Different Effects of Typical and Atypical Antipsychotics on Grey Matter in First Episode Psychosis: the ÆSOP Study Effectiveness of atypical antipsychotic medications in reducing violent behavior among persons with schizophrenia in community-based treatment. The impact upon extra‐pyramidal side effects, clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia Antipsychotic Drug Use and Mortality in Older Adults with Dementia Atypical (second generation) antipsychotic treatment response in very late-onset schizophrenia-like psychosis. Treatment adherence associated with conventional and atypical antipsychotics in a large state Medicaid program. Paediatric Atypical Antipsychotic Monitoring Safety (PAMS) Study Prescribing for inpatients with schizophrenia: an international multi-center comparative study. Effectiveness of maintenance treatments with atypical and typical antipsychotics in stable schizophrenia with early stage: 1-year naturalistic study Differences of satisfaction with medication between patients with schizophrenia treated with typical antipsychotics and atypical antipsychotics. Effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment. Medical-claims databases in the design of a health-outcomes comparison of quetiapine (`Seroquel') and usual-care antipsychotic medication Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine. Comparison of longer-term safety and effectiveness of 4 atypical antipsychotics in patients over age 40: a trial using equipoise-stratified randomization. Time to discontinuation of atypical versus typical antipsychotics in the naturalistic treatment of schizophrenia Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder.
Typical antipsychotic drugs act on the dopaminergic system , blocking the dopamine type 2 ( D2 ) receptors . Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors , and a high degree of occupancy of the serotoninergic receptors 5-HT2A . Whether these different pharmacological actions produce different effects on brain structure remains unclear . We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based , nonr and omized sample of patients at the first psychotic episode . Subjects were recruited as part of a large epidemiological study ( ÆSOP : aetiology and ethnicity in schizophrenia and other psychoses ) . We evaluated 22 drug-free patients , 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics .  We used high-resolution MRI and voxel-based methods of image analysis . The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes . However , typicals seem to affect more extensively the basal ganglia ( enlargement of the putamen ) and cortical areas ( reductions of lobulus para central is , anterior cingulate gyrus , superior and medial frontal gyri , superior and middle temporal gyri , insula , and precuneus ) , while atypical antipsychotics seem particularly associated with enlargement of the thalami . These changes are likely to reflect the effect of antipsychotics on the brain , as there were no differences in duration of illness , total symptoms scores , and length of treatment among the groups . In conclusion , we would like to suggest that even after short-term treatment , typical and atypical antipsychotics may affect brain structure differently This study prospect ively compared the effectiveness of atypical antipsychotic medications to that of conventional neuroleptics in reducing violent behavior  among patients with schizophrenia under " usual care " conditions in the community . Participants ( n = 229 ) were adults with schizophrenia spectrum disorders receiving inpatient or outpatient services in public sector mental health systems in North Carolina . Subjects were followed for 2 years in an observational study using multiple methods of data collection at 6-month intervals to assess treatment , sociodemographic characteristics , clinical features , and violence outcomes . Treatment with atypical antipsychotic medications ( clozapine , risperidone , or olanzapine ) was found to significantly reduce the risk of violent behavior , whereas treatment with conventional neuroleptics did not have this same beneficial effect . A cumulative effect on reduced violence was attributable to consistent compliance with atypical antipsychotic medications over a 2-year period . Concurrent reductions in psychotic symptoms , substance abuse , and adverse medication side effects were found to mediate the association between adherence with atypicals and lower violence risk . Treatment with atypical antipsychotic medications should be considered as an important component of violence risk management for schizophrenia patients at risk for violent behavior Atypical antipsychotics are commonly used in the management of schizophrenia in late life with evidence suggesting they induce lower rates of motor disturbance , but have similar efficacy to conventional antipsychotics . Trials in the elderly have been either retrospective , small , of short duration or of a single‐arm design Context Recent reports suggest that antipsychotics are associated with increased risk for death in patients with dementia . Contribution This large , population -based study from Canada assessed the risk for death after dispensation of antipsychotics in older adults with dementia . New use of antipsychotics compared with nonuse was associated with increased risk for death at 30 days . Conventional agents were associated with higher risks than were atypical agents . Caution Sensitivity analyses showed that unmeasured confounders might diminish or erase observed associations . Implication Both conventional and atypical antipsychotics may be associated with an increased risk for death in elderly persons with dementia . The Editors Various challenging behavioral and psychological symptoms