Effects of paliperidone extended release on the symptoms and functioning of schizophrenia

Huang et al. BMC Clinical Pharmacology 2012, 12:1http://www.biomedcentral.com/1472-6904/12/1 Effects of paliperidone extended release on thesymptoms and functioning of schizophrenia Min-Wei Huang1,2, Tsung-Tsair Yang3, Po-Ren Ten4, Po-Wen Su5, Bo-Jian Wu6, Chin-Hong Chan7, Tsuo-Hung Lan7,I-Chao Liu3, Wei-Cheh Chiu8, Chun-Ying Li1, Kuo-Sheng Cheng1,9 and Yu-Chi Yeh8* Background: We aimed to explore relations between symptomatic remission and functionality evaluation inschizophrenia patients treated with paliperidone extended-release (ER), as seen in a normal day-to-day practice,using flexible dosing regimens of paliperidone ER. We explored symptomatic remission rate in patients treatedwith flexibly dosed paliperidone ER by 8 items of Positive and Negative Syndrome Scale (PANSS) and change ofPersonal and Social Performance (PSP) scale.
Method: This was a 12-week multicenter, open-label, prospective clinical study conducted in in-patient and out-patient populations. Flexible dosing in the range 3-12 mg/day was used throughout the study. All subjectsattended clinic visits on weeks 0, 4, 8, and 12 as usual clinical practice for the 12-week observation period. Datawere summarized with respect to demographic and baseline characteristics, efficacy measurement with PANSSscale, PSP, and social functioning score, and safety observations. Descriptive statistics were performed to identifythe retention rate at each visit as well as the symptomatic remission rate. Summary statistics of average doses thesubjects received were based on all subjects participating in the study.
Results: A total of 480 patients were enrolled. Among them, 426 patients (88.8%) had evaluation at week 4 and350 (72.9%) completed the 12-week evaluation. Patients with at least moderate severity of schizophrenia wereevaluated as "mild" or better on PANSS scale by all 8 items after 12 weeks of treatment with paliperidone ER. Therewas significant improvement in patients' functionality as measured by PSP improvement and score changes.
Concerning the other efficacy parameters, PANSS total scale, PSP total scale, and social functioning total scale atthe end of study all indicated statistically significant improvement by comparison with baseline. The safety profilealso demonstrated that paliperidone ER was well-tolerated without clinically significant changes after treatmentadministration.
Conclusions: Although the short-term nature of this study may limit the potential for assessing improvements infunction, it is noteworthy that in the present short-term study significant improvements in patient personal andsocial functioning with paliperidone ER treatment were observed, as assessed by PSP scale.
Trial Registration: Clinical Trials. PAL-TWN-MA3 schizophrenia: in the early stages, during acute exacer- Schizophrenia is a severe form of mental illness affecting bations, and over long-term maintenance treatment.
about 24 million people worldwide (7 per 1000 adult The early course of schizophrenia typically includes a population), mostly in the age group 15-35 years.
prodromal phase characterized by nonspecific symptoms Although the incidence is low (3/10,000), the prevalence and behaviors, a formal onset/deteriorative stage with is high due to chronicity . Deficits in social function- active psychosis, cognitive impairment, negative symp- ing can be observed throughout the course of toms, and social deficits, and a period of several yearsfollowing the initial episode that often includes repeatedepisodes of psychosis with a progressive increase in resi- * Correspondence: 8Department of Psychiatry, Cathay General Hospital, Taipei 10630, Taiwan dual symptoms and functional decline. There is general Full list of author information is available at the end of the article 2012 Huang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License ), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Huang et al. BMC Clinical Pharmacology 2012, 12:1 agreement that approximately 5 years after the initial with schizophrenia. In daily clinical practice, however, a psychotic episode patients enter a chronic, but relatively more diverse population is treated, e.g. having higher more stable phase with no marked further decline in rates of comorbidities and/or comedications. Pivotal stu- functioning or increase in residual symptoms dies also used an initial washout period. Therefore, no With the advancement of new medications, treatment data for direct transition from a variety of oral antipsy- goals of patients with schizophrenia were raised. On the chotics to flexibly dosed paliperidone ER are available one hand, remission, instead of response was recognized as the optimal treatment goal for patients with schizo- In most treatment-related clinical trials, response, phrenia. Research on treatments for schizophrenia measured with certain percent improvement of rating focused predominantly on symptom improvement; how- scales, is used as outcome determinant. However, ever, outcomes such as cognition, health-related quality approaches focusing on psychotic patients' real life func- of life, and social functioning are now being recognized tioning are the main interest of clinical practice. Achiev- as important indices of treatment success. The Remis- ing symptom-free and normal life ought to be the key sion in Schizophrenia Working Group (RSWG) chose 8 measure in clinical studies. Moreover, understanding items of PANSS (delusions, unusual thought content, symptom-free function is of great value for treatment hallucinatory behavior, conceptual disorganization, man- goals in clinical practice. Therefore, we designed this nerisms/posturing, blunted affect, social withdrawal, and study to explore symptomatic remission and functional- lack of spontaneity) as determinants for the definition of ity evaluation in patients treated with paliperidone ER, remission [. Several studies have already implemented as seen in normal day-to-day practice, using flexible this concept and found that patients achieving remission dosing regimens.
