schizophrenia is a chronic mental disorder that affects approximately 1% of the world population and is characterized by a relapsing course with significant burden for patients , families , and society.13 although many patients receiving chronic antipsychotic therapy can be considered clinically stable , a subgroup of patients will eventually have poor outcomes , not achieving optimal symptom relief.4 premature discontinuation and poor prescription compliance are well established reasons for suboptimal effectiveness in clinical practice,512 and 40%50% of schizophrenic patients are believed to be only partially compliant.8,12 nonadherence to oral antipsychotic therapy is associated with potential symptom re - emergence and a higher risk of relapse.1318 relapses are responsible for frequent inpatient admissions , and account for 80% of overall schizophrenia treatment costs.19,20 their consequences include social and overall productivity impairment , increased risk of a poor prognosis , and prolonged recovery in subsequent episodes.21,22 in this setting , alongside symptom remission , relapse prevention is a major therapeutic goal for schizophrenic patients . atypical antipsychotics are currently a critical part of schizophrenia management worldwide , and several studies have demonstrated their efficacy and a better tolerability profile relative to conventional agents , with reduced risk of extrapyramidal side effects.2325 risperidone long - acting injection was the first injectable , long - acting , second - generation agent to become available , providing continuous medication delivery and reducing plasma level fluctuations.26,27 a robust set of evidence has shown that risperidone long - acting injection administered intramuscularly every 2 weeks improves symptom control , prevents relapses , positively impacts patients health - related quality of life , and reduces hospitalizations.13,21,2832 because compliance monitoring is a critical issue for patients with schizophrenia , risperidone long - acting injection can potentially minimize the risk of intermittent or interrupted treatment , by ensuring more stable drug levels through slow and steady release of risperidone over several weeks.13,29,30 individuals with a previous history of nonadherence or partial adherence are a subset of patients of special concern for clinicians regarding future compliance behavior . the purpose of the present study was to assess the efficacy , safety , and tolerability of switching clinically stable patients with schizophrenia and a history of nonadherence on oral antipsychotic therapy to long - acting risperidone . this was a 50-week , multicenter , open - label , noncomparative trial of risperidone long - acting injection ( risperdal consta ; janssen pharmaceutical companies , johnson and johnson , sao paolo , brazil ) in stable patients with schizophrenia attending seven brazilian centers who were switched from oral treatment . a 50-week study duration was chosen to provide information relevant to clinical decision - making in the real - world setting , given that long - term follow - up is essential for schizophrenia patients . as required in multicenter studies , raters from each of the seven sites went through a training process on all clinical assessment scales to be used before initiating the trial . all raters were required to have prior clinical experience with schizophrenic patients and documented experience administering at least the positive and negative syndrome scale ( panss ) , which was the primary outcome measure in the trial . the study was approved by the ethics committee at each participating site and written consent was obtained from each patient or their legal representative before enrollment . patients were recruited for the study if they met the following inclusion criteria : diagnostic and statistical manual of mental disorders fourth edition text revision ( dsm - iv ) criteria for schizophrenia ; age 1850 years ; current treatment with oral antipsychotics ( both first- and second - generation ) ; history of nonadherence to antipsychotic treatment within the previous 12 months ; and panss  90 and a panss  4 for conceptual disorganization , hallucinatory behavior , suspiciousness , and unusual thought content . nonadherent patients were those fulfilling at least one of the following criteria : hospitalization due to interruption or irregular use of medication within the previous 12 months ; clinical worsening due to irregular use of medication ; patient refusal to take medication , as reported by family members ; difficulty convincing patient to accept medication , as reported by family members ; and at least one treatment interruption with worsening of symptoms . exclusion criteria included a history of refractoriness to antipsychotic treatment , previous use of clozapine , use of another depot antipsychotic within the previous 12 months , another major axis disorder , and risk of suicide . women of childbearing age not using an approved method of birth control were also excluded . patients continued their outgoing antipsychotic for the first 3 weeks to ensure adequate drug coverage , and the previous medication was interrupted thereafter . at the first study visit , all eligible patients were prescribed oral risperidone1 mg for 3 days as a sensitivity and tolerability test . patients received intramuscular injections of risperidone long - acting injection at an initial dose of 25 mg every 2 weeks . the dose could be increased to up to 50 mg at the investigator s discretion . biperidene for extrapyramidal symptoms and clonazepam for anxiety and insomnia were allowed as