commonly develop in older adults with dementia and predispose them and their caregivers to poor outcomes ( 1 ) . Nonpharmacologic strategies are recommended as first-line management for these symptoms ( 2 ) , but they may be difficult to implement in clinical practice ( 3 ) . For many reasons , antipsychotic medications are routinely prescribed in this setting ( 4 , 5 ) . Conventional antipsychotics , such as haloperidol , have been available since the 1950s . Meta-analyses of clinical trials evaluating conventional antipsychotics to treat agitation in dementia show that these agents have modest efficacy and important adverse effects compared with placebo ( 6 , 7 ) . In the past decade , use of newer atypical antipsychotics has been rapidly increasing in clinical practice because these agents were thought to produce fewer adverse effects than conventional agents ( 2 ) . A Canadian study found that the prevalence of antipsychotic use in older adults increased from 2.2 % in 1993 to 3.0 % at the end of 2002 . In that study , atypical antipsychotics , which were unavailable in 1993 , accounted for 82.5 % of all antipsychotics dispensed in 2002 ( 8) . Short-term r and omized , controlled trials ( RCTs ) have studied the role of atypical antipsychotics in the management of behavioral and psychological symptoms of dementia ( 2 , 9 ) . An RCT involving 421 out patients with Alzheimer disease and psychosis , aggression , or agitation concluded that the adverse effects of these newer drugs offset their advantages ( 10 ) . As a result , improvements in behavioral symptoms with antipsychotic drug treatment do not necessarily lead to improvements in overall quality of life for patients or their caregivers ( 11 ) . In April 2005 , the U.S. Food and Drug Administration ( FDA ) issued a public health advisory that the use of atypical antipsychotics to treat elderly patients with dementia was associated with an increased risk for death compared with placebo ( 12 ) . In June 2005 , Health Canada issued a similar warning and additional data ( 13 ) . These warnings stem from review s of RCTs that involve the atypical agents risperidone , olanzapine , quetiapine , and aripiprazole . The mortality rate was approximately 1.6 to 1.7 times higher than with placebo and was greater with antipsychotics than with placebo in 15 of the 17 trials review ed by the U.S. FDA ( 12 ) . The warnings extend to all currently available atypical antipsychotics . Other publications have provided support for these warnings and have raised further safety concerns about older conventional antipsychotics ( 1416 ) . Important questions remain unanswered . Although RCTs provide the best evidence of treatment efficacy and harm , the individual RCTs in this case had low event rates . Reliable estimates of the mortality risk were generated only when data were combined by meta- analysis ( 14 ) . Furthermore , these RCTs were generally short in duration and could not provide information about the long-term effect of antipsychotics on mortality ( 14 , 17 ) . Finally , these trials provide estimates of harm primarily for atypical antipsychotics . Relatively few data are available on harms associated with older conventional antipsychotics . Studies suggest that important differences may exist in the safety profiles of conventional and atypical agents ( 15 , 16 , 18 , 19 ) . Using population -based data , we sought to determine the risk for all-cause mortality in older adults with dementia who received atypical antipsychotics , conventional antipsychotics , or no antipsychotic .  Because important baseline differences exist among these groups , we used propensity score matching to improve their comparability . We also evaluated the effect of duration of treatment with antipsychotics on the risk for death . Methods Data Sources Ontario is Canada 's most populous province . During our study , Ontario had a population of approximately 12 million people , of whom 1.4 million were 65 years of age or older . A universally funded health program covers nearly all physician services , medications , and hospital services for patients 65 years of age or older in Ontario . Information from 4 administrative health care data bases was linked to develop the study cohort : pharmacy records from the Ontario Drug Benefit program , hospitalization records from the Canadian Institute for Health Information Discharge Abstract Data base , physician billing information for inpatient and outpatient services from the Ontario Health Insurance Plan , and basic demographic information and vital statistics from the Registered Persons Data base . We used encrypted unique identifiers that are common among data bases to link anonymous information on demographic characteristics and health services utilization for patients in our study . Little basic information on patients is missing in these data bases . For example , the coding accuracy of drug cl aims in the Ontario Drug Benefit program data base is excellent , with an error rate of only 0.7 % ( 20 ) . The study was approved by the ethics review board of Sunnybrook and Women 's College Health Sciences Centre , Toronto , Ontario , Canada . Dementia Cohort We identified a cohort of all Ontario residents 66 years of age or older with a diagnosis of dementia ( in the Ontario Health Insurance Plan or Discharge Abstract Data base ) between 1 April 1997 and 31 March 2002 . To focus on antipsychotic drug treatment for behavioral and psychological symptoms of dementia , we excluded patients who had evidence of other psychotic disorders ( such as schizophrenia ) or were receiving palliative care services . To reduce the potential for selection bias , we studied only new users of antipsychotics and excluded those who had received antipsychotics in the year