , lifetime panic disorder or GAD , and concurrent moderately severe anxiety symptoms , and it was associated with a more negative side-effect profile relative to placebo . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01172652 BACKGROUND Second-generation antipsychotics ( SGAs ) differ from first-generation antipsychotics ( FGAs ) with respect to induction of less extrapyramidal morbidity , partially reducing negative symptoms , and causing modest improvement in neurocognitive functioning in patients with schizophrenia . SGAs demonstrate 5-HT2a antagonism . Differential effects of SGAs and FGAs on cortical gray volumes are explored herein . METHODS Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs ( risperidone and ziprasidone ; n = 13 ) or a FGA ( haloperidol ; n = 6 ) . Seven ( untreated ) control subjects were also assessed at a similar interval . RESULTS During treatment with the SGAs risperidone and ziprasidone , cerebral cortical gray of 13 patients with schizophrenia exp and ed 20.6 + /- 11.4 cc ( p < .0005 ) . Six patients receiving the FGA haloperidol , as well as 7 control subjects , showed no change in cortical gray volumes ( p = .983 and p = .932 , respectively ) at the time of re assessment . CONCLUSIONS Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone , but not with the FGA haloperidol . Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment
Overall , a general lack of efficacy of SGAs on panic symptoms was observed .
Except for ziprasidone , SGAs were well tolerated in these short-term trials
A role for second-generation antipsychotics ( SGAs ) in the treatment of  panic disorders ( PD ) has been proposed , but the actual usefulness of SGAs in this disorder is unclear .