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00004714-201208000-0000300004714_2012_32_449_schreiner_schizophrenia_4article< 139_0_22_4 >Journal of Clinical Psychopharmacology© 2012 Lippincott Williams & Wilkins, Inc.Volume 32(4)August 2012p 449–457Metabolic Effects of Paliperidone Extended Release Versus Oral Olanzapine in Patients With Schizophrenia: A Prospective, Randomized, Controlled Trial[Original Contributions]Schreiner, Andreas MD*; Niehaus, Dana MD†; Shuriquie, Nasser Aldien MD‡; Aadamsoo, Kaire MD§; Korcsog, Peter MD∥; Salinas, Rolando MD¶; Theodoropoulou, Pitsa MD#; Fernández, Lorena García MD**; Üçok, Alp MD††; Tessier, Christophe MD‡‡; Bergmans, Paul MSc§§; Hoeben, Dagmar PhD∥∥From the *Medical Affairs EMEA, Janssen-Cilag GmbH, Neuss, Germany; †Flexivest Fourteen Research Centre, Cape Town, South Africa; ‡Al-Rashid Hospital, Abu Nsair, Amman, Jordan; §Clinic of Psychiatry, North Estonian Regional Hospital, Tallin, Estonia; ∥Department of Psychiatry, General Hospital Rimavska Sobota, Rimavska Sobota, Slovakia; ¶Instituto para la Prevención de las Enfermedades Mentales, Buenos Aires, Argentina; #Department of Psychiatry, Sismanoglio Hospital, Maroussi-Athens, Greece; **Servicio de Psiquiatría, Hospital Clínico Universitario San Juan Alicante, San Juan Alicante, Spain; ††Department of Psychiatry, Istanbul Faculty of Medicine, Istanbul, Turkey; ‡‡Medical Affairs EMEA, Janssen-Cilag SAS, Paris, France; §§Janssen-Cilag BV, Tilburg, Netherlands; and ∥∥Medical Affairs EMEA, Janssen Pharmaceutica NV, Beerse, Belgium.Received December 1, 2010; accepted after revision December 13, 2011.Reprints: Andreas Schreiner, MD, Medical Affairs EMEA, Janssen-Cilag GmbH, Johnson & Johnson Platz 1, 41470 Neuss, Germany (e-mail: aschrein@its.jnj.com).This study and the writing/editorial support were funded by Janssen Pharmaceutical Companies of Johnson & Johnson in EMEA. The writing/editorial support was provided by Tam Vo and team from Excerpta Medica.AbstractAbstract: Metabolic effects are generally more pronounced with second-generation than first-generation antipsychotics. This study was designed to compare long-term metabolic effects and efficacy of paliperidone extended release (ER) with those of oral olanzapine in patients with schizophrenia. In this 6-month, multicenter, prospective, randomized, controlled, open-label, parallel-group study, adults with schizophrenia were treated with paliperidone ER (6–9 mg/d; n = 239) or oral olanzapine (10–15 mg/d; n = 220). The primary outcome was mean change in the ratio of serum triglyceride level to high-density lipoprotein level (TG/HDL), a marker of insulin resistance. Other outcome measures included the Positive and Negative Syndrome Scale scores, measures of lipid and glucose metabolism, and body weight. Significant improvements in psychotic symptoms were observed with both treatments (P < 0.0001). The TG/HDL ratio was significantly higher at end point versus baseline with olanzapine compared with that of paliperidone ER. Mean end point change in TG/HDL ratio was 0.097 ± 2.72 for olanzapine (P < 0.0001, reflecting worsening), with no significant change for paliperidone ER (−0.17 ± 2.51). Newly diagnosed impairment in TG and metabolic syndrome was more common with olanzapine (P < 0.05). Insulin resistance, as measured by the homeostasis model assessment of insulin resistance, worsened significantly with olanzapine (P = 0.0003), but not with paliperidone ER. Glucose sensitivity for insulin worsened significantly with olanzapine (P < 0.03), with no significant changes for paliperidone ER. End point increase in body weight was significantly higher with olanzapine than paliperidone ER (3.8 vs 1.2 kg; P = 0.0013). In summary, both paliperidone ER and olanzapine effectively treated schizophrenia; however, undesirable metabolic effects were significantly greater with olanzapine.Second-generation (or atypical) antipsychotics are generally considered to be at least as effective as first-generation antipsychotics, with fewer extrapyramidal side effects1; however, efficacy varies among second-generation antipsychotics, with clozapine, olanzapine, risperidone, and amisulpride being particularly efficacious.2 Unwanted metabolic effects are generally more pronounced with second-generation compared with those of first-generation antipsychotics3,4; metabolic effects may vary considerably and are more pronounced with olanzapine and clozapine.5–9 The pooled incidence of clinically significant (≥7%) weight gain with atypical antipsychotics from US product label data using short-term treatment of generally 4 to 6 weeks is 22% with olanzapine, 23% with quetiapine, 18% with risperidone, 10% with ziprasidone, and 8% with aripiprazole.6,10 Insulin resistance (IR) has also been shown to be significantly greater with olanzapine or clozapine compared with that of risperidone or ziprasidone.5,11,12 Dyslipidemia occurs more often with olanzapine,13 with the risk of dyslipidemia being 5 times greater with olanzapine than when using no antipsychotic and 3 times greater than that with conventional neuroleptics.14 A 12-month study directly comparing treatment with olanzapine and aripiprazole reported significantly higher new-onset elevations in cholesterol and triglyceride (TG) levels, as well as a higher percentage of patients with clinically significant weight gain, with olanzapine (P < 0.001 for each).15 Finally, the risk of metabolic syndrome has been reported to be highest with clozapine and olanzapine.16 The