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ORIGINAL ARTICLE
Year : 2011  |  Volume : 20  |  Issue : 1  |  Page : 25-31  Table of Contents     

Tolerability and efficacy of paliperidone ER compared to olanzapine in the treatment of schizophrenia: A randomized, double-blind, multicentric trial


Department of Psychiatry, SBKS MIRC, Sumandeep Vidyapeeth, Pipaira, Vadodara, Gujarat, India

Date of Web Publication12-Jul-2012

Correspondence Address:
Sandip Shah
Department of Psychiatry, SBKS MIRC, Sumandeep Vidyapeeth, At & PO: Pipaira, Dist. Vadodara - 391 760, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-6748.98411

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   Abstract 

Background: Paliperidone is an active metabolite of risperidone and actss through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. Aim: The present randomized, double-blind, multicentric trial was designed to determine the safety and efficacy of paliperidone extended release (ER) compared to olanzapine in the treatment of acute schizophrenia. Materials and Methods: A total of 214 patients with diagnosis of schizophrenia were randomized to paliperidone ER (n=109) and olanzapine (n=106) treatment groups. Totally 206 patients were evaluated for efficacy parameters using Positive and negative syndrome scale (PANSS) score and Clinical Global Impression-severity of illness (CGI-S) and Clinical Global Impression-improvement of illness (CGI-I) scales. Safety was assessed by treatment-emergent adverse events and movement disorders. Results: All patients showed significant reduction in PANSS scores at the end of treatment. However, the results were comparable and there was no significant difference at the end of the trial between paliperidone ER group and olanzapine group. Both the treatment groups showed decrease in the severity of illness and improvement in symptomatology. The most common adverse events reported in paliperidone ER versus olanzapine group were Extra Pyramidal Syndrome (EPS) (13.7% vs. 15.6%), headache (12.7% vs. 8.9%), increased appetite (8.8% vs. 10.0%) and drowsiness (4.9% vs. 303%). There was no clinically relevant difference in change from baseline to the end of the trial in abnormal involuntary movement scale (AIMS) and barnes akathisia rating scale (BARS) total scores between both the groups. Conclusion: Paliperidone ER is effective in controlling schizophrenic symptoms as well as exhibits comparable tolerability profile. Thus, paliperidone ER has the potential to be a useful new treatment option for patients with schizophrenia.

Keywords: Paliperidone, olanzapine, schizophrenia


How to cite this article:
Shah S, Joshi D. Tolerability and efficacy of paliperidone ER compared to olanzapine in the treatment of schizophrenia: A randomized, double-blind, multicentric trial. Ind Psychiatry J 2011;20:25-31

How to cite this URL:
Shah S, Joshi D. Tolerability and efficacy of paliperidone ER compared to olanzapine in the treatment of schizophrenia: A randomized, double-blind, multicentric trial. Ind Psychiatry J [serial online] 2011 [cited 2019 Aug 20];20:25-31. Available from: http://www.industrialpsychiatry.org/text.asp?2011/20/1/25/98411

Schizophrenia is a devastating illness with significant psychological, physical, social, and economic impacts. Although the disease course is variable, it is most often chronic as characterized by ongoing function impairment and the frequent recurrence of acute psychotic symptoms. Relapse rates are substantial, resulting in re-hospitalization, decreased quality of life and increased economic burden. Successive relapses are also associated with a poorer prognosis and progressively declining outcomes.

Thus, the general goals of treatment are to quickly reduce symptom severity, improve patient functioning and prevent recurrences of symptomatic episodes and associated deterioration of functioning.

Antipsychotic medication is the primary intervention for the stabilization of acute episodes and the prevention of symptom recurrence in patients with schizophrenia. [1],[2],[3] The atypical antipsychotics are associated with lower risk of reversible and irreversible movement disorders than conventional antipsychotics. [1],[2],[4],[5],[6] There is also evidence to suggest that atypical antipsychotics have an advantage in their ability to delay the time to relapse, [2],[3],[4],[5],[6],[7] although there is variability in both the efficacy and safety characteristics of these drugs. [8] Optimal effectiveness and the risk of adverse events must be considered when evaluating longer-term treatment strategies as discontinuation rates remain high among the currently available oral preparations of antipsychotic agent. [9]

Paliperidone is the major active metabolite of the well-established antipsychotic agent, risperidone. It has a pharmacological activity at monoaminergic receptors that is similar to risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. [10] Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H 1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic, muscarinic or β 1 - and β 2 -adrenergic receptors. Even though paliperidone is a strong D 2 -antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects. [10]

Paliperidone extended-release (ER) tablets provide a consistent and continual drug delivery for a period of more than 24 hours, thereby reducing the fluctuations in plasma concentrations. Importantly, this release profile of paliperidone ER permits initiation of treatment with a therapeutically effective dose which may reduce the need for initial dose titration. [11] The present study was aimed for evaluating the efficacy and tolerability of paliperidone ER tablets developed by Torrent Pharmaceuticals Ltd., India, in Indian schizophrenic patients.


