Differences in Lipid and Cognitive Change Between One-month and 3-month Paliperidone Palmitate Treatment in Stable Schizophrenia
Phase: PHASE1
Conditions: Schizophrenics
Sponsor: Calo Psychiatric Center

Proposal No: 100-046 
 
Title: 
Differences in Lipid and Cognitive change between one-month and 
3-month Paliperidone Palmitate treatment in stable schizophrenia 
 
Study institution: Calo Psychiatric Center, Pintung County, Taiwan 
Study period: January 01, 2015 to June 30, 2017 
 
PI: Professor For-Wey Lung (forwey@seed.net.tw) 
Calo Psychiatric Center, Pingtung County, Taiwan 
Graduate Institute of Medical Sciences, National Defense Medical University, Taipei, 
Taiwan 
 
Co-PI: Dr. Chen-Lin Chang (changchenling@gmail.com)  
Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan 
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 
Kaohsiung, Taiwan 
Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 
Taiwan 
 
 
Date: January 01, 2015 
The study will approved by the Institutional Review Board at Kaohsiung Armed Forces 
General Hospital (IRB-100046) in Taiwan. 
 

Abstract  
Schizophrenia is a chronic and severe psychiatric disorder, these patients suffer from 
positive symptoms, negative symptoms and cognitive deficits, of which working 
memory problems are considered a central cognitive impairment. Atypical 
antipsychotics are believed to have a superior effect in reducing both positive and 
negative symptoms of schizophrenia, coupled with a low risk of extrapyramidal 
symptoms. Particularly, 2nd-generation antipsychotic medications are commonly used 
in treatment of schizophrenia. An antipsychotic drug, Paliperidone palmitate (PDP), is 
administered to patients with schizophrenia as injections at one-month (PP1M) or 
three-month (PP3M) intervals. This study was compare the effects of treatment, social 
function, and side effects between PP1M and PP3M in patients with schizophrenia. 
Moreover, the changes of cognitive and lipid profile between two PDP were also 
explored. Firstly, participants were received the one month long-acting injection 
(PP1M) three months. Then, the stable participants were shifted to the three month 
long-acting injection (PP3M). Concomitant medications were allowed to prescribe 
except other antipsychotics. Outcome measurements were 20-item Toronto 
Alexithymia Scale (TAS-20), 45-itme quality of life for mental disorder (QOLMD), 
Short-version of the Udvalg for Kliniske Undersogelser (short-version UKU), and 
Wisconsin Card Sorting test (WCST). These measurements were performed every 
three-month except WCST which was performed every six-month. The different 
effects of PP1M and PP3M will be expected to find out in this study.  
 
Key words: paliperidone palmitate, social function, cognitive function, quality of life 

Abbreviations 
PDP: Paliperidone palmitate 
PP1M: one month long-acting injection 
PP3M: three month long-acting injection 
TAS-20: 20-item Toronto Alexithymia Scale 
QOLMD: 45-itme quality of life for mental disorder 
UKU: Udvalg for Kliniske Undersogelser scales 
WCST: Wisconsin Card Sorting test 
PSP: Personal and Social Performance scales 
TC: total cholesterol 
TG: Triglyceride 
HDL: High-density Lipoprotein 
LDL: Low-density Lipoprotein 
GEE-I: Generalized Estimating Equations-I 
SEM: structural equation model 
AGFI: adjusted goodness-of-fit index) 
RMSEA: root mean square error of approximation 
DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
 