status had better performance in neuropsychologicaltests and greater social and occupational functions On the other hand, functionality became an important focus of treatment in psychotic patients. Patients who This was a 12-week, multicenter, open-label, prospective returned to normal life were considered as undergoing clinical study conducted in inpatients and outpatients.
"truly recovery" The Personal and Social Perfor- Throughout the study flexible dosing in the range 3-12 mance (PSP) scale, developed to measure patients' per- mg/day was used so as to allow investigators to adjust sonal and social functionality, is a convenient tool in the dosage of each subject based on individual needs. In clinical practice. Several clinical trials measured patients' general, the recommended paliperidone ER dose was 6 functioning as study endpoints with this scale mg once daily, although some subjects benefited from Typically with antipsychotic drugs, dose titration to lower or higher doses in the recommended dose range.
the maintenance dose is recommended. Paliperidone is After obtaining informed consent, baseline characteris- available in a formulation using extended-release (ER) tics, PANSS scale, PSP, and social functioning scale were osmotic release technology (OROS®), hereinafter assessed and recorded. Treatment of these subjects was referred to as paliperidone ER. This formulation was decided by clinicians' opinion. As for patients with phar- designed to deliver paliperidone at a controlled rate over macotherapy, dosing was flexible throughout the study a 24-hour period, resulting in a gradual increase in period according to investigators' discretion based on plasma concentration after the first intake and low individual subjects' clinical response to and tolerability peak-to-trough fluctuation at steady state ]. Paliperi- of study drug. During the study observation period, sub- done is the major metabolite of risperidone. It is a pro- jects attended clinic visits on weeks 0, 4, 8, and 12 as longed release oral atypical antipsychotic for the usual clinical practice. At the preplanned clinic visits, treatment of schizophrenia. Based on preclinical experi- PANSS and PSP scale, reports of adverse events, and ments and clinical investigations, paliperidone is an treatment information were recorded. Subjects could effective and safe antipsychotic medication for the treat- withdraw from this study at any time; reasons of with- ment of schizophrenia. Some studies showed that pali- drawal or loss of follow-up were recorded. The study peridone ER significantly improved symptoms and was approved by the Institutional Review Board of functioning in schizophrenia patients regardless of time Cathay General Hospital (protocol no. PAL-TWN- since diagnosis The phase III well-controlled pivotal efficacy and safety studies were performed usingrandomly applied fixed dosages (3, 6, 9, 12, or 15 mg/ 2.2 Patient Population day) of paliperidone ER. In daily clinical practice, how- Participants were male or female and met DSM-IV diag- ever, flexible dosing is applied based on the individual nostic criteria above aged 18 years. They were drug needs of patients. The pivotal studies were also per- naïve; their previous treatment was considered unsuc- formed in well-defined homogenous groups of subjects cessful due to one or more of the following reasons: Huang et al. BMC Clinical Pharmacology 2012, 12:1 lack of efficacy, lack of tolerability or safety, lack of was performed by a qualified rater defined as a trained compliance, and/or other reasons. Subjects or their leg- clinician. If possible, for a given subject, the same rater ally acceptable representatives had signed an informed assessed this scale at all visits. Subjects were interviewed consent document indicating that they understood the at each visit to assess the psychiatric symptoms of purpose of and procedures required for the study and were willing to participate in the study. Female subjects The following 8 items were used as determinants for were postmenopausal for ≥ 1 year, surgically sterile, abstinent, or, if sexually active, agreed to practice an effective method of birth control before entry and -P2 Conceptual disorganization throughout the study. Effective methods of birth control -P3 Hallucinatory behavior included prescription hormonal contraceptives, contra- -G9 Unusual thought content ceptive injections, intrauterine devices, double-barrier -G5 Mannerisms and posturing method, contraceptive patch, and male partner steriliza- -N1 Blunted affect tion. Female subjects also had a negative urine preg- -N4 Social withdrawal nancy test at screening.