   Materials and Methods Top


A total of 13 centers across India participated in this randomized, double-blind, multicentric study to evaluate the safety and efficacy of paliperidone ER compared to olanzapine in patients with schizophrenia.

Patients

Male or female patients aged between 18 and 59 years with diagnosis of schizophrenia as per diagnostic and statistical manual of mental disorders (DSM)-IV, and with PANSS score between 70 and 120 and clinical global impression (CGI) score ≥4 were included in the present study. Both newly diagnosed patients of schizophrenia and those who received antipsychotic treatment were included in the study.

Patients were excluded if they had any one of the following.

  1. Patients with history of allergy or hypersensitivity to paliperidone, olanzapine and risperidone
  2. Patients who had used depot antipsychotics 120 days prior to the screening
  3. Patients who received electroconvulsive treatment within 3 months before screening or had involuntary admission to a psychiatric hospital
  4. Pregnant or nursing women
  5. Patients with DSM-IV axis I diagnosis other than schizophrenia
  6. Patients who had significant risk of suicidal or aggressive behavior within last 4 weeks
  7. Patients with any major unstable medical illness in the past 3 months
  8. Patients with abnormal ECG and abnormal lab values
  9. Patients with history of significant gastrointestinal diseases
  10. Patients who participated in any clinical trial within the past 3 months
  11. Patients with history of Tardive Dyskinesia or Neuroleptic Malignant Syndrome
  12. Patients who had used antidepressant or mood stabilizer within past 2 weeks
  13. Patients taking barbiturates, lithium, sodium valproate, gabapentin, carbamazepine
  14. Patients resistant to antipsychotic treatment (defined as patients who failed to respond to two conventional antipsychotic drugs for at least 6 weeks and to each in the past 6 months).
Study design

The patients gave a signed informed consent before any study-related procedure was undertkaken, including screening. The total duration of the trial included treatment of 6 weeks and 5 days of screening and run-in period. Patients underwent a comprehensive physical examination including body weight, body mass index (BMI) and 12-lead ECG, psychiatric evaluation, appropriate laboratory investigations including hematology, serum chemistry with random blood glucose and prolactin levels and urine pregnancy test (females). Patients meeting the eligibility criteria at screening were enrolled in the study. During 5 days run-in period, patients receiving antipsychotic treatment had discontinued their existing medications. In this run-in period, the patients were allowed to take concomitant medication like zolpidem, trihexifenidyl, lorazepam, propanolol as per investigator's judgment. After run-in period, patients who were stable were randomized to any of the two treatment groups as per randomization schedule. The study protocol was approved by the institutional review boards or independent ethics committee for all participating study centers and by the Drug Regulatory Authority of India (Drug Controller General of India). The baseline efficacy parameter assessment was done on the first day of active treatment.

Follow-up visits

After successful screening (visit 1) and enrollment (day 1, visit 2), the patients reported for visit 3 (end of 1 st week), visit 4 (end of 2 nd week), visit 5 (end of 4 th week) and the final assessment was done at visit 6 (end of 6 th week).

Drugs and dose administration

The medication was taken by the patient once daily 30 minutes after dinner. The patients were advised to take the medications around the same time on each day. For blinding purpose, investigational products (paliperidone ER tablet and olanzapine tablet) were kept in an identical capsule. The dosage of drugs was titrated as given in [Table 1].
Table 1: Schedule of up-titration

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Efficacy measures

Primary endpoint

  1. Change in the total PANSS score (from baseline to the end of the trial)
  2. Change in the CGI scale score (from baseline to the end of the trial)
Secondary endpoint

Change in PANSS Marder factor scores (positive and negative symptoms, depression/anxiety, uncontrolled hostility/excitement and disorganized thoughts) (from baseline to the end of the trial).

Safety and tolerability measures

All treatment-emergent adverse event (TEAEs) using WHO adverse reaction terminology preferred terms, which were observed and enquired during the trial, were reported. Additional information on the adverse event (AE) that was recorded included date of onset, duration of event, concurrent therapies, the investigator's assessment of severity, possible causative relationship to study drug, and whether a change in dose or withdrawal of treatment was required.