concomitant medications . the primary efficacy measure was the change from baseline to endpoint for the total score on panss.33 secondary efficacy measures included the change from baseline in panss subscales ( negative symptoms , positive symptoms , general psychopathology ) , clinical global impression ( cgi),34 and personal and social performance scale ( psp).35 the drug attitude inventory ( dai-10 ) was employed to assess patients attitudes towards psychiatric medication.36 psp is a 100-point classification scale that measures personal and social activity in four behavioral domains ( socially useful activities , personal and social relationships , self - care , and disturbing and aggressive behaviors ) . the final scale score is obtained summing the scores of all four domains , and ranges from 1 to 100 . dai-10 is a 10-item dichotomous ( true or false ) answer scale that enables classification of patients based upon their attitudes towards medication . a positive final total score means a positive subjective response ( compliant ) and a negative total score means a negative subjective response ( noncompliant ) . answers are coded as positive ( + 1 point ) or negative ( 1 point ) , and the final score is the sum of all points . spontaneously reported adverse events were recorded by the investigator at all visits ( weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 38 , and 50 ) , and severity of movement disorders was evaluated using the extrapyramidal symptom rating scale ( esrs).37 electrocardiograms and blood samples for laboratory analysis were obtained at screening , week 24 , and endpoint . the sample size required to provide the desired 80% power at a two - sided alpha of 0.05 was 60 patients , considering the mean reduction in panss scores reported in two previously published clinical studies of risperdal consta.30,38 all patients who received at least one injection of risperidone long - acting injection and had at least one postbaseline efficacy assessment ( intention - to - treat population ) were included in the efficacy analysis . the safety population comprised patients who received at least one injection , regardless of efficacy measurement status . changes in efficacy measures from baseline to endpoint ( week 50 ) were analyzed by the paired t - test and the wilcoxon signed - rank test for normal and asymmetric continuous variables as appropriate . scores measured over time ( panss , cgi , psp , dai , and esrs ) were compared by repeated - measures analysis of variance using a mixed linear model for time effect ( within - group factors ) . statistical analyses were carried out using sas ( v 9.1.3 ; sas institute , cary , nc ) patients were recruited for the study if they met the following inclusion criteria : diagnostic and statistical manual of mental disorders fourth edition text revision ( dsm - iv ) criteria for schizophrenia ; age 1850 years ; current treatment with oral antipsychotics ( both first- and second - generation ) ; history of nonadherence to antipsychotic treatment within the previous 12 months ; and panss  90 and a panss  4 for conceptual disorganization , hallucinatory behavior , suspiciousness , and unusual thought content . nonadherent patients were those fulfilling at least one of the following criteria : hospitalization due to interruption or irregular use of medication within the previous 12 months ; clinical worsening due to irregular use of medication ; patient refusal to take medication , as reported by family members ; difficulty convincing patient to accept medication , as reported by family members ; and at least one treatment interruption with worsening of symptoms . exclusion criteria included a history of refractoriness to antipsychotic treatment , previous use of clozapine , use of another depot antipsychotic within the previous 12 months , another major axis disorder , and risk of suicide . women of childbearing age not using an approved method of birth control were also excluded . patients continued their outgoing antipsychotic for the first 3 weeks to ensure adequate drug coverage , and the previous medication was interrupted thereafter . at the first study visit , all eligible patients were prescribed oral risperidone1 mg for 3 days as a sensitivity and tolerability test . patients received intramuscular injections of risperidone long - acting injection at an initial dose of 25 mg every 2 weeks . the dose could be increased to up to 50 mg at the investigator s discretion . biperidene for extrapyramidal symptoms and clonazepam for anxiety and insomnia were allowed as concomitant medications . the primary efficacy measure was the change from baseline to endpoint for the total score on panss.33 secondary efficacy measures included the change from baseline in panss subscales ( negative symptoms , positive symptoms , general psychopathology ) , clinical global impression ( cgi),34 and personal and social performance scale ( psp).35 the drug attitude inventory ( dai-10 ) was employed to assess patients attitudes towards psychiatric medication.36 psp is a 100-point classification scale that measures personal and social activity in four behavioral domains ( socially useful activities , personal and social relationships , self - care , and disturbing and aggressive behaviors ) . the final scale score is obtained summing the scores of all four domains , and ranges from 1 to 100 . dai-10 is a 10-item dichotomous ( true or false ) answer scale that enables classification of patients based upon their attitudes towards medication . a positive final total score means a positive subjective response ( compliant ) and a negative total score