-N6 Lack of spontaneity/flow of conversation Individuals were excluded from the study if the Subjects were rated for their personal and social per- patients were on clozapine, paliperidone ER, any con- formance at each visit by PSP scale. This scale assessed ventional depot neuroleptic or Risperdal® Consta® dur- the degree of difficulty a subject exhibited over a 1- ing the last 3 months. Subjects experienced serious month period within 4 domains of behavior: socially unstable medical condition including known clinically useful activities, personal and social relations, self-care, relevant laboratory abnormalities, history of neuroleptic and disturbing and aggressive behavior. The score ran- malignant syndrome, hypersensitivity to paliperidone ER ged from 1 to 100, divided into 10 equal intervals to or risperidone or inability to swallow the study medica- rate the degree of difficulty (absent to very severe) in tion whole with the aid of water (subjects may not each of the 4 domains. Subjects with scores 71-100 had chew, divide, dissolve, or crush the study medication a mild degree of difficulty, 31-70 varying degrees of dis- because this may affect the release profile) were ability, and ≤ 30 functioning so poorly as to require excluded. Pregnant or breast-feeding woman and parti- cipation in another investigational drug trial in the 30days prior to selection were also excluded from the 2.3 Statistical Analysis study. Of course, employees of the investigator or study Data were analyzed on intent-to-treat (ITT) principle.
center, persons with direct involvement in the proposed All statistical tests were performed with an alpha level study or other studies under the direction of that inves- of 0.05. Descriptive analysis of the demographic vari- tigator or study center, or family members of the ables and other baseline line variables was conducted employees or the investigator were not allowable.
using measures of central tendency and variation for At each visit subjects received the amount of medica- quantitative variables and frequency distributions for tion required until the next visit. Subjects from any oral categorical variables. Assessment of safety included antipsychotic medication could be switched to an effec- computation of the incidence of AEs and of disconti- tive dose of paliperidone ER without the need for titra- nuation due to AEs, and presented in a frequency distri- tion. Subjects could be cross-tapered in different ways bution table.
from their previous antipsychotic medication, e.g. a Two cohorts were introduced into the study: decrease of the previous antipsychotic drug may occur - All enrolled subjects (overall); at the time of or after initiation of paliperidone ER. The - An ITT population comprising all enrolled subjects period of cross-tapering also varied among subjects, who received paliperidone ER at least once and provided since both dosing and timing of transition depended on ≥ 1 post-baseline efficacy measurement.
relevant individual subject characteristics such as kind The efficacy analysis was mainly performed on the and severity of current symptoms or adverse events, ITT population, but also performed on all enrolled sub- course of previous relapses and rehospitalizations, or jects. The safety profile was assessed for the ITT type and dose of previous antipsychotic medication (e.g.
with or without anticholinergic and/or sedating Data were summarized with respect to demographic and baseline characteristics, efficacy measurement with The neuropsychiatric symptoms of schizophrenia were PANSS scale, PSP, and social functioning score, and assessed by 30-item PANSS scale, which provides a total safety observations. Descriptive statistics were performed score (sum of the scores of all 30 items). Each scale is to identify the retention rate at each visit as well as the rated 1 (absent) to 7 (extreme). The PANSS assessment symptomatic remission rate. Summary statistics of Huang et al. BMC Clinical Pharmacology 2012, 12:1 average doses that subjects received were based on all Summary statistics of demographic characteristics for subjects participating in the study. Descriptive analysis the overall and ITT populations are listed in Table In was performed including frequency and percentage for the ITT population, there were more men (55.9%) than categorical parameters, and mean, standard deviation, women (44.1%). The mean age was 40.4 (range, 17-72) minimum, and maximum for continuous parameters.