Movement disorders were assessed using abnormal involuntary movement scale (AIMS) and barnes akathisia rating scale (BARS). A comprehensive physical examination including body weight, BMI and 12-lead ECG (QT interval) was performed before and at the end of treatment. Clinical laboratory evaluations (hematology, serum chemistry including random blood glucose, prolactin levels) were carried out at screening and at the end of treatment.

Statistical analysis

The primary statistical analysis was intent to treat (ITT) for all efficacy variables and safety variables with last observation being carried forward (LOCF). ITT population included those patients who were administered at least a single dose of the study drug and one post-administration evaluation being performed. The final evaluation was done for ITT population as well as for patients completing the whole duration for primary and secondary efficacy parameters. Descriptive statistics or percentage frequency were reported for all the efficacy and safety parameters.

Primary efficacy variables

  1. Change in total PANSS score
    1. percentage mean reduction from baseline to each visit
    2. Difference from the baseline to each visit between paliperidone ER and olanzapine calculated using Analysis of Covariance (ANCOVA)
  2. Change in the CGI from baseline to the end of the trial.
Secondary efficacy variables

Change in PANSS Marder factor scores (positive and negative symptoms, depression/anxiety, uncontrolled hostility/excitement and disorganized thoughts) from baseline to the end of the trial, calculated using ANCOVA.

Safety variables

  1. Percentage frequency was reported for total number and severity of AEs, AIMS and BARS
  2. Mean±SD were reported for laboratory parameters, vital signs, weight and QT interval of ECG. The statistical significance was analyzed using paired t-test.
Response analysis for responders' and non-responders' evaluation was performed using Cochran-Mantel-Haenszel test. All the statistical tests performed were two-tailed, and P value less than 0.05 was considered to be statistically significant.


   Results Top


Demography

A total of 214 patients with age 34.25±10.52 years (mean±SD) (males 138, females 76) were randomized to receive either paliperidone ER or olanzapine in the present study as shown in [Figure 1]. The demographic data of the patients are shown in [Table 2]a and b. Out of 214 patients, 109 received paliperidone ER and 106 patients received olanzapine. Totally 33 patients were dropped out from the study: 15 from paliperidone ER group and 18 from olanzapine group. The reasons for the dropout from the study are presented in [Table 3].
Figure 1: Patient's disposition in the trial

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Table 2:

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Table 3: Dropouts and reasons for dropping out

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Efficacy

Total PANSS score

All the patients at baseline had a diagnosis of schizophrenia represented by the baseline mean±SD total PANSS score of 96.1±12.5 and 96.4±11.9 in paliperidone ER group and olanzapine group, respectivley. Total PANSS score decreased from 96.1±12.5 to 54.7±15.9 in paliperidone ER group and from 96.4±11.9 to 55.0±15.2 in olanzapine group [Figure 1]. The change in total PANSS score was statically significantly different from baseline to the end of the trial for both the treatments. The least square mean difference from baseline to the end of the trial was −41.5 [95% CI (−44.3, −38.7); P value <0.01] and -41.3 [95% CI (−44.2, −38.4); P value <0.01] for paliperidone ER group and olanzapine group, respectively [Table 4].
Table 4: Mean difference in reduction of PANSS score

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Results revealed that the adjusted least square mean difference and 95% CI between reduction in total PANSS score with paliperidone ER and olanzapine from baseline to the end of the trial was −0.17 [95% CI (−4.20, 3.86); P value=0.93], which indicated the difference between both the treament groups was not statically significant [Table 4].

CGI-severity of illness

At the end of the trial, the number of markedly ill patients reduced from 47.2 to 2.8% in paliperidone ER group, while in olanzapine group the same reduced from 55.0 to 6.0%. The number of severely ill patients in paliperidone ER group reduced from 12.3 to 0% at the end of the trial, while in case of olanzapine group it reduced from 11 to 1% at the end of the trial. However, there was no statistically significant difference from baseline to the end of the trial (P value=0.77) in CGI-severity (CGI-S) between paliperidone ER group and olanzapine group.