means a negative subjective response ( noncompliant ) . answers are coded as positive ( + 1 point ) or negative ( 1 point ) , and the final score is the sum of all points . spontaneously reported adverse events were recorded by the investigator at all visits ( weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 38 , and 50 ) , and severity of movement disorders was evaluated using the extrapyramidal symptom rating scale ( esrs).37 electrocardiograms and blood samples for laboratory analysis were obtained at screening , week 24 , and endpoint . the sample size required to provide the desired 80% power at a two - sided alpha of 0.05 was 60 patients , considering the mean reduction in panss scores reported in two previously published clinical studies of risperdal consta.30,38 all patients who received at least one injection of risperidone long - acting injection and had at least one postbaseline efficacy assessment ( intention - to - treat population ) were included in the efficacy analysis . the safety population comprised patients who received at least one injection , regardless of efficacy measurement status . changes in efficacy measures from baseline to endpoint ( week 50 ) were analyzed by the paired t - test and the wilcoxon signed - rank test for normal and asymmetric continuous variables as appropriate . scores measured over time ( panss , cgi , psp , dai , and esrs ) were compared by repeated - measures analysis of variance using a mixed linear model for time effect ( within - group factors ) . statistical analyses were carried out using sas ( v 9.1.3 ; sas institute , cary , nc ) of the 60 patients who were screened , seven patients could not be enrolled in the study for the following reasons : injectable depot antipsychotic use within the previous 12 months ( n = 1 ) ; a clinically significant abnormality in the screening tests ( n = 2 , one electrocardiographic abnormality and one anemia ) ; self - withdrawal ( n = 2 ) ; and loss to follow - up ( n = 2 , both before receiving the study medication . fifty - three patients received at least one dose of risperidone long - acting injection ( safety population , n = 53 ) ; of these , two were excluded from the efficacy analysis for not undergoing any postbaseline assessment ( intention - to - treat efficacy population , n = 51 ) . most dropouts were due to patient s request for withdrawal ( 62.5% ) ; 16.7% were adverse event - related , and none were due to lack of efficacy . clinical and demographic characteristics of the total sample and the subsample of study completers are summarized in table 1 . the study group was predominantly male ( 73.6% ) with a mean age of 33.6 years . the median disease duration was 5.5 years ( mean  standard deviation 9.2  9.9 years ) . most patients were switched from oral risperidone ( 41.5% ) , followed by haloperidol ( 22.6% ) and chlorpromazine ( 11.3% ) . final doses ( week 48 ) of risperidone long - acting injection were 25 mg in 38.1% , 37.5 mg in 38.1% , and 50 mg in 23.8% of patients . regarding concomitant medication , 15 ( 28.3% ) patients received clonazepam , 10 ( 18.9% ) received biperidene , 17 ( 32.1% ) received risperidone , and 14 ( 26.4% ) received haloperidol . it was not possible to identify clinically relevant differences between study completers and the initial sample . over a 50-week period , there were significant reductions in total panss score and also in the panss positive , negative , and general psychopathology subscales ( table 2 ) . the mean panss total score was significantly reduced from baseline to endpoint ( 58.8  1.82 vs 49.72  2.32 ; p = 0.0002 ) . a significant improvement was seen at week 4 , and this effect was maintained throughout the study . in addition , significant improvements were observed from baseline to endpoint and during the study in all panss subscales . mean cgi also significantly improved from baseline to endpoint ( mean  standard error of the mean = 3.55  0.13 vs 3.19  0.16 ; p = 0.0131 ) . the factor  week of treatment  had a statistically significant effect from week 4 ( p < 0.01 ) and these clinical benefits remained stable until the final visit ( table 3 ) . for the psp scale , the time factor also had a positive impact on mean performance scores , which improved from 60.0 ( 95% confidence interval [ ci ] : 54.265.7 ) at baseline to 69.1 ( 95% ci : 64.873.4 ) at week 50 ( p = 0.0002 , table 3 ) . dai-10 scores were measured at four different visits from baseline to endpoint . at all visits , significant improvements were observed and the mean (  standard error of the mean ) scores rose from 2.78  0.68 to 5.07  0.77 ( p = 0.0062 ) . there was a progressive and sustained increase in dai-10 scores , showing positive attitudes towards risperidone long - acting injection throughout the study , as shown in table 3 . adverse events reported in more than 10% of patients were insomnia ( 22.6% ) , increased prolactin levels ( 17.0% ) , and weight gain ( 13.2% ) . investigators categorized 22 ( 41.5% ) adverse events as likely or very likely related to the study drug ( table 4 ) . three serious adverse events were reported by the investigators , ie , psychomotor agitation , worsening of symptoms , and worsening of psychotic symptoms . there were three ( 5.7% ) early discontinuations due to adverse events ( sexual dysfunction , decreased libido , psychomotor agitation , and worsening of pre - existing symptoms ) . severity of movement disorders was significantly reduced during treatment with risperidone long - acting injection ( table 5 ) . significant improvements were noted on the esrs overall scale , subjective evaluation , and extrapyramidal