years; median age was 40 years. Subjects' schizophrenia Descriptive analyses comprised summary statistics and subtype distribution was paranoid 61.7%, undifferen- 95% confidence intervals (95%CI). The paired t test was tiated 18.9%, disorganized 10.8%, residual 7.3%, catatonic also performed to compare changes in scores of contin- 1.2%, and other subtypes 0.2%. Overall, 33.3% of the uous variables.
subjects had symptom onset > 10 years but < 20 years.
The assessment of safety was based mainly on the fre- There were 4.9% of subjects with history of drug abuse.
quency of AEs. The Medical Dictionary for Regulatory The results of all enrolled subjects were similar to those Activities (MedDRA, Version 12.1) AE dictionary was of the ITT population.
used to map AEs to preferred terms and system organ The reasons for subjects switching their treatments class. Patients reporting an individual preferred term AE are displayed for all enrolled patients and the ITT popu- and the total number of patients reporting at least one lation in Figures and respectively. For the ITT adverse event per system organ class were tabulated.
population, there were 4 subjects who did not receive Each AE based on preferred terminology was counted any antipsychotics at enrollment. For the remaining 422 only once for a given subject for each group. The fre- subjects, 409 received antipsychotics within 30 days quency and percent AEs (preferred terms and system prior to enrollment. The treatments included oral ris- organ class) are presented. Descriptive statistics were peridone for 188 subjects (45.97%), olanzapine for 40 provided to evaluate the changes of vital signs at each subjects (9.78%), quetiapine for 29 subjects (7.09%), ari- piprazole for 28 subjects (6.85%), and other treatmentsfor 166 subjects (40.59%). The major reason of switching treatment was insufficient efficacy, accounting for a total A total of 480 patients were enrolled. Among them, a of 321 subjects. AEs (82 subjects), noncompliance (42 total of 426 subjects (88.8%) had evaluation at week 4 subjects), and other (2 subjects) were the reasons for and 350 (72.9%) completed the 12-week evaluation. The switching. Thirteen subjects received antipsychotics > 30 details of patient disposition are summarized in Figure days prior to enrollment. The switching reasons were insufficient efficacy (n = 7), noncompliance (n = 6), and Reasons of patient withdrawal before week 4 were AEs other (n = 1).
(n = 6), insufficient response (n = 2), ineligible to con- Table summarizes previous antipsychotic treatment tinue (n = 15), lost to follow-up (n = 12), consent with- received for consecutive 3 months. The most frequently drawn (n = 16), and noncompliance (n = 3). Therefore used antipsychotics were oral risperidone (207 subjects; these 54 patients did not have any safety and efficacy 48.6%) for the ITT population. The results of all evaluation, resulting in 426 subjects included in the ITT enrolled subjects were similar to those of the ITT The initial dose disposition at baseline for these 426 Table summarizes the complicating diseases for sub- patients was 3 mg/day for 154 patients, 6 mg/day for jects. For the ITT population, the most commonly com- 232 patients, 9 mg/day for 29 patients, and 12 mg/day plained complications were psychiatric (329 subjects; for 11 patients. The average dosage was 5.5 mg/day.
77.23%), gastrointestinal (145 subjects; 34.04%), and The end doses for 350 subjects who completed the study were distributed as 45 patients with 3 mg/day, 183 patients with 6 mg/day, 64 patients with 9 mg/day, and Dose disposition of study medication paliperidone ER 58 patients with 12 mg/day.