before cohort entry ( 21 ) . Exposure to Antipsychotics We identified new use of antipsychotics if any agent available through the Ontario Drug Benefit program was dispensed after cohort entry . Cohort entry ( that is , the index date ) was defined as the date of the first dispensed antipsychotic drug . Available atypical drugs included olanzapine , quetiapine , and risperidone , and available conventional drugs included chlorpromazine , flupenthixol , fluphenazine , haloperidol , loxapine , pericyazine , perphenazine , pimozide , thioridazine , and trifluoperazine . Clozapine was rarely used in Ontario during the study period , and we therefore excluded patients who were receiving this medication . Other atypical antipsychotics ( such as aripiprazole and ziprasidone ) are not licensed for use in Canada . We decided that exposure to an antipsychotic was discontinued ( and we censored follow-up ) if the patient did not refill his or her antipsychotic prescription within an interval composed of the days of drug supply plus a grace period of 20 % . For example , we censored follow-up for a patient who did not refill his or her 60-day antipsychotic prescription within 72 days . We also censored follow-up for patients who switched from atypical to conventional antipsychotics ( or vice versa ) . However , we continued follow-up for patients who switched from 1 atypical antipsychotic to another , because data suggest no statistically significant difference in the risk for death associated with individual drugs in this class ( 13 , 14 , 16 ) . We applied the same rules to conventional antipsychotics .  All-Cause Mortality The primary outcome was all-cause mortality , as recorded in the Registered Persons Data base ( for patients who were not hospitalized at the time of death ) or the Discharge Abstract Data base ( for patients who died while hospitalized ) . To assess the influence of the duration of antipsychotic exposure on the outcome , we evaluated the risk for death at 30 , 60 , 120 , and 180 days after the initial dispensing of antipsychotic medication . Cohort Matching We stratified the dementia cohort to support separate analyses among persons living in the community and those residing in long-term care at cohort entry . Studies have demonstrated that rates of antipsychotic prescribing are substantial among older adults newly admitted to long-term care facilities ( 4 ) . Furthermore , long-term care residents typically carry a greater burden of comorbid disease and are more vulnerable to adverse drug events than are their counterparts in the community ( 22 , 23 ) . Our first objective was to determine the risk for death among older adults with dementia who received atypical antipsychotics compared with those who were not exposed to any antipsychotic .  Because antipsychotic use was not r and omly assigned in the study cohorts , we addressed potential confounding and selection biases by developing a propensity score for antipsychotic use . We then applied this score to match users of atypical antipsychotics with nonusers in the dementia cohort . The rationale and methods underlying the use of a propensity score for a proposed causal exposure variable are described elsewhere ( 24 ) . Recent studies provide guidance on the selection of variables to include in the propensity score ( 25 , 26 ) . We developed a logistic regression model by using 42 covariates describing patient characteristics . Tables 1 and 2 list many of the characteristics included in the propensity score . After a structured and iterative assessment of the balance of measured covariates INTRODUCTION Symptom amelioration in older patients with very late onset schizophrenia-like psychosis ( VLOSLP ) is often difficult , with limited psychotropic response reports yielding variable findings . Information about atypical ( second generation ) antipsychotic use in this population is scant . METHODS A consecutive sample of geriatric psychiatry out patients and in patients with psychotic disorders were retrospectively identified over a 31-month period based on systematic information abstract ion from an electronic medical record ( e-record ) . After exclusion criteria were applied , 8/138 out patients and 13/362 in patients met inclusion criteria for VLOSLP and had been naturalistically treated with an atypical antipsychotic during hospitalization or nine months of outpatient care . M and atorily completed e-record st and ardized symptom severity response ratings were converted into positive treatment response thresholds . RESULTS 38 % of out patients and 77 % of in patients ( mean age = 76 years for both groups ; mean age of onset of psychosis = 70 years for out patients and 74 years for in patients ) met criteria for positive treatment response to an atypical antipsychotic ( either aripiprazole , olanzapine , quetiapine , or risperidone ) with sign/symptom amelioration , rather than eradication . CONCLUSIONS Various atypical antipsychotics at geriatric doses yielded a positive treatment response in nearly two-thirds of VLOSLP patients . Patients with less chronic , more severe symptoms responded at a higher rate . Prospect i ve , double-blind , placebo-controlled trials with representative subject sample s are needed to vali date these preliminary findings OBJECTIVES Rates of medication adherence over a one-year period were assessed among out patients with schizophrenia who initiated therapy with conventional or atypical antipsychotic agents .  