prevalence of metabolic syndrome based on National Cholesterol Education Program/Adult Treatment Panel III criteria was evaluated prospectively in a randomized double-blind study in which 99 drug-naive patients with their first onset of schizophrenia were treated with olanzapine, risperidone, or haloperidol.17 The prevalence of metabolic syndrome was assessed after 6 weeks of treatment, with metabolic syndrome diagnosed in 20% treated with olanzapine, 9% with risperidone, and 0% with haloperidol. A second study evaluating long-term effects in patients with a first episode of schizophrenia reported the highest prevalence of metabolic syndrome in patients treated with clozapine (58%) and olanzapine (47%) and lower prevalences with risperidone (17%), quetiapine (15%), and aripiprazole (10%).18Patients with schizophrenia may be particularly susceptible to negative metabolic effects.19 A survey of hospital discharges showed that patients with schizophrenia were more likely to have a variety of comorbid illnesses compared with hospitalized patients without schizophrenia.20 Proportional morbidity ratios were 2.0 for obesity (95% confidence interval [CI], 1.9–2.1), 1.2 for type 2 diabetes (95% CI, 1.2–1.3), and 1.2 for essential hypertension (95% CI, 1.1–1.2). Metabolic syndrome was identified in 35% of a sample of patients with chronic psychotic illness.21 In addition, metabolic syndrome was identified at baseline in 52% of women and 36% of men with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study compared with 25% of women and 20% of men in an age-matched National Health and Nutrition Examination Survey III general-population sample.22The atypical antipsychotic paliperidone extended release (ER) uses an innovative osmotic-controlled extended-release oral delivery system (OROS) to achieve minimal peak-to-trough fluctuations with once-daily dosing.23 Paliperidone ER in the approved dose range of 3 to 12 mg once daily has proven to be effective, well tolerated, and associated with significant improvement in patient functioning.24–28 A 13-week, double-blind, head-to-head, comparative trial of paliperidone ER versus risperidone long-acting injectable in adults with schizophrenia showed similar efficacy and tolerability with both treatments, with a mean baseline–to–end point weight gain of 1.1 ± 3.4 kg with paliperidone ER and 1.0 ± 3.1 kg with risperidone long-acting injectable.29 Furthermore, a study evaluating data from 6 short-term (4–8 weeks) clinical trials in adults with acute schizophrenia reported mean body weight changes of 0.7 kg with paliperidone ER and 1.0 to 1.3 kg with risperidone.30 Recent long-term paliperidone ER data have likewise suggested a beneficial weight and metabolic profile.31 The current study was designed to directly compare longer term metabolic effects of treatment with paliperidone ER versus oral olanzapine in patients with schizophrenia. In particular, this study was intended to explore in more detail potential negative metabolic consequences, including weight gain, lipid parameters, glucose metabolism, and metabolic syndrome. Although weight gain has often been reported as an adverse event with commonly prescribed medications, the long-term effects of this weight gain and its associated metabolic effects have often not been reported.32MATERIALS AND METHODSThis 6-month, randomized, controlled, open-label, parallel-group, multicenter study was conducted in 62 sites in 15 countries (Argentina, Egypt, Estonia, France, Greece, Italy, Jordan, Latvia, Lebanon, Lithuania, Romania, Slovakia, South Africa, Spain, and Turkey) from August 2007 to April 2009. This study was conducted in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice, and the study protocol was approved by the Independent Ethics Committee at each study site. Before study enrollment, all potential patients gave informed written consent.Study DesignIn this prospective, randomized, controlled, open-label, parallel-group study, adult patients with schizophrenia were treated with paliperidone ER (6–9 mg/d) or oral olanzapine (10–15 mg/d). These doses were selected to allow patients to be treated with typically recommended effective doses (defined daily dose) and the next higher dose level to permit flexibility in dosing. Patients were stratified according to the metabolic effects of their previous antipsychotic medication as weight neutral (high-potency conventional neuroleptics and the atypical antipsychotics amisulpride, aripiprazole, and ziprasidone) versus not weight neutral (olanzapine, risperidone, and quetiapine).An open-label design was selected because both drugs are currently available for the treatment of schizophrenia, and open-label treatment permits optimizing individual therapy by allowing the possibility of flexible dosing within the recommended dose range and according to the needs of individual patients. In addition, as long-term treatment is essential to provide meaningful information on key end points, that is, changes in metabolic laboratory values and weight, adherence of patients in the study is of major relevance. In schizophrenia trials, patient acceptance is higher and dropout rates are considerably lower in open-label studies because of better individually optimized treatment. Therefore, an open-label design helps retain more patients and, thus, provide meaningful data on longer term metabolic changes. Finally, because the key end points of this study consist of objective laboratory values, these are free of bias that