Introduction 
Schizophrenia is a chronic and severe psychiatric disorder, these patients suffer 
from positive symptoms, negative symptoms and cognitive deficits, of which working 
memory problems are considered a central cognitive impairment [1-5]. Atypical 
antipsychotics are believed to have a superior effect in reducing both positive and 
negative symptoms of schizophrenia, coupled with a low risk of extrapyramidal 
symptoms [6]. Particularly, 2nd-generation antipsychotic medications are commonly 
used in treatment of schizophrenia [7]. Second-generation antipsychotics have 
reducing the incidence and severity of side-effect from 1st-generation antipsychotics, 
however, 2nd-generation antipsychotics may induce cardiovascular and metabolic 
abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic 
syndrome) that are associated with an increased risk of type 2 diabetes mellitus and 
cardiovascular disease [8-10]. 
In fact, one of major problem for patients with schizophrenia is non-adherence 
with maintenance treatment, hence, the depot antipsychotics have been developing. 
Long-acting injections (LAIs) were administering only once every 2-4 weeks rather 
than each day for addressing the problem of noncompliance [10]. Despite intuitive 
assumptions that LAIs will bring the superior compliance rates comparing with oral 
antipsychotics for patients with schizophrenia. Several studies have found no 
differences in compliance rates between oral and injecting antipsychotics [11,12]. 
However, several studies have found, LAIs can led to lower rates of noncompliance 
and re-hospitalization than oral antipsychotics [13-15]. Overall, the previous studies 
have demonstrated LAIs are as safe and effective treatment in schizophrenia as oral 
antipsychotics, particularly 2nd-generation LAIs [10-15].  
Paliperidone palmitate (PDP), is a LAIs of the atypical antipsychotic 

paliperidone, the primary active metabolite of risperidone. Comparing with other 
LAIs, PDP is able to more rapidly achieve steady stat and maintain this steady state of 
longer period of time [10]. PDP has been found that its efficacy with more safety and 
tolerability, better cost–benefit ratio, lower withdrawal rate, incidence of relapse and 
weight gain than other atypical antipsychotics [16,17], and the pharmacokinetic 
characteristics are similar in different ethnic people [18]. The standard dosing 
schedule is induction therapy with maintenance dose every 4 weeks (PP1M) or 12 
weeks (PP3M). However, the differences between PP1M and PP3M still remain 
unknown. 
Hence, the aim of this study was to compare the effects of treatment and side 
effects between PP1M and PP3M in patients with schizophrenia. Moreover, the 
changes of cognitive and lipid profile between two kinds of PDP were also explored. 
Furthermore, the psychological function and performance, and quality of life would be 
investigated in this study. 
 
Methods 
 
The study will approved by the Institutional Review Board at Kaohsiung Armed 
Forces General Hospital (IRB-100046) in Taiwan, and following an explanation, 
written informed consents are obtained either directly form the patients or from their 
legal guardians. All participants will notified that they could withdraw at anytime. 
 
Study design 
This is a two and half-one years, single-arm, nonrandomized, open-label study 
which will conducted between Jan 2015 to Jun 2017 including from a psychiatric 
center in southern Taiwan. The stable schizophrenic patients who previously received 

risperidone long-acting injection for more than one year and shifted to paliperidone 
palmitate after including in the study. Firstly, participants will received the one month 
long-acting injection (PP1M) three months. Then, the stable participants will shifted 
to the three month long-acting injection (PP3M). Concomitant medications will 
allowed to prescribe except other antipsychotics. Outcome measurements include 
20-item Toronto Alexithymia Scale (TAS-20), 45-itme quality of life for mental 
disorder (QOLMD), Short-version of the Udvalg for Kliniske Undersogelser 
(short-version UKU), and Wisconsin Card Sorting test (WCST). These measurements 
will performed every three-month except WCST which was performed every 
six-month. The effect of treatment will assessed using Personal and Social 
Performance (PSP) scales [19,20] for the evaluation of psychosocial functioning at 0, 
4, 8, and 12 weeks in first study, and at 0, 3, 6, 9, 12 months in second study, 
respectively. In addition, all participants will assessed for body weight, waist 
circumference, and blood lipid profile. To evaluate the lipid profiles, fasting blood 
samples were analyzed for total cholesterol (TC), Triglyceride (TG), High-density 
Lipoprotein (HDL) and Low-density Lipoprotein (LDL). These blood samples will 
collected at every month until study completion. 
 
Participants 
Total of 72 participants, including 41men and 31 female, will recruited in the 
PP1M three months. The stable participants will shifted to PP3M. Patients who had 
comorbid serious medical illnesses, and may therefore present substantial clinical risk 
due to pharmacotherapy, were excluded from the sample, as were pregnant and lactating 
women. All of them had to meet the diagnostic criteria for schizophrenia according to 
the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) 

[21]. 
 