of the ITT population and completed population is pre- The withdrawal reasons are summarized in Table sented in Table and Table respectively. In the ITT Overall, 130 subjects (27.1%) discontinued the study population, the number of subjects who started paliperi- prematurely. The details are as follows: 1 subject (0.2%) done ER treatment with the initial dose of 3 mg/day died, 12 subjects (4.8%) withdrew because of adverse and increased to 6, 9, and 12 mg/day at the end of events, 18 (3.8%) subjects withdrew because of insuffi- study was 69, 17, and 18, respectively. There were 43 cient response, 15 subjects (3.1%) were ineligible to con- and 30 subjects with the initial dose of 6 mg/day and tinue, 28 subjects (5.8%) were lost to follow-up, 35 increased to 9 and 12 mg/day, respectively, at the end of subjects (7.3%) withdrew their consent, 8 (1.7%) subjects study, whereas 11 subjects with the initial dose of 9 mg/ discontinued because of non-compliance, and 2 subjects day increased to 12 mg/day at the end of study. All sub- (0.4%) because of other reasons.
jects with initial dose of 12 mg/day remained on 12 mg/ Huang et al. BMC Clinical Pharmacology 2012, 12:1 Figure 1 Patient Disposition. A total of 480 patients were enrolled. Among them, a total of 426 subjects (88.8%) had evaluation at week 4 and350 (72.9%) completed the 12-week evaluation. The details of patient disposition are summarized.
day till the end of study. The completed population had Table 1 Summary of Withdrawal Reason a similar dose pattern of study dose disposition.
PANSS and PAP total score both showed significant improvements after 12-week treatment (PANSS score, from 89.88 ± 29.20 to 72.72 ± 26.36; PSP score, from 47.07 ± 16.34 to 56.61 ± 14.32; both p < 0.05). The results of symptomatic remission are summarized in Insufficient Response Figure The symptomatic remission rate was 3.5% Ineligible to Continue (95%CI, 1.98%, 5.74%) at baseline and improved to Lost to Follow-up 11.7% (95%CI, 8.84%, 15.18%) at the end of study (p < 0.05). The criteria for PSP improvement was at least one 10-point interval on PSP scale. In the ITT population, subjects showed an increasing PSP improvement after Huang et al. BMC Clinical Pharmacology 2012, 12:1 Table 2 Summary of Demographics treatment began. The improvement rate was increased from 28.1% (95%CI, 23.94%, 32.70%) at week 4 to 47.4% (95%CI, 42.59%, 52.28%) at the end of study.
AEs with occurrence ≥ 2% during the study are sum- marized in Table There were 213 patients (50.0%) with ≥ 1 AE during study. The most commonly experi- enced AEs were disease progression (33 patients; 7.7%), upper respiratory tract infection (30 patients; 7.0%), extrapyramidal disorder (25 patients; 5.2%), insomnia (17 patients; 4.0%), and constipation (14 patients; 3.3%).
Among the 30 schizophrenia events 27 were recorded as serious AEs.
The severity of the symptoms and long-lasting, chronicpattern of schizophrenia can impact all areas of daily liv- ing including work or school, social contacts, and rela- tionships. Treatment typically involves antipsychotic Symptom onset (years) medications to stabilize the mood and treat the psycho- tic symptoms for individual patients. Paliperidone ER tablets have been approved in the USA and Europe for > 10 < = 20 the treatment of schizophrenia based on three 6-week, > 20 < = 30 placebo-controlled clinical trials in patients with acute symptoms of schizophrenia These studies indi- cate that paliperidone ER at dosages 3-15 mg/day was associated with statistically significant improvement (relative to placebo) in schizophrenia symptoms as Figure 2 Summary of switching reasons of previous antipsychotic treatment of all enrolled patients. For the enrolled population, therewere 9 subjects who did not receive any antipsychotics at enrollment. For the remaining 471 subjects, 449 received antipsychotics within 30days prior to enrollment. The treatments included oral risperidone for 201 subjects (44.77%), olanzapine for 41 subjects (9.13%), quetiapine for 31subjects (6.90%), aripiprazole for 30 subjects (6.68%), and other treatments for 187 subjects (41.65%). The major reason of switching treatmentwas insufficient efficacy, accounting for a total of 344 subjects. AEs (92 subjects), noncompliance (51 subjects), and other (2 subjects) were thereasons for switching. Twenty-two subjects received antipsychotics > 30 days prior to enrollment. The switching reasons were insufficientefficacy (n = 10), side effects (n = 1), noncompliance (n = 11), and other (n = 1).