METHODS Data were drawn from paid medical and pharmacy cl aims for a r and om sample of 10 percent of all California Medicaid ( " Medi-Cal " ) recipients . Out patients with schizophrenia who were aged 18 years or older and who initiated monotherapy with a conventional or atypical antipsychotic medication in the last quarter of 1997 were identified . The percentages of patients who discontinued antipsychotic therapy or who had a switch in medications over a one-year period were determined . The use of selected concomitant medications was also assessed . Data were analyzed by means of chi square tests and multivariate statistics that adjusted for demographic and clinical differences between medication groups . RESULTS A total of 298 patients who initiated therapy with a conventional ( N=93 ) or atypical ( N=205 ) antipsychotic medication were identified . The groups were similar in mean age ( about 42 years ) and gender distribution ( about 54 percent were male ) . Compared with patients who received conventional antipsychotics , those receiving atypical antipsychotics were significantly less likely to have a switch in medication and to use concomitant anticholinergic and anxiolytic medications . In each group , antipsychotic medication was available for about 60 percent of days over one year of follow-up . CONCLUSIONS Compared with the use of conventional antipsychotics , the use of atypical antipsychotic medications was associated with significantly less treatment switching and less use of concomitant medications . However , undertreatment , evidence d by a lack of prescription refills , occurred among patients taking both medication classes , which highlights the need for further research on nonadherence Abstract Background : In the UK , treatment with  antipsychotic medications  for children is usually initiated by specialists in secondary care . Recent studies have shown an increase in the prescribing of atypical antipsychotics in children . The severity of possible adverse effects to antipsychotics in adults has lead to awareness of the importance of investigating the potential adverse effects of these agents in children . Additionally , there have been many reports proposing that the newer atypical antipsychotics are associated with many of the same adverse effects seen with the older generation drugs in children . The aim of the Paediatric Atypical Antipsychotic Monitoring Safety ( PAMS ) study was to determine the feasibility of conducting a prospect i ve targeted pharmacovigilance study to monitor adverse drug reactions ( ADRs ) associated with atypical antipsychotic therapy in children seen in secondary - and tertiary-care setting s. Methods : Participants were identified from the clinical members of the UK Paediatric Psychopharmacology Groups in London and the West Midl and s. Participating clinicians reported the number of patients ( aged ≤18 years ) taking atypical antipsychotic treatment who were under their care and any reportable ADRs experienced by these patients during the period September 2006–September 2007 . Participants contributed data via password protected online data collection forms . Results : A total of 35 clinicians consented to participate in the study . However , data from 22 of the participating clinicians were excluded because of incomplete reporting . Data from the remaining 13 ( 37 % ) clinicians were eligible for the final analysis . There were 281 patients who received atypical antipsychotic treatment under the care of the 13 participating clinicians . From these 281 patients , 40 ADR reports ( 0.14 ADR reports per patient ; 95 % CI 0.10 , 0.19 ) from 37 patients were entered into the data base . Of the 37 patients , 13 experienced more than one ADR , bringing the total number of ADRs to 56 ( 0.20 ADR per patient ; 95 % CI 0.15 , 0.25 ) . The most commonly reported ADRs were weight gain , extrapyramidal symptoms and hyperprolactinaemia . Rare ADRs , including neuroleptic malignant syndrome , were also reported . The duration s of atypical antipsychotic drug exposure were recorded for 54 of the 56 ADRs reported . The median duration of exposure was 42 days ( interquartile range 23.25–90 days ) . Conclusions : Our study demonstrates that a clinician-based targeted pharmacovigilance study on  atypical antipsychotics in children provides useful qualitative data . However , this pilot study raised many method ological issues , which should be addressed for the study to be extended nationally . Specifically , significant funding is needed to improve the reporting rate and the overall data obtained . Furthermore , the study yielded a very high incidence of serious ADRs , thus supporting the need for a larger and improved pharmacovigilance study to evaluate the safety of atypical antipsychotics in children BACKGROUND This study compares prescription practice s for acute in patients with schizophrenia among six academic departments located in China , Japan , Hungary , and the U.S. METHODS Prescription data for a sample of 429 in patients from six academic departments were collected on a r and omly chosen census day . All patients met criteria for schizophrenia according to DSM-IV and had a length of illness of at least two years . RESULTS While patients at the different centers varied in their demographic and clinical characteristics , i. e. , age , sex , and length of illness , a great variation in prescription patterns for antipsychotic and other psychotropic drugs among centers was observed even within the same country for all the variables studied ( i. e. , number and dose antipsychotics , atypical and depot antipsychotics , other psychotropic drugs , multiple antipsychotics , and daily dose ) except antidepressant use . In most cases these differences persisted even after adjusting for demographic and clinical characteristics ( age , sex , and length of illness ) of the subjects . Antipsychotics were usually prescribed in divided daily doses in combination with one or more other psychotropic drugs , including anticholinergics , anticonvulsants , benzodiazepines , and non-benzodiazepine hypnotics .  