might be introduced for other outcome measures when using open-label treatment.PatientsAdults with a diagnosis of schizophrenia aged 18 to 65 years and considered likely to benefit from paliperidone ER or oral olanzapine were candidates for this study. Eligible patients were required to have baseline Positive and Negative Syndrome Scale (PANSS) total scores within the range of 60 to 100, both inclusive. Patients using concomitant lipid-lowering therapy could be enrolled if they were on a stable dose of statins, niacin, ezetimibe, and resins for 4 weeks or longer or fibrates for 12 weeks or longer.Patients were excluded if they were naive to antipsychotics or had been treated within the previous 6 months with paliperidone ER, olanzapine, or clozapine, or within the last 3 months with a depot antipsychotic; treated with a mood stabilizer or antidepressant within 3 months of study onset; or currently receiving a glucose-lowering agent or had a history of diabetes. Patients with abnormal fasting plasma glucose (>126 mg/dL) or fasting TG levels (>400 mg/dL) at screening were also excluded. Previous studies have shown that younger patients first starting treatment with antipsychotics may be particularly prone to developing weight gain and other metabolic effects.33–35 Antipsychotic-naive patients were excluded from the current study to avoid potentially confounding influences from disproportionate numbers of antipsychotic-naive patients between groups.TreatmentTreatment was assigned based on a secure computer-generated randomization schedule. Stratified randomization was used based on the expected metabolic effects of each patient’s previous antipsychotic medication (weight neutral vs not weight neutral) to ensure comparability of treatment arms. Patients were randomized 1:1 to paliperidone ER or oral olanzapine using a dynamic allocation method. Paliperidone ER was initiated at 6 mg once daily (or 9 mg/d, if needed). Olanzapine was initiated at 10 mg once daily (or 15 mg/d, if needed). Dosage adjustments for both treatment arms were determined by the investigator, with maximum permitted daily doses of 9 mg for paliperidone ER and 15 mg for olanzapine. Compliance was measured as a percentage of pills taken based on pill counts at treatment week 6, at months 3 and 6, and at end point.Outcome MeasuresPrimary outcome was the mean change in the ratio of serum TG level to high-density lipoprotein level (TG/HDL) at end point versus baseline. The TG/HDL ratio is a simple and effective marker of IR.36 A TG/HDL ratio greater than 3.0 is a simple and effective marker of significant IR in nondiabetic patients, with a 64% sensitivity for those in the upper tertile of steady-state plasma glucose level (specificity, 68%; positive predictive value, 67%). More difficult to obtain fasting insulin levels carry only a 57% sensitivity, although the specificity (85%) and the positive predictive value (80%) are higher. Patients who started lipid-lowering medication during the study or had a dose change in lipid-lowering therapy were excluded from the primary analysis.Additional metabolic evaluations were carried out at baseline, at months 3 and 6, and at end point; body weight was additionally recorded at treatment week 6. Metabolic assessments included body weight, body mass index ([BMI] calculated using height measurement obtained at the time of screening), waist circumference, fasting TG, fasting HDL, and measures of glucose metabolism. Plasma insulin and glucose were measured after fasting and after a 75-g oral glucose tolerance test. Homeostasis model assessment of IR (HOMA-IR) and β-cell function (HOMA-%B) were also determined. The HOMA-IR measures IR, with higher values indicating more IR. Lean healthy individuals should have HOMA-IR values near 1. The HOMA-%B measures β-cell function, with higher values indicating more insulin secretion for a given glucose level. Lean healthy individuals should have HOMA-%B values near 100%. The HOMA values could only be calculated for those patients with no missing data during their glucose tolerance test. Insulin sensitivity was measured using the insulinogenic index defined as insulin at 30 minutes minus insulin at 0 minutes divided by glucose at 30 minutes minus glucose at 0 minutes. To further assess potential changes in the relationship between insulin secretion and glucose concentrations, glucose sensitivity for insulin was calculated as a derived parameter based on measured glucose concentrations taken during the glucose challenge using a simplified version of the method described by Mari and colleagues.37Efficacy was assessed at baseline, at 6 weeks, and at 3 and 6 months by measuring PANSS scores, Clinical Global Impression–Severity, and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Adverse events (AEs) were assessed at baseline, at 6 weeks, and at 3 and 6 months.Data AnalysisSample size was based on the expected between-treatment group difference in TG/HDL ratio. Based on available data, it was estimated that the TG/HDL ratio would decrease by 0.344 with paliperidone ER, with an expected increase of 0.573 with olanzapine. The common standard deviation of the change was estimated to be 3.209. A sample size of 205 patients in each treatment arm would give 80% power to detect a difference of 0.917 in change of the TG/HDL ratio using a Wilcoxon 2-sample test with a 0.05 two-sided significance level. It was estimated that baseline and end point TG and HDL data would not be available for 10% of patients, resulting