Huang et al. BMC Clinical Pharmacology 2012, 12:1 Figure 3 Summary of switching reasons of previous antipsychotic treatment of ITT population. For the ITT population, there were 4subjects who did not receive any antipsychotics at enrollment. For the remaining 422 subjects, 409 received antipsychotics within 30 days priorto enrollment. The treatments included oral risperidone for 188 subjects (45.97%), olanzapine for 40 subjects (9.78%), quetiapine for 29 subjects(7.09%), aripiprazole for 28 subjects (6.85%), and other treatments for 166 subjects (40.59%). The major reason of switching treatment wasinsufficient efficacy, accounting for a total of 321 subjects. AEs (82 subjects), noncompliance (42 subjects), and other (2 subjects) were thereasons for switching. Thirteen subjects received antipsychotics > 30 days prior to enrollment. The switching reasons were insufficient efficacy (n= 7), noncompliance (n = 6), and other (n = 1).
measured by PANSS, personal and social functioning as Paliperidone palmitate demonstrated a statistically sig- measured by the PSP, and clinician's overall assessment nificant treatment benefit in terms of maintenance of as measured by CGI-S. Paliperidone ER was well toler- ated in this patient population during acute treatment, The current phase IV, open-label, prospective study with tolerability measured by low discontinuation rates was conducted with the main objective of exploring the and low adverse event burden The mainte- relationship between achieving symptomatic remission nance of social functioning is important treatment status by means of the 8 items of Positive and Negative objective in the long-term management of schizophre- Syndrome Scale (PANSS) and personal and social func- nia. However, the aim of this study is to measure main- tioning by means of the Personal and Social Perfor- tenance of social functioning with Personal and Social mance (PSP) scale in patients treated with flexibly dosed Performance scale (PSP) to assess treatment benefit in Paliperidone ER. The proportion of patients achieving clinical trials. The 10-point PSP decrement is a clinically the definition of symptomatic remission status was relevant measure of maintenance of functioning in 3.52% with 95% C.I. [1.98%, 5.74%] at baseline and Table 4 Summary of Concurrent Disease with Incidence ≧ Table 3 Summary of Previous Antipsychotics Treatment Received for Consecutive 3 Months Antipsychotic Treatments Ears, Nose, Throat Huang et al. BMC Clinical Pharmacology 2012, 12:1 Table 5 Summary of Dose Disposition of ITT Population Dose at the End of Study improved to 11.74% with 95% C.I. [8.84%, 15.18%] at the The safety profile also demonstrated that paliperidone end of study of the ITT population.(Figure The sig- ER was well-tolerated without clinically significant nificant improvements in personal and social function- changes after treatment administration. The most fre- ing that resulted subsequent to paliperidone ER quently reported adverse event was disease progression treatment, as measured by the validated and reliable (33 patients, 7.7%), upper respiratory tract infection (30 PSP instrument may be an important clinical considera- patients, 7.0%), extrapyramidal disorder (25 patients, tion for patient treatment. Apart from improvement in 5.2%), insomnia (17 patients, 4.0%) and constipation (14 positive and negative symptoms, medications that patients, 3.3%). As well, one patient committed suicide, improve personal and social function may lead to better and another attempted suicide and was comatose in a social integration and overall functioning The vegetative state. Vital signs, such as weight, SBP, DBP, sensitivity demonstrated that the cut point 60 of PSP and pulse had no clinically significant change. Various scale revealed best relationship between PSP scale and clinical studies have demonstrated that paliperidone ER symptomatic remission. It would be useful to be able to is safe and well-tolerated and have similar adverse event assess the importance of both PSP scores and changes profile. Pooled safety data indicated that paliperidone in PSP scores by relating them to real-life outcomes.
