Improving of Cognition and Quality of Life in Schizophrenia With One-month and Three-month Paliperidone Palmitate Treatment

An antipsychotic drug, Paliperidone palmitate (PDP), is administered to schizophrenics as injections at one-month (Sustenna) or three-month (Trinza) intervals. The present study was a series of clinical trial study, which included two sub-study, sought to compare the effects of treatment, social function, and side effects between two treatments in schizophrenics. In Study 1, total of 42 participants were received the Sustenna treatment for three months. In Study 2, total of 72 participants were recruited for Trinza treatment. The results showed Personal and Social Performance scales (PSP) signicantly increased over time with both two treatments. Total cholesterol levels signicantly decreased with Sustenna, which negatively inuenced the cognitive functions, and the quality of life. UKU scales signicantly decreased with Trinza after 15 months. In Brief, schizophrenics receiving PDP treatment presented improvements in their cognitive and social functions over the time, whether with the Sustenna or Trinza treatment. Total cholesterol and waist circumference decreased, and the LDL/HDL ratios increased over the time after PDP treatment. Furthermore, patients receiving Trinza treatment experienced decreased side effects. Nonetheless, schizophrenics had a signicantly better quality of life after both Sustenna and Trinza treatment. Future studies should be consider larger samples and longer follow up.


Introduction
Schizophrenia is a chronic and severe psychiatric disorder. Affected patients experience positive symptoms, negative symptoms, and cognitive de cits, of which working memory problems are considered a central cognitive impairment. [1][2][3][4][5] Atypical antipsychotics are believed to have a superior effect in reducing both the positive and negative symptoms of schizophrenia, coupled with a low risk of extrapyramidal symptoms. 6 Particularly, 2nd -generation antipsychotic medications are commonly used in the treatment of schizophrenia. 7 Second-generation antipsychotics reduce the incidence and severity of side effects from 1st -generation antipsychotics, but 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][9][10] In fact, one of major problems for patients with schizophrenia is their non-adherence to treatment. In fact, one of major problems for patients with schizophrenia is their non-adherence to treatment. As such, depot antipsychotics have been developed. Long-acting injections (LAIs) are administered only once every 2-4 weeks rather than each day to address the challenge presented by patient noncompliance. 10 Despite the intuitive assumptions that LAIs will yield superior compliance rates than oral antipsychotics for patients with schizophrenia, several studies have found no differences in compliance rates between oral and injected antipsychotics. 11,12 However, several studies have found that LAIs can lead to lower rates of noncompliance and re-hospitalization than oral antipsychotics. [13][14][15] Overall, previous studies have demonstrated that LAIs are as safe and effective a treatment in schizophrenia as oral antipsychotics, particularly 2nd -generation LAIs. [10][11][12][13][14][15] Paliperidone palmitate (PDP) is delivered in the form of an LAI of the atypical antipsychotic paliperidone, the primary active metabolite of risperidone. Compared with other LAIs, PDP is able to more rapidly allow patients to reach and maintain a steady state over a longer period of time. 10 PDP's e cacy has been linked to its greater safety and tolerability, better cost-bene t ratio, lower withdrawal rate, lower relapse rates, and lower weight gain than other atypical antipsychotics. 16,17 Its pharmacokinetic characteristics are similar across ethnicities. 18 The standard dosing schedule is by induction therapy with a maintenance dose every 4 weeks (INVEGA SUSTENNA, once monthly injection) or 12 weeks (INVEGA TRINZA, once every 3 months injection). However, the differences between Sustenna and Trinza treatment remain unknown.
Hence, the aim of this study was to compare the treatment and side effects between Sustenna and Trinza protocols in patients with schizophrenia. Moreover, the changes in cognitive and lipid pro les between these two types of PDP were assessed. Furthermore, psychological functioning and performance, as well as quality of life, were assessed in this study.

Ethical statement
The present study was a series of clinical trial study, which included two sub-study. All procedures performed in the current study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board at Kaohsiung Armed Forces General Hospital (IRB-100046), and Joint Institutional Review Board at Taipei Veterans General Hospital (JIRB-08-013-P) in Taiwan. Also, this series of clinical trial study have registered in ClinicalTrials.gov (NCT03730857 in 05/11/2018 and NCT04754750 in 12/02/2021). After an explanation by senior psychiatrists, written informed consents were obtained either directly from the patients or from their legal guardians. All participants were noti ed that they could withdraw at anytime.