in a planned required sample of at least 228 patients per treatment group.Intent-to-treat analyses were conducted for demographics and baseline characteristics. Outcomes were assessed in all patients treated with at least one dose of study drug who provided at least 1 posttreatment assessment. Changes from baseline were evaluated for each individual drug, that is, within-treatment group changes. Changes in assessment and outcome measures between patients treated with paliperidone ER and olanzapine were also assessed, that is, between-treatment group changes. The between-treatment group change in TG/HDL ratio from baseline to end point was assessed using the Wilcoxon 2-sample test.As the insulinogenic index is poorly defined when glucose at 30 minutes is equal to or lower than glucose at 0 minutes, the insulinogenic index was calculated only when glucose at 30 minutes was greater than glucose at 0 minutes. Also, because the index is sensitive to noise if the difference between glucose at 30 minutes and glucose at 0 minutes is very small, sensitivity analyses were performed in 3 ways. The calculations were performed whenever glucose at 30 minutes was greater than glucose at 0 minutes (method 1) and when glucose at 30 minutes was more than 10% higher than glucose at 0 minutes. If glucose at 30 minutes was less than 10% higher than glucose at 0 minutes, no result was calculated (method 2a). If glucose was less than 10% higher than glucose at 0 minutes, but there was at least a 10% rise in glucose at 60 minutes, the index at 60 minutes was used (method 2b). Also, if the change in insulin was less than zero, a value of zero was used. The HOMA model is derived from a mathematical assessment of the interaction between β-cell function and IR in an idealized model that is then used to compute steady-state insulin and glucose concentrations. The output of the model is calibrated to give a normal β-cell function of 100% and a normal IR of 1. Once this interrelationship has been calculated, β-cell function and IR can be estimated for any pair of plasma glucose and insulin concentrations.Noninferiority in efficacy of paliperidone ER versus olanzapine was measured by the change in PANSS total scores. A between-treatment group change of 6 points versus baseline for PANSS total score was considered to be a minimum clinically relevant difference. A 6-point change was used based on data from a previously published placebo-controlled study with risperidone long-acting injectable.38 In that study, the lower limit of the confidence interval for treatment benefit for improvement in PANSS total score was 5.94. Therefore, an end point difference less than 5.94 was considered to likely represent an advantage for paliperidone ER over olanzapine. This same measure of noninferiority was previously used in a double-blind study comparing paliperidone ER and risperidone long-acting injectable.29 Noninferiority was tested with the Schuirmann test. Changes from baseline to each visit and end point for secondary efficacy and safety measures were evaluated using the Wilcoxon signed-rank test for ordinal/continuous data and the sign test for nominal data. Between-treatment group changes were tested using the Wilcoxon 2-sample test for ordinal/continuous data and the Fisher exact test for nominal data. In addition, a correlation analysis between the change in PANSS total score and weight gain was performed using the Spearman rank correlation coefficient.RESULTSPatientsA total of 462 patients were randomized: 239 patients received paliperidone ER, and 220 patients received olanzapine. Baseline characteristics were similar between the treatment groups, with no statistically significant differences in baseline demographics, comorbid illness, or antipsychotics used in the 3 months before enrollment. Most patients were male (55.6% of those treated with paliperidone ER and 60.5% with olanzapine), with a mean age of 38.8 ± 11.1 years with paliperidone ER and 37.5 ± 11.4 years with olanzapine. Most patients were diagnosed with paranoid schizophrenia (68.2% of those treated with paliperidone ER and 71.4% with olanzapine), with a mean time since diagnosis of 10.1 ± 9.2 years for patients treated with paliperidone ER and 11.2 ± 9.9 years for patients treated with olanzapine. Metabolic syndrome was identified at baseline in 22.1% of patients randomized to paliperidone ER and 19.7% olanzapine, with a mean baseline weight and BMI, respectively, of 76.0 ± 17.0 kg and 26.9 ± 6.3 kg/m2 for patients randomized to paliperidone ER and 77.9 ± 16.4 kg and 27.0 ± 5.7 kg/m2 for olanzapine patients. Lipid-lowering medications were used by 4 patients at baseline.Antipsychotic treatments were used during the 3 months before enrollment in 92.1% of patients randomized to paliperidone ER and 95.9% to olanzapine, most commonly oral risperidone (35.6% of patients randomized to paliperidone ER and 44.1% to olanzapine) and haloperidol (23.4% paliperidone ER and 18.6% olanzapine). Last doses of those antipsychotics used during the months before enrollment were also similar between treatment groups.Six months of treatment were completed by 168 patients treated with paliperidone ER (70.3%) and 178 with olanzapine (80.9%). Primary reasons for early discontinuation in the paliperidone ER and olanzapine groups, respectively, were patient choice (12.6% and 10.0%), lack of efficacy (6.3% and 2.7%), AEs (4.6% and 2.3%), lost to follow-up (2.5% and 1.8%), and other (3.8% and 2.3%). Metabolic AEs leading to