ER was generally well tolerated. Discontinuations related Ultimately, a real-life assessment of PSP scores would to treatment-emergent AEs were similarly low for have to be addressed by long-term observational studies patients receiving paliperidone ER or placebo. Although incorporating relatively objective measures of social the incidence of EPS-related AEs was higher in paliperi- functioning, possibly drawing on multiple observers (e.
done ER-treated patients, primarily those receiving g., clinicians, family members, friends, caregivers) as higher doses, the severity of EPS was very low through- well as patient self-assessment ]. The PSP may be out the study []. Therefore, no safety concerns were a useful tool to assess social functioning and importantly raised in this study ]. In this study, short-term treat- to predict relapse, enabling management teams to inter- ment with paliperidone ER significantly improved psy- vene before the deleterious clinical and economic chiatric symptoms and functioning, with no unexpected impact of relapse negatively affects the patient's course safety or tolerability findings. Paliperidone is the active of illness. The high predictive value of the PSP criteria metabolite of risperidone, and nearly half of the subjects and relapse is particularly relevant in an illness such as were on risperidone prior to study entry. Oral risperi- schizophrenia where noncompliance and partial compli- done may have failed to provide adequate efficacy in ance to medication is substantial Patients with patients even though it is metabolized to paliperidone schizophrenia may present with negative, cognitive, dis- because of the short plasma half-life of paliperidone.
organization and mood symptoms, which persist during This would make the case that paliperidone ER treat- periods of acute exacerbation when more overt positive ment would be more effective since it stays in blood cir- symptoms are evident. The post-hoc analysis showed culation for an extended period of time and hence, the that acutely ill patients with or without predominant controlled drug release from the osmotic drug delivery negative symptoms respond similarly to treatment with system demonstrates clear formulation benefits as high- lighted specifically in the title of this study. The Table 6 Summary of Dose Disposition of Complete Study Subjects Complete Study Subjects Dose at the End of Study Huang et al. BMC Clinical Pharmacology 2012, 12:1 *: p-value of change from baseline <0.05 Figure 4 Summary of Efficacy Result. The symptomatic remission rate was 3.5% (95%CI, 1.98%, 5.74%) at baseline and improved to 11.7%(95%CI, 8.84%, 15.18%) at the end of study (p < 0.05). The criteria for PSP improvement was at least one 10-point interval on PSP scale. In theITT population, subjects showed an increasing PSP improvement after treatment began. The improvement rate was increased from 28.1% (95%CI, 23.94%, 32.70%) at week 4 to 47.4% (95%CI, 42.59%, 52.28%) at the end of study.
symptomatic remission rate was 3.52% with 95% C.I.
symptomatic remission rate after the 12-week treatment [1.98%, 5.74%] at baseline and improved to 11.74% with of paliperidone ER. Another study showed that the 95% C.I. [8.84%, 15.18%] at the end of study (p-value < remission rate was increased from 43.9% at baseline to 0.05). The results demonstrated an improvement in 51.7% at 12 weeks after aripiprazole treatment ]. Theoriginal RSWG criteria requires 6 month duration, we Table 7 Adverse Events with Incidence have not used the criteria for remission as originally defined. There are three key limitations to the study.
These are as follows. First, the study is the short study Patients with any Adverse Event design. The study attempts to explore the relationship Disease progression between symptomatic remission and function, however, Upper respiratory tract infection this aspect of the investigation requires additional Extrapyramidal disorder assessment for validity. A third limitation is the hetero- geneous nature of the population, with some patients being remitted at baseline. Prospectively designed and longer-term studies are needed to further assess this The diminished social functioning in schizophrenia is probably responsible for more burdens in patients,families, and care systems than residual symptoms.
*27 events were recorded as serious adverse events.
Huang et al. BMC Clinical Pharmacology 2012, 12:1 Finding a psychotropic treatment that improves social functioning is critically important. The clinical program World Health Organization: Mental health, Disorder management. 2006 of paliperidone ER was designed to incorporate the PSP Keshavan MS, Schooler NR: as a measure of social functioning [The result Schizophr Bull 1992, 18:491-513.