Anticholinergic use was more common with typical antipsychotics . Rates of atypical antipsychotic drug use were lowest in the Japanese center . The Japanese center had by far the highest mean daily dose of antipsychotics .  CONCLUSIONS The results indicate that prescription patterns in different centers do not follow any specific guidelines for the treatment of schizophrenia . The results also confirm previous findings that prescribing practice s for schizophrenia vary greatly among centers and countries . A common prescribing pattern found was the use of atypical antipsychotic drugs in combination with psychotropic drugs , such as anticholinergics , hypnotics , anticonvulsants , and benzodiazepines , administered in multiple daily doses Rationale The relative effectiveness of the atypical antipsychotic drugs and conventional agents in patients with early-stage schizophrenia has not been comprehensively determined . Objectives The aim of our study was to evaluate the efficacy and safety of seven antipsychotic drugs for the maintenance treatment in patients with early-stage schizophrenia . Methods In a 12-month open-label , prospect i ve observational , multicenter study , 1,133 subjects with schizophrenia or schizophreniform disorder within 5 years of onset were monotherapy with chlorpromazine , sulpiride , clozapine , risperidone , olanzapine , quetiapine , or aripiprazole . The primary measure was the rate of treatment discontinuation for any reason . Secondary outcomes included measures for clinical and functional outcomes and tolerability . Results The percentage of patients discontinued treatment within 12 months was 41.4 % for chlorpromazine , 39.5 % for sulpiride , 36.7 % for clozapine , 40.2 % for risperidone , 39.6 % for olanzapine , 46.9 % for quetiapine , and 40.2 % for aripiprazole , a nonsignificant difference ( p = 0.717 ) ; there were no significant differences among these seven treatments on discontinuation due to relapse , intolerability , patient decision , or nonadherence ( all p values ≥ 0.260 ) . Extrapyramidal symptoms were more prominent in chlorpromazine and sulpiride treatment groups . Anticholinergic side effects were most common with clozapine and chlorpromazine . Weight gain was most common with olanzapine and clozapine . Conclusions The efficacy of seven antipsychotic medications for the maintenance treatment appeared similar in early-stage schizophrenia . With regard to the high dropout rate and side effects , special programs are needed to keep efficacy and safety of antipsychotics maintenance treatment for schizophrenia with early Many studies have demonstrated that atypical antipsychotics are superior to typical antipsychotics in that they have fewer side-effects and produce better improvement of cognitive deficits and quality of life in patients with schizophrenia . However , most of these studies dealt with objective indices assessed by research ers rather than subjective indices that are indeed important to patients themselves . In 126 patients with schizophrenia , annoyance of side-effects and psychotic symptoms , satisfaction with medication , wish to change medication , and knowledge of atypical antipsychotics  were assessed using question naires . Patients treated with typical antipsychotics complained less of annoyance of poor attention and concentration than those treated with atypical antipsychotics , which can be explained by increased awareness of these symptoms by the patients due to the improvement of cognitive function . There were no significant differences between the two groups in other variables . The present results that satisfaction and annoyance were similar between patients treated with typical antipsychotics and those with atypical antipsychotics , may partly explain why patients hesitated and rejected changing or shifting from typical to atypical antipsychotics . But because 98 of 126 patients did not know about atypical antipsychotics , it is important to educate the patients on the merits of atypical antipsychotics BACKGROUND In two recent r and omised clinical trials , a meta- analysis and in an effectiveness study analysing routine data from the U.S. Veterans Administration the superiority of the newer atypical drugs over typical antipsychotic drugs , concerning both their efficacy and their side-effect profile , has been question ed . AIMS OF THE STUDY To analyse the effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care . METHODS Cohort study using routine care data from a statutory sickness fund with 5.4 million insured in Germany . To be included , patients had to be discharged with a diagnosis of schizophrenia in 2003 and fulfil membership criteria . Main outcome measures were rehospitalisation rates , mean hospital bed days , mean length of stay , cost of inpatient and pharmaceutical care to the sickness fund during follow-up and medication used to treat side-effects . RESULTS 3121 patients were included into the study . There were no statistically significant differences in the effectiveness of atypical and typical antipsychotics on rehospitalisation during follow-up ( rehospitalisation rate ratio 1.07 , 95 % confidence interval 0.86 to 1.33 ) . However , there were consistent observations of atypical antipsychotics being more effective for severe cases of schizophrenia ( 14.6 % of study population ; > 61 prior bed days per year in 2000 - 2002 ) in the follow-up period , whereas for the other severity strata typical antipsychotics seemed more effective in reducing various rehospitalisation outcomes .  