withdrawal were hyperglycemia (n = 1) in the paliperidone ER group and blood glucose increase (n = 1) and weight increase (n = 1) in the olanzapine group.Mean initial daily drug dose was 6.4 ± 1.2 mg for paliperidone ER and 10.6 ± 2.0 mg for olanzapine. Mean daily doses were 6.9 ± 1.3 mg for paliperidone ER and 11.6 ± 2.3 mg for olanzapine. Mean duration of exposure was 151 ± 52 days with paliperidone ER and 160 ± 47 days with olanzapine. Treatment compliance was 92% or higher at each assessment and at end point for both treatments.Primary End Point: TG/HDL RatioThe primary end point was evaluated in 215 patients treated with paliperidone and 198 patients treated with olanzapine. Patients with missing baseline or follow-up data (n = 45) and 1 patient who started lipid-lowering medication during the study were excluded. Mean end point change in TG/HDL ratio versus baseline was significant for olanzapine (0.097 ± 2.72; P < 0.0001, reflecting worsening), but not for paliperidone ER (−0.17 ± 2.51; P = 0.4748). The between-treatment group change at end point showed that paliperidone ER was significantly less likely to result in an undesirable metabolic effect compared with olanzapine (P < 0.0001). Changes in TG/HDL ratio versus baseline within each treatment group (ie, within-treatment group change) were significant for olanzapine at each assessment and at end point (P < 0.0001; Fig. 1) but not for paliperidone ER. Differences in change in TG/HDL ratio versus baseline between values for patients treated with paliperidone ER versus olanzapine (ie, between-treatment group changes) were significant at each assessment and at end point (P < 0.0001).FIGURE 1. Mean TG/HDL ratio, with SE bars, at each visit and at end point. Change in TG/HDL ratio versus baseline was significant for olanzapine (***P < 0.0001).Secondary Metabolic End PointsLipidsSerum TG increased (P < 0.0001 at each assessment and at end point) and HDL decreased (P = 0.0588 at month 3 and P ≤ 0.0083 at month 6 and at end point) significantly for olanzapine, with no significant changes at any time point with paliperidone ER. Between-treatment group changes versus baseline were significant at each assessment and at end point for TG (P ≤ 0.0001) and HDL (P < 0.038). New onset of impaired TG, that is, plasma TG level of 150 mg/dL or higher, occurred in 27.0% of patients treated with paliperidone ER and 39.8% with olanzapine (P = 0.0433). New onset of impaired HDL, that is, plasma HDL level less than 40 mg/dL, was noted in 19.8% with paliperidone ER and 23.8% with olanzapine (P = not significant).Glucose MetabolismComplete glucose tolerance testing data at baseline and at end point were available for 183 patients treated with paliperidone ER and 174 with olanzapine. At end point, HOMA-IR had worsened significantly with olanzapine (P = 0.0003), with a trend (P = 0.0917) for worsening shown for HOMA-%B (Table 1). There were no significant within-treatment group changes with paliperidone ER. Between-treatment group changes versus baseline for olanzapine versus paliperidone ER were significant at each assessment and at end point for HOMA-%B (P < 0.045).TABLE 1 Outcome Measures for PAL ER and OLZThe insulinogenic index, when calculated when glucose at 30 minutes was higher than glucose at 0 minutes, had significantly increased for olanzapine at 6 months (P = 0.0478) and a trend toward an increase was seen at end point (P = 0.0629; Table 1). There were no significant within-treatment group changes with paliperidone ER. No significant between-treatment group changes versus baseline were seen. Sensitivity analyses for the insulinogenic index were performed when glucose at 30 minutes was more than 10% higher than glucose at 0 minutes. These analyses showed similar results using several methods. Therefore, results were not dependent on the specific method used for dealing with cases where glucose and/or insulin did not rise during glucose tolerance testing.Glucose sensitivity for insulin, calculated as a parameter derived from the oral glucose tolerance test using a Mari-type analysis,37 showed significant increases from baseline for olanzapine at each assessment and at end point (P < 0.05; Table 1), but not for paliperidone ER. There were no significant between-treatment group changes versus baseline.Glucose dysfunction was assessed by evaluating glucose tolerance, fasting glucose, and incidence of type 2 diabetes. Type 2 diabetes was identified when at least one of the following conditions was met: fasting plasma glucose level was 126 mg/dL or higher, 2-hour postload plasma glucose level during the glucose tolerance test was 200 mg/dL or higher, or a glucose-lowering agent was initiated during the course of the study. There were no significant between-treatment group changes in first onset of glucose dysfunction. The incidence of glucose dysfunction for paliperidone ER and olanzapine, respectively, was 19.1% and 23.9% for impaired glucose tolerance defined as a 2-hour postload glucose level of 140 mg/dL or higher but less than 200 mg/dL; 3.7% and 4.8% for impaired glucose tolerance defined as a 2-hour postload glucose level of 200 mg/dL; 38.3% and 40.1% for impaired fasting glucose (≥100 mg/dL but <126 mg/dL); and 6.2% and 7.2% for type 2 diabetes.Metabolic SyndromeNew onset of metabolic syndrome, based on National Cholesterol Education Program/Adult Treatment Panel III criteria, occurred in 13.2% of patients treated with paliperidone ER and 23.3% of patients treated with olanzapine. This