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treatment with paliperidone ER. There were also signifi- Canuso CM, Bossie CA, Amatniek J, Turkoz I, Pandina G, Cornblatt B: cant improvement in patients' functionality as measured Early intervention in psychiatry 2010, 4(1):64-78.
by PSP improvement and score changes. The cut point 60 of PSP scale revealed best relationship between PSP Schizophr Bull 2005, 31:735-50.
scale and symptomatic remission. Besides, PANSS scale Nancy CAndreasen, William TCarpenter, John MKane, Robert ALasser, revealed better correlation with PSP scale rather than Stephen RMarder, Daniel social functioning scale. Safety profile was also accepta- Am J Psychiatry 2005,162:441-449.
ble. This 12-week, multi-center, open-label; prospective Emsley R, Oosthuizen P, Koen L, Niehaus DJ, Medori R, Rabinowitz J: study established the efficacy, safety, and tolerability of paliperidone ER and significantly showed that symptom Int Clin Psychopharmacol 2008, 23(6):325-31.
severity and social functioning improve with paliperi- Emsley R, Chiliza B, Schoeman done ER treatment. In the future, the correlations Current Opinion in Psychiatry 2008, 21(2):173-177.
between PSP and PANSS to prove the close interplay Kane JM, Crandall DT, Marcus RN, Eudicone J, Pikalov A, Carson WH,Swyzen W: between social functioning and psychopathology in the Schizophr Res 2007, chronic course of schizophrenia should be further evalu- ated. The interaction of psychopathological states and Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R: psychosocial functioning determines the long-term course of schizophrenia and its treatment.
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Herbert YMeltzer, William VBobo, Isaac FNuamah, Rosanne Lane, The statistical analysis will be done by or under the supervision of Janssen- David Hough, Michelle Kramer, Marielle Cilag Taiwan. The study results have not been previously published in a peer review journal. This research was supported by Janssen-Cilag Taiwan, Johnson & Johnson.
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Kane J, Canas F, Kramer M, Ford L, Gassmann-Mayer C, Lim P, Eerdekens M: Institute of Biomedical Engineering, National Cheng Kung University, Tainan Schizophr Res 2007, 90(1-3):147-61.
70403, Taiwan. 2Department of Psychiatry, Chiayi Branch, Taichung Veterans Marder SR, Kramer M, Ford L, Eerdekens E, Eerdekens M, Lim P: General Hospital, Chia-Yi 60090, Taiwan. 3Department of Psychiatry, Cardinal Tien Ken-Sin Hospital, Taipei 23148, Taiwan. 4Department of Psychiatry, Show Biol Psychiatry 2007, 62:1363-70.
Chwan Memorial Hospital, Changhua 50008, Taiwan. 5Department of Michelle Kramer, George Simpson, Valentinas Maciulis, Stuart Kushner, Psychiatry, Chu-Tung Branch, National Taiwan University Hospital, Hsinchu Ujjwala Vijapurkar, Pilar Lim, Mariëlle 31064, Taiwan. 6Department of Psychiatry, Yuli Hospital, Hualien 98147, Taiwan. 7Department of Psychiatry, Taichung Veterans General Hospital, Taichung 40705, Taiwan. 8Department of Psychiatry, Cathay General Hospital, Clin Psychopharmacol 2007, 27:6-14.
Taipei 10630, Taiwan. 9Medical Devices Innovation Center, National Cheng Priebe S, Watzke S, Hansson L, Burns Kung University, Tainan 70403, Taiwan.
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Authors' contributions Nicholl D, Nasrallah H, Nuamah I, Akhras K, Gagnon DD, Gopal YCY and MWH conceived the study, analyzed the data and prepared the manuscript. PPY participated in the study design and provided significant Current Medical Research comments on the manuscript. PRT participated in the study design and & Opinion 2010, 26(6):1471-84.
helped to draft the manuscript. PWS, BJW, CHC, THL, ICL, WCC, CYL and KSC Michael Davidsona, Robin Emsleyb, Michelle Kramerc, Lisa Fordc, participated in the study design and helped to provide clinical service. All Guohua Pand, Pilar Limd, Mariëlle Eerdekense: authors have read and approved the final version of the manuscript.
Competing interests 2007, 93:117-30.
This research was supported by Janssen-Cilag Taiwan, Johnson & Johnson.
Kawata AK, Revicki All the authors are clinical psychiatrists. The authors declare that they have no competing interests.
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Pre-publication historyThe pre-publication history for this paper can be accessed here: doi:10.1186/1472-6904-12-1Cite this article as: Huang et al.: Effects of paliperidone extendedrelease on the symptoms and functioning of schizophrenia. BMC ClinicalPharmacology 2012 12:1.
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