symptoms item from week 4 ( p < 0.0001 ) . changes in laboratory findings other than serum prolactin were not clinically significant , although high - density lipoprotein and creatinine changes reached statistical significance ( table 6 ) . the 29 patients for whom weight data at baseline and endpoint were available showed a mean weight gain of 2.8  4.6 kg ( p < 0.001 ) . the findings of this open - label study demonstrate that risperidone long - acting injection was an effective treatment in a real - world setting for clinically stable brazilian patients with schizophrenia who were switched from other antipsychotic agents due to poor compliance , as assessed by change in scores on panss measures and cgi - s . patients achieved significant clinical improvements in terms of symptom control when switched directly to risperidone long - acting injection from their current antipsychotic therapy . most patients maintained the lower doses of risperidone long - acting injection , ie , 25 mg and 37.5 mg , during the trial . the mean panss total score was significantly reduced from baseline to endpoint , and patients remained stable , not showing any worsening of symptoms . results from a number of other clinical studies have also reported significant and sustained clinical improvement in patients directly switched to risperidone long - acting injection from their previous antipsychotic agents.29,38,39 in a 12-week , randomized , placebo - controlled trial by kane et al , risperidone long - acting injection was associated with significantly greater improvements in panss and cgi - s scores at endpoint compared with placebo.30 significant improvements in total panss scores ( p < 0.01 ) , positive symptoms ( p < 0.01 ) , and negative symptoms ( p < 0.001 ) were also observed during an international , open - label , 12-month study conducted by fleischhacker et al in patients with schizophrenia who were switched to risperidone long - acting injection from oral or long - acting conventional or oral atypical antipsychotics.29 risperidone long - acting injection was well - tolerated , with minimal weight change and an overall favorable safety profile . although of minimum magnitude in clinical terms , the statistically significant change in high - density lipoprotein could potentially raise concern about metabolic side effects . however , the observed decrease was not accompanied by consistent changes in total cholesterol , low - density lipoprotein , very low - density lipoprotein , triglycerides , and fasting glycemia , reinforcing the absence of clinically sound metabolic effects of risperidone long - acting injection in this sample . the creatinine increase , although statistically significant , was considered clinically irrelevant . the incidence of adverse events was comparable with those reported in previous studies . according to the report by kane et al , risperidone long - acting injection was generally well - tolerated , with an overall incidence of adverse events similar to that with placebo in comparative trials.30 in that study , similar proportions of patients reported adverse events in the active and control group , while serious adverse events were more frequent in the placebo group ( 23.5% ) than in the 25 , 50 , and 75 mg risperidone long - acting injection groups ( 13% , 14% , and 15% , respectively).30 results from other studies have also reported that patients can be safely switched from oral conventional or atypical therapy and conventional long - acting agents to risperidone long - acting injection.38,4042 these findings confirm the effectiveness of switching stable patients with schizophrenia from other antipsychotics to risperidone long - acting injection in a brazilian real - world setting . following a switch to risperidone long - acting injection , stable patients showed further significant improvements in symptom control over the treatment period , reducing their panss total score and subscales and cgi - s scores . some of the limitations of the study were its small sample size , a relatively high dropout rate ( 42.5% ) , and the open - label design . in absolute terms , the observed dropout rate was not significantly greater in magnitude than that observed in previous atypical antipsychotic trials ( 33.5% in fixed - dose studies and 45.0% in flexible - dose studies).43 this study enrolled only patients with a previous history of compliance issues , which could also be a factor explaining the higher dropout rates , especially those due to patient request . another limitation is the lack of inter - rater reliability assessments as part of the trial . rater training was performed to improve raters clinical skills and to ensure standardized clinical assessments before the study initiation , but statistical evaluation of inter - rater reliability was not conducted . nevertheless , this study yielded useful knowledge on the effectiveness and safety of risperidone long - acting injection in a brazilian population over a 12-month study period , and observed significant clinical improvements after switching from oral antipsychotics to risperidone long - acting injection . long - acting injectable risperidone is an effective and safe treatment alternative for patients with schizophrenia and a history of poor adherence to oral treatment . the study indicates a favorable tolerability profile , a positive effect on personal and social functioning , and adequate patient treatment acceptance . these findings reinforce long - acting injectable risperidone as a reasonable alternative for long - term care of stable schizophrenia patients in whom compliance issues are anticipated .