between-treatment group change was significant (P = 0.0230).Body Weight, BMI, and Waist CircumferenceAt end point, mean body weight increased by 1.2 ± 4.6 kg with paliperidone ER and 3.8 ± 5.9 kg with olanzapine. Within-treatment group change and between-treatment group changes in weight versus baseline were significant at each assessment and at end point (Fig. 2A). At end point, a weight change of 7% or more versus baseline occurred for 18.3% of patients treated with paliperidone ER and 28.5% of patients treated with olanzapine. Likewise, within-treatment group and between-treatment group changes in BMI were significant at each assessment and at end point, with significantly greater increases in BMI with olanzapine versus paliperidone ER at each assessment and at end point (Fig. 2B).FIGURE 2. Mean body weight (A) and BMI (B), with SE bars. The SE values ranged from 1.1 to 1.2 for weight and 0.4 to 0.5 for BMI, making them difficult to visualize on the graph. All within-treatment group and between-treatment group changes at each assessment and end point versus baseline were significant for body weight (***P ≤ 0.0001) and BMI (***P ≤ 0.0001).At end point, the mean increase in waist circumference was 0.7 ± 5.4 cm with paliperidone ER (P = 0.140) and 3.4 ± 6.2 cm with olanzapine (P < 0.0001). This between-treatment group change was statistically significant (P < 0.0001).Difference in percentage change of dropouts increased from 1.5% at week 6 to 4.2% at month 3, and 8.6% at month 6, with a higher percentage of dropouts with paliperidone ER resulting in less exposure to drug in the paliperidone ER group. This difference did not appear to influence outcome measures because the difference in TG/HDL ratio was highest at month 3 (+0.45 olanzapine vs −0.11 paliperidone ER). The difference did not increase further from months 3 to 6. This suggests that the increase of the TG/HDL ratio is more associated with treatment initiation than duration of exposure. In addition, body weight was significantly higher with olanzapine compared with paliperidone at week 6, month 3, and month 6. With olanzapine, the largest body weight increase occurred during the first 6 weeks of treatment (+2.0 kg), with additional increases to 2.9 kg at month 3 and 4.0 kg at month 6. With paliperidone ER, body weight increase was 0.7 kg during the initial 6 weeks of treatment, increasing to 1.1 kg at month 3 and 1.5 kg at month 6. As a substantial amount of the increase in body weight occurred during the early stages of the study, body weight increase does not appear to be entirely linked to duration of drug exposure.EfficacySignificant improvements in psychiatric symptoms occurred for patients in both groups, with no significant between-treatment group changes. Within-treatment group improvements in PANSS total and subscale scores were significant at each assessment and at end point for both paliperidone ER and olanzapine (P < 0.0001 versus baseline at each assessment and at end point; Table 1). At end point, PANSS total scores were decreased by 13.5 ± 15.9 with paliperidone ER and 16.6 ± 15.0 with olanzapine. Therefore, the difference in the change of mean PANSS total scores from baseline to end point between treatments was 3.1 points. This difference was significantly lower than the minimum prespecified clinically relevant difference set at 6.0 points in the PANSS total score using Schuirmann test (P < 0.0242). Thus, noninferiority in efficacy, that is, treatment efficacy equivalence of paliperidone ER and olanzapine, was confirmed within the specified equivalence bounds. The percentage of patients with improvement in PANSS total scores of 20% or higher at end point versus baseline was similar for both treatments (60.3% with paliperidone ER and 65.9% with olanzapine).Overall, the change in PANSS total score and weight change were found to have a very weak negative correlation at month 3 (r = −0.15) and at month 6 (r = −0.06), meaning that less weight gain is very weakly associated with better PANSS scores. The strongest correlation, although not stronger than intermediate level (r = 0.50 at month 3 and r = 0.67 at month 6), was found in the subgroup of patients who experienced weight gain but did not improve on PANSS (meaning that the follow-up PANSS total score was equal to or higher than the baseline PANSS total score). Exploring correlation based on treatment found a weak correlation for the paliperidone ER arm and no correlation with olanzapine. Correction of baseline body weight by means of partial correlation did not change results.Based on Clinical Global Impression–Severity categories, the percentage of patients “not at all ill” to “mildly ill” was 17.0% at baseline and 51.1% at end point with paliperidone ER, and 11.3% at baseline and 56.8% at end point with olanzapine. Baseline SF-36 mental component scores were significantly lower with olanzapine versus paliperidone ER (33.9 ± 13.2 vs 37.1 ± 11.8; P = 0.0095), with no significant difference in baseline physical component scores (48.5 ± 8.4 with olanzapine vs 48.1 ± 8.0 with paliperidone ER). These small differences in baseline SF-36 mental and physical component scores were not clinically relevant. Improvements from baseline to end point for SF-36 physical and mental component scores, respectively, were 0.9 ± 8.5 (P = 0.09) and 3.4 ± 12.6 (P < 0.0001) for paliperidone ER and 1.8 ± 7.0 (P < 0.0001) and 6.5 ± 11.8 (P < 0.0001) for olanzapine. Between-treatment group change at end point versus baseline was