Study design
This series of clinical trial study, which included two sub-study, was a two and a half-one years, single- Stable schizophrenic patients who previously received risperidone by long-acting injection for more than one year were switched to a paliperidone palmitate treatment (INVEGA SUSTENNA, once monthly injection) after being included in the study. Participants were received the one-month long-acting injection (PP1M) for three months. Stable schizophrenic patients who previously received paliperidone palmitate by one-month long-acting injection for three month were switched to the three-month long-acting injection treatment (INVEGA TRINZA, once every 3 months injection; PP3M). Concomitant medications were allowed to prescribe except other antipsychotics.

Participants
In study 1 (PP1M study), total of 42 participants, including 25 men and 17 female, were received the onemonth long-acting injection treatment for three months. In the study 2 (PP3M study), total of 72 participants, including 41men and 31 female, were recruited. Figure 1 presented the ow diagram of participants collecting process in PP1M and PP3M study. 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). 19 Outcome measurements Outcome measurements included the 20-item Toronto Alexithymia Scale (TAS-20), 45-item 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 months except for the WCST, which was measured every six-months. The effect of treatment was assessed using Personal and Social Performance (PSP) scales 20,21 for the evaluation of psychosocial functioning at 0, 4, 8, and 12 weeks in the PP1M study, and at 0, 3, 6, 9, 12 months in the PP3M study, respectively. In addition, all participants were assessed for body weight, waist circumference, and their blood lipid pro le. To assess the lipid pro les, fasting blood samples were analyzed for total cholesterol (TC), Triglyceride (TG), High-density Lipoprotein (HDL), and Low-density Lipoprotein (LDL) levels. These blood samples were collected at every month until study completion.

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) di culty identifying feelings (DIF), 2) di culty 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, considering reversed items, was used to generate a TAS total score. Those scoring greater or equal to 61 were considered alexithymic (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), which has 87 items and Quality of Life Scale (QLS), 24 which has 21 items. The QOLMD contains 45 items with eight dimensions, including 7 items on life satisfaction, 7 items on autonomy, 6 items on health maintenance, 5 items on family support, 5 items on economic ability, 7 items on social activities, 4 items on physical health, and 4 items on mental health, rated from 0 to 3. The internal consistency of the eight dimensions of the QOLMD revealed a Cronbach's alpha of .58-.84, and the corrected item-total correlations revealed a Pearson's r > .30. 25 A higher score represents a 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 the co-administration of antipsychotics, 27 and the deletion of the sexual dysfunction item. The selection process resulted in the two items on sedation and reduced sleep in the psychic side effect dimension, the four items on rigidity, tremor, akathisia and headache in the neurological side effects dimension, and the three items on reduced salivation, constipation and orthostatic dizziness in the autonomic side effects dimension. The procedure for using the short version is the same as that for the original UKU, 28 except that each item is de ned 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 the 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 rst category, conceptual level response, failure to maintain set, and learning-to-learn indices. The performance of cognitive function is to be assessed on the rst week before receiving PDP treatment, as a baseline. Next, cognitive function is to be assessed at month 12 in the rst, second, and after completed of the study.

Statistical Analysis
Data were analyzed using the SPSS 21.0 for Windows software package and subject to a demographic analysis and descriptive analysis. This study was based on a monotherapy design in two different antipsychotic treatments, 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 the variables analyzed in this study. SEM uses the χ 2 t test to assess the overall t of the hypothesized models; χ 2 values resulting in p > 0.05 and an adjusted goodness-of-t 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

Results
Demographic data are listed in Table 1. After the generalized estimating equation analysis (GEE-I analysis), the results of the personal and social performance (PSP) scales demonstrated different effects of the two different long-acting injections of paliperidone palmitate (PP1M and PP3M) ( Table 2). The results showed that the PSP scales were statistically signi cantly increasing over time in both PP1M (ß=3.438, p = 0.027) and PP3M (ß=0.969, p = 0.001) treatment protocols. In the PP1M treatment, the changes in PSP scales were related to the percent of conceptual level responses (ß=0.059, p = 0.001), waist circumference (ß=-0.143, p = 0.046), and sex (ß=-6.836, p = 0.001). In the PP3M treatment, the changes in the PSP scales were correlated to UKU scales (ß=1.262, p = 0.003) and LDL/HDL ratios (ß=0.197, p = 0.000).
Furthermore, the parsimonious structural equation models (SEM) con rmed the ndings of the GEE-I analysis (Figs. 2 and 3). The results of these SEMs yielded p values greater than 0.05 (p = 0.543 and p = 130); the p values of the adjusted goodness-of-t models were greater than 0.9 (AGFI = 0.954 and AGFI = 0.954), and yielded an RMSEA < 0.05 (RMSEA = 0.000 and RMSEA = 0.027). Hence, both of these two null models corresponded to the conceptual construct.