Patients treated with atypical antipsychotics  received significantly less prescriptions for anticholinergics or tiaprid ( relative risk 0.26 , 95 % confidence interval 0.18 to 0.38 ) . DISCUSSION The effectiveness of atypical antipsychotics for schizophrenia on rehospitalisation measures appeared similar to that of typical antipsychotics . With the exception of severe cases , the higher costs for atypical antipsychotics were not offset by savings from reduced inpatient care . Major limitations include the lack of statistical power for subgroup analyses , the lack of clinical severity scale data and of life-course medical history data which both increase the risk of residual confounding by disease severity . CONCLUSIONS This study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care . IMPLICATION S FOR HEALTH CARE PROVISION AND USE From a clinical perspective , this study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care . IMPLICATION S FOR HEALTH POLICIES Routine data studies can yield valuable information for policy decision-makers on the costs and the effectiveness of pharmaceuticals in routine care , complementing efficacy data from r and omised clinical trials currently used for licensing and reimbursement decisions . IMPLICATION S FOR FURTHER RESEARCH The non-significant differences in the effectiveness of atypical compared to typical antipsychotics according to severity of disease should be investigated in a prospect i ve observational study or in a r and omised clinical trial OBJECTIVES To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to , or having unacceptable side-effects from , their current medication . DESIGN Two pragmatic , r and omised controlled trials ( RCTs ) were undertaken . The first RCT ( b and 1 ) compared the class of older , inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders , whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects . The second RCT ( b and 2 ) compared the new ( non-clozapine ) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs . Both RCTs were four-centre trials with concealed r and omisation and three follow-up assessment s over 1 year , blind to treatment . SETTING Adult mental health setting s in Engl and . PARTICIPANTS In total , 227 participants aged 18 - 65 years ( 40 % of the planned sample ) were r and omised to b and 1 and 136 ( 98 % of the planned sample ) to b and 2 . INTERVENTIONS Participants were r and omised to a class of drug . The managing clinician selected the individual drug within that class , except for the clozapine arm in b and 2 . The new atypical drugs included risperidone , olanzapine , quetiapine and amisulpride . The conventional drugs included older drugs , including depot preparations . As in routine practice , clinicians and participants were aware of the identity of the prescribed drug , but clinicians were asked to keep their participating patient on the r and omised medication for at least the first 12 weeks . If the medication needed to be changed , the clinician was asked to prescribe another drug within the same class , if possible . MAIN OUTCOME MEASURES The primary outcome was the Quality of Life Scale ( QLS ) . Secondary clinical outcomes included symptoms [ Positive and Negative Syndrome Scale ( PANSS ) ] , side-effects and participant satisfaction . Economic outcomes were costs of health and social care and a utility measure . RESULTS Recruitment to b and 1 was less than anticipated ( 40 % ) and diminished over the trial . This appeared largely due to loss of perceived clinical equipoise ( clinicians progressively becoming more convinced of the superiority of new atypicals ) . Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75 % power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks . The recruitment to b and 2 was approximately as planned . Follow-up assessment s were completed at week 52 in 81 % of b and 1 and 87 % of b and 2 participants . B and 1 data showed that , on the QLS and symptom measures , those participants in the conventional arm tended towards greater improvements . This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample . Participants reported no clear preference for either class of drug . There were no statistically significant differential outcomes for participants entering b and 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance . Net costs over the year varied widely , with a mean of 18,850 pounds sterling in the conventional drug group and 20,123 pounds sterling in the new atypical group , not a statistically significant difference . Of these costs , 2.1 % and 3.8 % were due to antipsychotic drug costs in the conventional and atypical group , respectively . There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year . The results for b and 2 showed an advantage for commencing clozapine in quality of life ( QLS ) at trend level ( p = 0.08 ) and in symptoms ( PANSS ) , which was statistically significant ( p = 0.01 ) , at 1 year . Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects . Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals ( p < 0.05 ) . Net costs of care varied widely , but were higher than in b and 1 , with a mean of 33,800 pounds sterling in the clozapine group and 28,400 pounds sterling in the new atypical group . Of these costs , 4.0 % and 3.3 % , respectively , were due to antipsychotic drug costs . The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient admission for commencing the drug . There was a trend towards higher mean participant utility scores in the clozapine group . CONCLUSIONS For b and 1 , there is no disadvantage in terms of quality of life and symptoms , or associated costs of care , over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs . Conventional drugs were associated with non-significantly better outcomes and lower costs . Drug costs represented a small proportion of the overall costs of care ( < 5 % ) . For b and 2 , there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs , but with increased associated costs of care . The results suggest that conventional antipsychotic drugs , which are substantially cheaper , still have a place in the treatment of patients unresponsive to , or intolerant of , current medication . Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance , valid measures of utility in serious mental illness , low-dose ' conventional ' treatment in first episode schizophrenia , QLS validity and determinants of QLS score in schizophrenia , and into the possible financial and other mechanisms of rewarding clinician participation in trials Treating schizophrenia is expensive . Preventing rehospitalization of patients with schizophrenia provides an attractive opportunity for cost savings , especially for patients with ' revolving-door ' or multiple-episode schizophrenia . Reducing the occurrence of extrapyramidal symptoms and other adverse events associated with st and ard antipsychotic agents may increase compliance and reduce the rate of rehospitalization of patients with schizophrenia .  Quetiapine ( ' Seroquel ' , ICI 204,636 , Zeneca Pharmaceuticals ) is a new dibenzothiazepine antipsychotic agent with a low propensity for extrapyramidal symptoms . We describe here a unique methodology to compare quetiapine with usual-care medications in real-world treatment setting s. The trial objective is to determine if therapy with this new atypical antipsychotic agent can reduce the rate of rehospitalization and , therefore , treatment costs . Using two secondary medical-cl aims data bases , we defined the minimal threshold for revolving-door status as 1.0 admission per year ; this definition allows our trial to focus on the sub population of schizophrenic patients with the greatest potential for cost savings by either the new atypical antipsychotic quetiapine or usual-care therapy . We describe here the approach used in our trial Accepted clinical evidence suggests superior efficacy of novel antipsychotics in the treatment of cognitive symptoms in schizophrenia . Whether this constitutes a primary drug effect or a secondary effect due to easing extrapyramidal side-effects or improving positive symptoms when converting from a first- to a second-generation neuroleptic is still open to debate . Long-term efficacy as well as differential drug effects on cognitive performance are also poorly documented . We therefore compared cognitive performance of olanzapine vs. clozapine treatment in a controlled , r and omized , double-blind trial . Fifty-four patients were assessed following a 2- to 9-day washout and again after 4 and 26 wk of neuroleptic treatment . Patients were rated on the PANSS for psychopathological changes , extrapyramidal side-effects were assessed on the Simpson-Angus Scale , and cognitive performance was assessed with the Stroop , Wisconsin Card Sorting and the Tower of London tests . Schizophrenia symptoms , extrapyramidal side-effects and cognitive performance improved significantly in the course of either drug treatment . Stroop test performance and Tower of London planning time improved significantly over 26 wk compared to baseline and 4-wk follow-up assessment while Wisconsin Card Sorting and Tower of London execution time improved significantly after 4 wk with no further improvement after 26 wk . Improved executive function was not related to improving positive symptoms and easing extrapyramidal side-effects , thus indicative of a primary treatment effect of either antipsychotic . However , Stroop reaction time improved with olanzapine while clozapine had a stronger effect on improving negative symptoms , thus suggestive of a differential drug effect OBJECTIVE To compare longer-term safety and effectiveness of the 4 most commonly used atypical antipsychotics ( aripiprazole , olanzapine , quetiapine , and risperidone ) in 332 patients , aged > 40 years , having psychosis associated with schizophrenia , mood disorders , posttraumatic stress disorder , or dementia , diagnosed using DSM-IV-TR criteria . METHOD We used equipoise-stratified r and omization ( a hybrid of complete r and omization and clinician 's choice methods ) that allowed patients or their treating psychiatrists to exclude 1 or 2 of the study atypical antipsychotics due to past experience or anticipated risk . Patients were followed for up to 2 years , with assessment s at baseline , 6 weeks , 12 weeks , and every 12 weeks thereafter . Medications were administered employing open-label design and flexible dosages , but with blind raters . The study was conducted from October 2005 to October 2010 . OUTCOME MEASURES Primary metabolic markers ( body mass index , blood pressure , fasting blood glucose , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , and triglycerides ) , percentage of patients who stay on the r and omly assigned atypical antipsychotic for at least 6 months , psychopathology , percentage of patients who develop metabolic syndrome , and percentage of patients who develop serious and nonserious adverse events . RESULTS Because of a high incidence of serious adverse events , quetiapine was discontinued midway through the trial . There were significant differences among patients willing to be r and omized to different atypical antipsychotics ( P < .01 ) , suggesting that treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with metabolic problems . Yet , the atypical antipsychotic groups did not differ in longitudinal changes in metabolic parameters or on most other outcome measures . Overall results suggested a high discontinuation rate ( median duration 26 weeks prior to discontinuation ) , lack of significant improvement in psychopathology , and high cumulative incidence of metabolic syndrome ( 36.5 % in 1 year ) and of serious ( 23.7 % ) and nonserious ( 50.8 % ) adverse events for all atypical antipsychotics in the study . CONCLUSIONS Employing a study design that closely mimicked clinical practice , we found a lack of effectiveness and a high incidence of side effects with 4 commonly prescribed atypical antipsychotics across diagnostic groups in patients over age 40 , with relatively few differences among the drugs . Caution in the use of these drugs is warranted in middle-aged and older patients . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00245206 Background There is an ongoing debate over whether atypical antipsychotics are more effective than typical antipsychotics in the treatment of schizophrenia . This naturalistic study compares atypical and typical antipsychotics on time to all-cause medication discontinuation , a recognized index of medication effectiveness in the treatment of schizophrenia . Methods We used data from a large , 3-year , observational , non-r and omized , multisite study of schizophrenia , conducted in the U.S. between 7/1997 and 9/2003 . Patients who were initiated on oral atypical antipsychotics ( clozapine , olanzapine , risperidone , quetiapine , or ziprasidone ) or oral typical antipsychotics ( low , medium , or high potency ) were compared on time to all-cause medication discontinuation for 1 year following initiation . Treatment group comparisons were based on treatment episodes using 3 statistical approaches ( Kaplan-Meier survival analysis , Cox Proportional Hazards regression model , and propensity score-adjusted bootstrap resampling methods ) . To further assess the robustness of the findings , sensitivity analyses were performed , including the use of ( a ) only 1 medication episode for each patient , the one with which the patient was treated first , and ( b ) all medication episodes , including those simultaneously initiated on more than 1 antipsychotic . Results Mean time to all-cause medication discontinuation was longer on atypical ( N = 1132 , 256.3 days ) compared to typical antipsychotics ( N = 534 , 197.2 days ; p < .01 ) , and longer on atypicals compared to typicals of high potency ( N = 320 , 187.5 days ; p < .01 ) , medium potency ( N = 140 , 213.5 days ; p < .01 ) , and low potency ( N = 74 , 208.7 days ; p < .01 ) . Among the atypicals , only clozapine , olanzapine , and risperidone had significantly longer time to all-cause medication discontinuation compared to typicals , regardless of potency level , and compared to haloperidol with prophylactic anticholinergic treatment . When compared to perphenazine , a medium-potency typical antipsychotic , only clozapine and olanzapine had a consistently and significantly longer time to all-cause medication discontinuation . Results were confirmed by sensitivity analyses . Conclusion In the usual care of schizophrenia patients , time to medication discontinuation for any cause appears significantly longer for atypical than typical antipsychotics regardless of the typical antipsychotic potency level . Findings were primarily driven by clozapine and olanzapine , and to a lesser extent by risperidone . Furthermore , only clozapine and olanzapine therapy showed consistently and significantly longer treatment duration compared to perphenazine , a medium-potency typical antipsychotic CONTEXT Violent behavior of patients with schizophrenia prolongs hospital stay and interferes with their integration into the community . Finding appropriate treatment of violent behaviors is of primary importance . OBJECTIVE To compare the efficacy of 2 atypical antipsychotic agents , clozapine and olanzapine , with one another and with haloperidol in the treatment of physical assaults and other aggressive behaviors in physically assaultive patients with schizophrenia and schizoaffective disorder . DESIGN AND SETTING R and omized , double-blind , parallel-group , 12-week trial . Physically assaultive subjects with schizophrenia or schizoaffective disorder who were in patients in state psychiatric facilities were r and omly assigned to treatment with clozapine ( n = 37 ) , olanzapine ( n = 37 ) , or haloperidol ( n = 36 ) . MAIN OUTCOME MEASURES Number and severity of physical assaults as measured by the Modified Overt Aggression Scale ( MOAS ) physical aggression score and the number and severity of all aggressive events as measured by the MOAS overall score . Psychiatric symptoms were assessed through the Positive and Negative Syndrome Scale ( PANSS ) . RESULTS Clozapine was superior to both olanzapine and haloperidol in reducing the number and severity of physical assaults as assessed by the MOAS physical aggression score and in reducing overall aggression as measured by the MOAS total score . Olanzapine was superior to haloperidol in reducing the number and severity of aggressive incidents on these 2 MOAS measures . There were no significant differences among the 3 medication groups in improvement of psychiatric symptoms as measured by the PANSS total score and the 3 PANSS subscales . CONCLUSIONS Clozapine shows greater efficacy than olanzapine and olanzapine greater efficacy than haloperidol in reducing aggressive behavior . This antiaggressive effect appears to be separate from the antipsychotic and sedative action of these medications
In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator .
Conclusion Atypical antipsychotics are effective in treating both phases of bipolar disorder compared with placebo , and as effective as established drug therapies .
Atypical antipsychotics produce fewer extrapyramidal symptoms , but weight gain is more common ( with olanzapine ) .
There is insufficient data confidently to distinguish between different atypical antipsychotics
Background Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder , and considered to have fewer extrapyramidal effects than older antipsychotics .