CGI-improvement of illness

Significant improvements from baseline to the end of the trial were observed in CGI-improvement (CGI-I) scale for both the paliperidone ER and olanzapine treatment groups [Table 5]a and b, although there was no statistically significant difference from baseline to the end of the trial (P value=0.97) in CGI-Ibetween paliperidone ER group and olanzapine group.
Table 5:

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PANSS subscores

Between-group comparisons of the reduction in PANSS subscores, like PANSS positive symptoms, PANSS negative symptoms, BPRS total, BPRS psychosis score, PANSS general psychopathology symptoms, PANSS Marder factor score, from baseline to the end of the trial were made using ANCOVA, considering baseline (enrollment, visit 2) as a covariate. Adjusted least square mean difference with 95% CI was calculated to check the reduction from baseline to end of the treament for both the groups. Results revealed that although a significant reduction was observed in both the groups, there was no statistically significant difference between both the treatment groups [Table 6].
Table 6: Secondary efficacy endpoint parameters

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A total of 206 patients were considered for response analysis and they were evaluated as "responder" or "non-responder" on the basis of total PANSS score reduction. Patients were considered as responders if there was at least 30% reduction in total PANSS score compared to baseline in any visit. After the end of 1 st week treatment, the number of responders with paliperidone ER and olanzapine group was found to be 23% and 26%, respectively. The number of responders in either group was increased form visit 3 to visit 6 in an incremental manner. After 4 weeks of treatment, the number of responders in paliperidone ER group (84%) was meaningfully higher than the number of responders in olanzapine group (72%). The number of responders (90%) in paliperidone ER group was comparable to that in olanzapine group (87%) at the end of the trial.

Safety

There was no unexpected serious AE reported in any of the treatment groups. Totally 192 AEs were reported during the trial. Most of the reported AEs were mild or moderate in nature. A total of 102 AEs were reported in 54 patients receiving paliperidone ER treatment and 90 AEs were reported in 48 patients receiving olanzapine treatment. The most common events reported were EPS (13.7%), headache (12.7%), increased appetite (8.8%) and drowsiness (4.9%) in paliperidone ER group; and EPS (15.6%), increased appetite (10.0%), headache (8.9%) and drowsiness (3.3%) in olanzapine group.

Totally 49.5% of patients in paliperidone ER group and 45.7% of patients in olanzapine group experienced at least one AE, which was not statically significant. Out of the total reported AEs, 1% in paliperidone ER group and 4.4% of in olanzapine group were classified as severe.

The vital signs (systolic blood pressure, diastolic blood pressure and pulse) were measured during every visit. In both the treatment groups, there was no statistically significant change in the vital signs after 6 weeks of treatment, except diastolic blood pressure in olanzapine group which showed statistically significant change (P value=0.02) at the end of treatment, but it was not clinically significant as per investigator's judgment. Changes in RBC count, WBC count, platelet count, hemoglobin, hematocrit, lymphocytes, eosinophils, serum alkaline phosphatase and serum prolactin were statistically significant in paliperidone ER treatment group, while in case of olanzapine group, RBC count, WBC count, platelet count, hemoglobin, hematocrit, monocytes, eosinophils and serum glutamate oxaloacetate transaminase (SGOT) were significantly changed after 6 weeks of treatment. In both the treatment groups, they were clinically nonsignificant as per the investigator's judgment.

Body weight was measured at baseline and end of the trial in both the treatment groups. The mean body weight was significantly increased by 1.5 kg in paliperidone ER group (P value=0.01) and by 2.0 kg in olanzapine group (P value <0.01). Increase in body weight was statistically significant from baseline to end of the treatment in both the treatment groups.

ECG measurement was carried out at baseline, on day 15 (visit 4) and at end of the trial. The QT interval was measured to evaluate the effect of both the treatments. A total of two sets were analyzed in each treatment group, comparing baseline to visit 4 and baseline to end of the trial. In both paliperidone ER group and olanzapine group, there was no statistically significant change in QT interval from baseline to visit 4 and from baseline to end of the trial.

The mean AIMS score showed a difference ranging from −9 to +14 in both the treatment groups from baseline to end of the trial. Out of total evaluable patients, 6.5% patients from paliperidone ER group and 7.8% patients from olanzapine group showed decrease in AIMS total score at the end of the trial compared to baseline. 73.1% of patients from paliperidone ER group and 76.4% of patients from olanzapine group did not show any change in total AIMS score at the end of the trial compared to baseline.


   Discussion Top


Paliperidone ER tablets provide a consistent and continual drug delivery for more than 24 hours, which may offer improved tolerability profile compared with other oral formulations, minimizing the variations in peak-to-trough plasma levels at a steady state. It has been previously suggested that minimal fluctuations in plasma concentrations of antipsychotic medications may be associated with lower occurrences of AEs. [12]

Torrent Pharmaceuticals Ltd., India, has developed a unique ER formulation of paliperidone for the treatment of schizophrenia. The present Phase III study was planned to evaluate the safety and efficacy of paliperidone ER in comparison to olanzapine in patients with schizophrenia.