Discussion
Second-generation antipsychotics can attenuate the symptoms of schizophrenia, such as cognitive slowing, affective blunting, loss of spontaneity and volition. 34 As 2nd -generation LAI, PDP injections, including Sustenna (PP1M) and Trinza (PP3M), have been demonstrated to be effective in treatment maintenance in patients with schizophrenia. 10 However, the differences between PP1M and PP3M remain unknown. Hence, the current study sought to compare the effects of treatment and side effects between PP1M and PP3M. Moreover, changes in cognitive and lipid pro les, psychological function and performance, and quality of life were also assessed in this study.
In this study, results revealed that patients with schizophrenia experienced greater improvements in PSP total scores over time after receiving PP1M and PP3M. Particularly, the present study revealed that PP1M yields better improvements in the subdomains of disturbing and aggressive behaviors in PSP scores, while PP3M improved interpersonal and social interactions in patients with stable schizophrenia (data not shown). This means that whether patients received a PP1M or PP3M treatment would signi cantly improve total PSP scores (Table 2). Interestingly, both PP1M and PP3M improve PSP scores, although differentially so across different PSP subdomains.
Compared with PP3M, results showed an increase in the percentage of conceptual level responses in the WCST and a decrease in waist circumference in individuals receiving the PP1M treatment. Females tended to have higher PSP scores than males receiving PP1M (Table 2). Indeed, the higher waist circumference will increase total cholesterol, and further decrease cognitive function and quality of life. The structural equation model con rmed these ndings (Fig. 2).
On the contrary, compared with PP1M, the ndings also showed a decrease in UKU scores and increase in the LDL/HDL ratio in patients receiving PP3M treatment ( Table 2). The further structural equation model also con rmed these ndings (Fig. 3). That is, schizophrenics receiving the PP3M treatment will experience decreased side effects over the time. The LDL/HDL ratio, related to waist circumference, negatively in uenced the number of correct answers in the patients receiving the PP3M. A higher LDL/HDL ratio will decrease cognitive function, and further in uence interpersonal and social interactions, as well as patients' quality of life.
A previous study showed that a longer duration of untreated psychosis is associated poor social function in patients with schizophrenia. 35 The present study showed that an earlier onset of schizophrenia is associated with poor social function after a paliperidone palmitate dosage treatment, further decreasing patients' quality of life (Fig. 3). It is reasonable for chronic schizophrenia due to an earlier age of onset to be related to a longer duration of illness.
Previous studies showed that a drug with a lower or no 5-HT 2A a nity, such as quetiapine or amisulpride, is associated with a great improvement in cognitive function than a drug with a high a nity to 5-HT 2A receptors, such as risperidone, olanzapine, or clozapine. 36,37 However, these 5-HT 2A studies did not include the atypical antipsychotic paliperidone, which improves cognition and social functions. 38, 39 The current study also con rmed the ndings that both PP1M and PP3M improve cognitive and social function in patients with schizophrenia over time (Figs. 2 and 3).
In conclusion, patients with schizophrenia received paliperidone palmitate experienced improve cognitive and social function over the time, whether receiving a PP1M or PP3M treatment. Particularly, PP1M therapy yielded a signi cant improvement in the subdomains of disturbing and aggressive behaviors, and PP3M therapy yielded signi cant improvements in the evaluation of interpersonal and social interactions. Total cholesterol and waist circumference decreased, and the LDL/HDL ratio increased over time after paliperidone palmitate treatment. Furthermore, patients receiving a PPM3 therapy experience a decrease in side effects. Nonetheless, patients with schizophrenia have a great quality of life after both PP1M and PP3M therapy. These ndings serve as a reference in clinical medicine. Future studies have to consider larger samples and longer follow up times.  All authors have no con ict of interest to declare. The ow diagram of participant collecting process Parsimonious and conditional model of the associations between changes in PP3M of paliperidone (Trinza) extended-release