significant for mental component scores, favoring olanzapine (P = 0.0284).Tolerability (AEs)Treatment-emergent AEs (TEAEs) are summarized in Table 2. Most TEAEs were mild or moderate in severity with paliperidone ER and olanzapine, with few patients discontinuing treatment because of a TEAE. Serious TEAEs were most commonly psychiatric symptoms. Weight increase affected nearly twice as many patients treated with olanzapine.TABLE 2 TEAEsDISCUSSIONAt 6 months, metabolic effects were more common with therapeutic doses of oral olanzapine versus paliperidone ER. Mean changes in TG/HDL ratio, body weight, and waist circumference were significantly higher for olanzapine compared with paliperidone ER, indicating higher IR and negative metabolic changes with olanzapine. High TG and low HDL are independent risk factors for cardiovascular disease.39 The TG/HDL ratio has been shown to be an independent predictor of coronary heart disease and predictor of mortality in women with suspected myocardial infarction,40–42 making the TG/HDL ratio a particularly useful measure of metabolic risk. Other metabolic parameters in the current study additionally demonstrated significantly increased metabolic effects with olanzapine. Glucose sensitivity for insulin worsened significantly with olanzapine, with no significant changes for paliperidone ER. The incidence rate of metabolic syndrome was 23.3% with olanzapine versus 13.2% with paliperidone ER (P = 0.0230). This significant difference in the development of metabolic syndrome with antipsychotic treatment is especially important as patients with schizophrenia are at a higher risk of having metabolic syndrome,22 and metabolic syndrome is an important risk factor for cardiovascular disease.43 As metabolic syndrome can contribute to overall health morbidity and mortality in patients with schizophrenia, understanding the important relationship between antipsychotic treatment and metabolic syndrome risk is an important part of the clinical management of patients with schizophrenia.44 Furthermore, in the current study, mean weight gain was significantly higher among patients treated with olanzapine, who experienced an overall weight gain that was more than 3 times greater than with paliperidone ER. The current study carefully evaluated negative metabolic consequences associated with weight gain, which should be considered when identifying optimal treatment solutions for patients with schizophrenia, given that antipsychotic treatment will be required for many years, if not lifelong.Mean baseline weight and BMI, 76 to 78 kg and 27 kg/m2, respectively, in the current overall study sample, were similar to previous reports in patients with schizophrenia. Mean baseline BMI in the CATIE study was 30.4 kg/m2.45 Previously published clinical trials conducted in the United States evaluating paliperidone ER in acute schizophrenia reported a mean baseline weight of 87 to 90 kg in one study24 and 77 to 78 kg in another.29 A European paliperidone ER study reported a mean baseline BMI of 26 to 27 kg/m2.27 A paliperidone ER study treating patients with acute schizophrenia in North and Central America, Europe, Asia, Israel, and South Africa reported a mean baseline weight of 75 kg.26 A virtual head-to-head comparison of paliperidone ER and immediate-release risperidone using data from 6 short-term clinical trials reported a mean baseline BMI of 25 to 26 kg/m2.30These data support earlier studies showing more substantial negative metabolic effects with olanzapine, which has been linked to IR, dyslipidemia, and excess weight gain.46,47 In the current study, olanzapine was likewise associated with a significantly greater increase in mean body weight, dyslipidemia, IR, and metabolic syndrome compared with paliperidone ER. Weight gain with olanzapine was substantially less than reported from an earlier double-blind study comparing outcome in patients treated with clozapine or high-dose olanzapine for 6 months.48 In that study, 71% of patients treated with olanzapine were dosed with 35 mg or more daily, and the mean weight gain at end point was 8 kg. The current study supports data from previous clinical trials reporting a relatively favorable metabolic profile with paliperidone ER.31 Efficacy and overall safety and tolerability were similar with paliperidone ER and olanzapine. Significant improvements from baseline to end point were shown in PANSS total and all subscale scores with both treatments. Based on prespecified PANSS total score parameters, the efficacy of paliperidone ER was demonstrated to be noninferior to olanzapine. Earlier work has shown that olanzapine may be particularly efficacious among second-generation antipsychotics.2 These data therefore confirm good efficacy with paliperidone ER. There were no clinically relevant differences between paliperidone ER and olanzapine in some of the additional study end points such as sleep quality or daytime drowsiness. Complete oral glucose tolerance test data were not available from all patients at baseline and/or during follow-up, in which case derived parameters could not be calculated.Six-month completion rate was good in the current study at 70% for patients treated with paliperidone ER and 81% with olanzapine. The median time to treatment discontinuation with atypical antipsychotics in the CATIE trial, for example, was 4.6 months overall, with time to discontinuation with olanzapine being longer at 9.2 months.49 A review of 3 randomized clinical trials evaluating 6-month treatment