Efficacy was assessed using PANSS score and CGI. There was a statistically significant and clinically meaningful reduction observed in PANSS score from baseline to the end of 6 weeks of treatment in both paliperidone ER and olanzapine treatment groups. However, the difference between both the treatments for reduction in PANSS score was not statistically significant at each visit over a period of time and at the end of the trial. Statistically significant improvements were observed for all of the five symptomatic domains (PANSS Marder factor scores) of schizophrenia: positive symptoms, negative symptoms, depression/anxiety, uncontrolled hostility/excitement and disorganized thoughts. Robust symptom improvement was further reflected in the percentage of responders achieving at least 30% PANSS total score reduction from baseline. Rapid symptom control is a clear goal of treatment for the acutely ill patients. Clinically significant improvement based on PANSS total score reduction was observed just after 1 st week of treatment with paliperidone ER.

Severity of illness and global improvement were assessed using CGI-S and CGI-I scales, respectively. After treatment of patients with schizophrenia, both the groups showed a decrease in the severity of illness and an improvement in symptomatology from baseline to end of the treatment. There was no statistically significant difference between the two treatments.

Paliperidone ER was well tolerated in this study. The reported AEs were generally mild to moderate and tolerable with both the treatments. In addition to a low frequency and occurrence of AEs in the paliperidone ER treatment group, the incidences were generally comparable with those observed in the olanzapine group.

BARS global clinical rating score was not significantly different between olanzapine group and paliperidone ER group at the end of treatment. Increase in body weight was observed in both the treatment groups. No serious AE was reported in any of the treatment groups during the trial. There have been substantial health concerns over issues related to metabolic side effects, such as weight gain and disturbances in glucose and lipid metabolism, in patients treated with atypical antipsychotics. The results from this trial are encouraging in terms of safety related to TEAEs. None of the patients in either group was associated with disturbance in random blood glucose level during the treatment. Additionally, only small increases in body weight were observed in both the treatment groups. QT interval was carefully assessed with multiple ECGs; no patient had any statistically significant change in QT interval from baseline to visit 4 and from baseline to the end of the trial in both paliperidone ER group as well as olanzapine group. This suggests little potential for QT-related cardiac risk. Although elevated prolactin levels were observed in both the groups, the incidences of potentially related prolactin AEs remained low.


   Conclusion Top


This study indicates that paliperidone ER is effective in controlling a broad range of schizophrenia symptoms as well as exhibits favorable tolerability profile. Both paliperidone ER and olanzapine are equally efficacious for the treatment of schizophrenia. Thus, paliperidone ER has the potential to be a useful new treatment option for patients with schizophrenia.


   Acknowledgment Top


This paper is based on the clinical trial funded by Torrent Pharmaceuticals Ltd., Ahmedabad.

 
   References Top

1.Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL,Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. AM J Psychiatry 2004;161 Suppl 2:1-56.  Back to cited text no. 1
    
2.Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. Comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346:16-22.  Back to cited text no. 2
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3.Association AP Practice Guideline for the treatment of patients with schizophrenia second edition. Work group on schizophrenia. 2004. Available. from: http://www.psych.org/psych_pract/treatg/pg/schiizophrenia2ePG_05-15-06.pdf. [Last accessed on 2006 Dec 5].  Back to cited text no. 3
    
4.Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.  Back to cited text no. 4
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5.Taylor DM. Aripiprazole: A review of its pharmacology and clinical use. Int J Clin Pract 2003;57;49-54.  Back to cited text no. 5
    
6.Schooler N, Rabinowitz J, Davidson M, Emsley R, Harvey PD, Kopala L, et al. Risperidone and haloperidol in first-episode psychosis: A long-term randomized trial. AM J Psychiatry 2005;162:947-53.  Back to cited text no. 6
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7.Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: A systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003;160:1209-22.  Back to cited text no. 7
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8.Csenansky JG. Treatment of schizophrenia: preventing the progression of disease. Psychiatr Clin North Am 2003;26:367-79.  Back to cited text no. 8
    
9.Valuation CWGoCT. Adverse effects of the atypical antipsychlotics. Collaborative working group on clinical trial evaluations. J Clin Psychiatry 1998;59 Suppl 12;17-22.  Back to cited text no. 9
    
10.Lieberman JA, Stroup TS, McEvoy JP, Swartz MS,Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.N Engl J Med 2005;353:1209-23.  Back to cited text no. 10
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11.Scientific Discussion: Invega. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/invega/H-746-en6.pdf. [Last cited 2007 Nov 3].  Back to cited text no. 11
    
12.Kane J, Canas F, Kramer M, Ford L, Gassmann-Mayer C, Lim P, et al. Treatment of schizophrenia with paliperidone extended-release tablets: A 6-week placebo-controlled trial. Schizophr Res 2007;90:147-61.  Back to cited text no. 12
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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