Assessment tools 
20-item Toronto Alexithymia Scale (TAS-20) 
The traditional Chinese-language version of the 20-item TAS was validated in a 
Taiwanese student population by Lin and Chan [22]. The TAS scores were calculated 
for three sub-factors: 1) difficulty identifying feelings (DIF), 2) difficulty describing 
feelings (DDF), and 3) externally-oriented thinking (EOT). The 20 items are rated 
from 1 (strongly disagree) to 5 (strongly agree). The sum of all 20 items, taking 
reversed items into account, was used to generate a TAS total score. Those scoring 
greater or equal to 61 is considered alexithymia (high in alexithymia) [23]. 
45-item Quality of Life for Mental Disorders (QOLMD) 
The QOLMD health survey measures HRQOL, and was revised based on the 
Quality of Life Interview Scale (QOLIS) with 87 items and Quality of Life Scale 
(QLS) [24] with 21 items. The QOLMD contains 45 items with eight dimensions, 
including 7 items of life satisfaction, 7 items of autonomy, 6 items of health 
maintenance, 5 items of family support, 5 items of economic ability, 7 items of social 
activities, 4 items of physical health, and 4 items of mental health, rated from 0 to 3. 
The internal consistency of the eight dimensions of the QOLMD was Cronbach’s 
alpha .58-.84, and the corrected item-total correlations were Pearson’s r >.30 [25]. A 
higher score represents better health status.  
Short-version of the Udvalg for Kliniske Undersogelser (short-version UKU) 
 
The nine items in the UKU-short were selected from those having high 
patient-doctor reliability (p less than 0.01) [26], with the addition of the four 
symptoms of somnolence, insomnia, dry mouth and dizziness, which were found to 

occur in co-administration of antipsychotics [27], and the deletion of the sexual 
dysfunction item. The selection process resulted in the two items of sedation and 
reduced sleep in the psychic side effect dimension, the four items of rigidity, tremor, 
akathisia and headache in the neurological side effects dimension, and the three items 
of reduced salivation, constipation and orthostatic dizziness in the autonomic side 
effects dimension. The procedure for the using the short version is the same as that for 
the original UKU [28], except each item is defined by means of a 2-point-scale (0-1). 
In general, 0 means "not or doubtfully present", and 1 indicates that a symptom is 
present to a mild or severe degree. The Chinese version of UKU presented good 
reliability and validity [29] 
Wisconsin Card Sorting Test (WCST) 
 
The computerized version of the WCST was developed based on the 
standardized criteria of Heaton, Chelune, Talley, Kay, & Curtiss [30] by Tien et al [31]. 
According to Heaton’s criteria [30], response results should be interpreted based on 
categories achieved, percent of perseverative errors and non-perseverative errors, 
percent of total errors, trials to complete the first category, conceptual level response, 
failure to maintain set, and learning-to-learn indices. The performance of cognitive 
function will be intend to examine at first week before receiving cassia obtusifolia as 
baseline. Then, we examine the cognitive function at month 12 in first, second and 
third year. 
 
Statistical Analysis 
 
Data were analyzed using the SPSS 21.0 for Windows software package and 
subject to demographic analysis and descriptive analysis. This study used a 
monotherapy design in two different antipsychotics treatment, and applied the 

Generalized Estimating Equations-I (GEE-I), developed by Liang and Zeger in 1986 
[32].  
 
AMOS for Windows 21.0 was used to apply a structural equation model (SEM) 
and to construct several theoretical models of variables analyzed in this study. SEM 
uses the χ2 fit test to investigate the overall fit of the hypothesized models; χ2 values 
resulting in p > 0.05 and an adjusted goodness-of-fit index (AGFI) > 0.9 indicated 
that the model described the observed data adequately. The root mean square error of 
approximation (RMSEA) is based upon the non-centrality parameter. Good models 
using SEM supposedly have an RMSEA ≤ 0.05; however, models with an RMSEA of 
0.10 or less are also acceptable [33]. 
 
Expectation 
 
To find out the different treatment effects between PP1M and PP3M in patients 
with schizophrenia. 
 
To find out the different side effects between PP1M and PP3M in patients with 
schizophrenia. 
 
To investigate the differences of cognitive performance, and lipid profile 
between PP1M and PP3M in patients with schizophrenia. 
 
To explore the differences of psychological function and performance, and 
quality of life between PP1M and PP3M in patients with schizophrenia. 
 
 

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