with olanzapine, ziprasidone, or aripirazole reported study completion by only 48% of participants.50 The high completion rate in the current study is likely to be related to the flexible treatment design using a pragmatic treatment approach. For example, completion rate in a 6-month naturalistic study treating patients with oral ziprasidone was 64%.51 A 6-month open-label study treating patients with schizophrenia with flexible doses of paliperidone ER reported a study completion rate similar to the current study at 71%.52Both treatments were generally well tolerated, with low rates of early discontinuation caused by a TEAE for both paliperidone ER and olanzapine. There were small differences in the various reasons for withdrawal, which added up to an overall 10% difference between paliperidone ER and olanzapine.The strengths of the current study include study design to specifically identify differences in metabolic outcome measures and the prospective, randomized, controlled, head-to-head comparison between paliperidone ER and olanzapine. Dosing used in the current study reflects dosages used in other clinical trials and in clinical practice. Olanzapine has been shown to have good efficacy in schizophrenia when dosed at 10 to 20 mg/d.53 Olanzapine doses used in clinical practice (eg, >15 mg) are often higher than those recommended from clinical trials (eg, usually 10 mg/d).54 Although target doses of 10 to 15 mg/d are typically recommended, some patients will benefit from treatment with higher doses, including doses more than 20 mg/d in patients who have previously responded suboptimally to typical antipsychotics.55 A review of the paliperidone ER studies reported 6 to 12 mg/d as the most frequently used doses for treating schizophrenia.56 Mean modal daily paliperidone ER doses in open-label clinical trials ranged from 9.4 mg to 10.7 mg.31 Furthermore, similar efficacy was established between treatment with paliperidone ER and olanzapine in the current study, similar to an earlier report showing a decrease in PANSS total score of at least 30% in 56% of patients randomized to paliperidone ER 6 mg/d, 51% with paliperidone ER 9 mg/d, 61% with paliperidone ER 12 mg/d, and 52% with olanzapine 10 mg/d.25 Interpretation of data is limited by the use of an open-label design; however, bias related to open-label treatment would not be expected to affect metabolic outcome measures, which were the primary focus of this study. Because of the propensity for developing unwanted metabolic effects in patients receiving first antipsychotic treatment, future studies may wish to replicate the current study using antipsychotic-naive patients.In summary, this study confirms that there are significant differences in the metabolic profiles of flexible therapeutic doses of paliperidone ER compared with oral olanzapine. Olanzapine was associated with significantly more weight gain, lipid changes, IR, and new-onset metabolic syndrome, whereas efficacy between the two antipsychotics was demonstrated to be noninferior.AUTHOR DISCLOSURE INFORMATIONAndreas Schreiner is a full employee and a member of Medical Affairs EMEA at Janssen-Cilag GmbH, Neuss, Germany. Dana Niehaus has received sponsorship for congresses/CME activities from Janssen-Cilag, AstraZeneca, Aspen Pharmacare, SKB, Lundbeck, Sanofi-Aventis, and Servier and had research contracts with Janssen-Cilag, AstraZeneca, Lundbeck, Sanofi-Aventis, Servier, and Quintiles. Nasser Aldien Shuriquie, Kaire Aadamsoo, Rolando Salinas, Pitsa Theodoropoulou, and Lorena García Fernández declare no conflicts of interest. Peter Korcsog is a consultant and a scientific advisory board member for AstraZeneca, Eli Lilly, and Janssen-Cilag. Alp Üçok is a consultant and a scientific advisory board member for Schering-Plough, Eli Lilly, and Janssen-Cilag. Christophe Tessier is a former employee of Janssen-Cilag SAS, Paris, France. Paul Bergmans is a full employee of Janssen-Cilag BV, Tilburg, Netherlands. Dagmar Hoeben is a former employee of Janssen Pharmaceutica NV, Beerse, Belgium.REFERENCES1. Leucht S, Corves C, Arbter D, et al.. 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Text]00003495-200161010-00011ovid.com:/bib/ovftdb/00004714-201208000-0000300003495_2001_61_111_bhana_schizophrenia_|00004714-201208000-00003#xpointer(id(R53-3))|11065405||ovftdb|00003495-200161010-00011SL0000349520016111111065405P129[Medline Link]11217867ovid.com:/bib/ovftdb/00004714-201208000-0000300004603_1999_60_31_stahl_antipsychotic_|00004714-201208000-00003#xpointer(id(R54-3))|11065405||ovftdb|SL000046031999603111065405P130[Medline Link]10340685ovid.com:/bib/ovftdb/00004714-201208000-0000300023727_2002_10_280_citrome_antipsychotics_|00004714-201208000-00003#xpointer(id(R55-3))|11065213||ovftdb|00023727-200209000-00003SL0002372720021028011065213P131[CrossRef]10.1080%2F10673220216279ovid.com:/bib/ovftdb/00004714-201208000-0000300023727_2002_10_280_citrome_antipsychotics_|00004714-201208000-00003#xpointer(id(R55-3))|11065405||ovftdb|00023727-200209000-00003SL0002372720021028011065405P131[Medline Link]12202454Metabolic Effects of Paliperidone Extended Release Versus Oral Olanzapine in Patients With Schizophrenia: A Prospective, Randomized, Controlled TrialSchreiner, Andreas MD; Niehaus, Dana MD; Shuriquie, Nasser Aldien MD; Aadamsoo, Kaire MD; Korcsog, Peter MD; Salinas, Rolando MD; Theodoropoulou, Pitsa MD; Fernández, Lorena García MD; Üçok, Alp MD; Tessier, Christophe MD; Bergmans, Paul MSc; Hoeben, Dagmar PhDOriginal Contributions432