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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 33  |  Issue : 3  |  Page : 135-141

Treatment effectiveness of shifting from risperidone long-acting injectable to first-generation long-acting injectable antipsychotics in patients with schizophrenia


1 Department of General Psychiatry, Taoyuan Psychiatric Center, Tauyuan City, Taiwan
2 Department of General Psychiatry, Taoyuan Psychiatric Center, Tauyuan City; Department of Psychiatry, National Taiwan University Hospital and School of Medicine, National Taiwan University, Taipei, Taiwan

Date of Submission26-Feb-2019
Date of Decision01-Apr-2019
Date of Acceptance10-Apr-2019
Date of Web Publication30-Sep-2019

Correspondence Address:
Hung- Yu Chan
No. 71, Longshou Street, Taoyuan District, Taoyuan 330
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_27_19

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  Abstract 


Objectives: Most studies of long-acting injectable antipsychotic (LAI) drugs have been focused on the efficacy of second-generation antipsychotic (SGA) LAIs through observation of the various outcomes of shifting from first-generation antipsychotic (FGA) LAIs to SGA LAIs. Rare studies have assessed the effectiveness of shifting from SGA LAIs to FGA LAIs. In this study, we intended to investigate the effectiveness of shifting from risperidone LAI to FGA LAIs in patients with schizophrenia.
Methods: We included patients with schizophrenia and with the ownership of catastrophic illness card in the study. All the study patients had received risperidone LAI at least two months with a minimal dose of 50 mg per month. The case group included the patients who had been shifting from risperidone LAI to FGA LAIs (fluphenazine, haloperidol, or flupentixol). The control group included the patients who were continuously maintaining on risperidone LAI. The primary outcome was the time to hospitalization. The secondary outcomes were the side effects requiring to receive the use of concomitant anticholinergics, propranolol, and benzodiazepines.
Results: We had 15 patients in the case group and 98 patients in the control group. The primary outcomes showed no significant between-group difference in the time to hospitalization (hazard ratio = 3.676, 95% confidence interval = 0.833 - 16.222). The secondary outcomes also showed no significant differences between the case and control groups.
Conclusion: This study showed no significant differences in the treatment effectiveness and side effects between FGA LAIs and risperidone LAI. The results are compatible with those from a previous LAI study from the National Institute of Mental Health of the United States. But the relatively small effect with inadequate statistical power is the major study limitation, which may produce no significant differences in side effects. We suggest that further large-sample study is needed to confirm the results of this study.

Keywords: extrapyramidal symptoms, nonadherence, side effects of antipsychotic drugs, time to hospitalization


How to cite this article:
Chang CY, Chan HY. Treatment effectiveness of shifting from risperidone long-acting injectable to first-generation long-acting injectable antipsychotics in patients with schizophrenia. Taiwan J Psychiatry 2019;33:135-41

How to cite this URL:
Chang CY, Chan HY. Treatment effectiveness of shifting from risperidone long-acting injectable to first-generation long-acting injectable antipsychotics in patients with schizophrenia. Taiwan J Psychiatry [serial online] 2019 [cited 2019 Nov 22];33:135-41. Available from: http://www.e-tjp.org/text.asp?2019/33/3/135/268315




  Introduction Top


Long-term antipsychotic therapy (maintenance treatment) is important for patients with schizophrenia. It can decrease relapse rate, improve functioning, prevent hospitalization, and increase quality of life. The treatment opinions of antipsychotic drugs include oral antipsychotics, short-acting injectable antipsychotics, and long-acting injectable antipsychotics (LAIs). Continuous antipsychotic treatment is important for patients with schizophrenia. But only about 50% of patients with schizophrenia have good adherence, and those with partial adherence and nonadherence are still frequent [1]. Previous studies showed that adherence to antipsychotic agents improve relapse rate remarkably for patients with schizophrenia [2]. Twenty-five percent of patients with schizophrenia who have received continuous treatment still have at least one relapse within one year, and 50% – 75% of patients without medications relapse within a year [2].

Clinicians frequently underestimate the levels of adherence because they often rely on patients' reports which tend to exaggerate their levels of adherence [3]. Adherence is not an “all” or “no” status, and at least 50% of patients become partially compliant or noncompliant within one year of discharge and 75% of patients within two years of discharge [3]. Although some studies showed that oral second-generation (atypical) antipsychotics (SGAs) have better adherence than oral first-generation (conventional) antipsychotics (FGAs), several studies have demonstrated no remarkable differences in adherence between oral SGA and oral FGA for patients with schizophrenia. Schizophrenic patients with partial or nonadherence increase the risk of relapse and hospitalization as well as worsen treatment response and functioning status [4],[5]. Increased risk of relapse has been reported even nonadherence persists as short as 10 days, and the hospitalization rate is almost two times greater in the group of patients who have had a maximum medication gap of 1-10 consecutive days during a one year period [6].

LAIs are considered to optimize the treatment of patients with schizophrenia through improving their adherence and reducing relapse risk and rehospitalization [7]. The result of meta-analysis study by Leucht et al. showed that LAIs have lower relapse risk than oral antipsychotics [8]. But some studies revealed ambiguous results [9], indicating that LAIs are not superior to oral antipsychotic drugs if patients have good oral antipsychotic drug adherence [10],[11]. A population-based cohort study through analyzing data retrieved from the Taiwan National Health Research Institute database showed that LAIs except haloperidol long-acting injectable drugs are not to be superior to oral antipsychotics in reducing rehospitalization [12].

Previous studies have shown an improvement in the mean total score of positive and negative syndrome scale (PANSS) when patients with stable schizophrenia were switched from oral antipsychotic drugs and FGA LAIs to SGA LAIs [13],[14]. But two nationwide retrospective studies comparing FGA LAIs to risperidone LAIs have shown no remarkable difference in symptom improvement [15],[16]. A US National Institute of Mental Health (NIMH)-funded multicenter randomized trial compared patients with schizophrenia or schizoaffective disorder who had kept fluphenazine or haloperidol LAIs and those who had been switched to risperidone LAI [17]. The results of that study showed that no remarkable differences exist in the severity of psychotic symptoms, time to hospitalizations, sexual side effects, or new-onset extrapyramidal symptoms (EPSs) [17]. The clinical antipsychotic trials of intervention effectiveness study also showed that SGA effects are not better than those of perphenazine (an FGA) in positive and negative syndrome scale (PANSS) total score, cognition, cost, quality of life, and psychosocial functioning [5]. The differences of treatment effectiveness between risperidone LAI and FGA LAIs are also a controversial issue. But many studies showed that risperidone LAI has a decreased severity of EPSs, but an increased risk of body weight gain and prolactin level elevation, and that FGA LAIs have a higher chance of akathisia [18],[19]. The study by Leucht et al. also showed that SGAs have fewer EPS than haloperidol, even at low dose [20]. SGA LAIs have a higher cost than FGA LAIs, and the study by Rosenheck et al. showed that haloperidol LAIs are more cost-effective than paliperidone palmitate [21]. We should consider different cost and side effects between FGAs and SGA LAIs and choose appropriate drugs. Patients with schizophrenia may respond to FGA LAIs when they have had poor treatment response to SGA LAIs.

In real clinical situations, patients may be switched from SGA LAIs to FGA LAIs because of problem of short injection interval, insufficient treatment response, side effects of SGA LAIs, patients' preference, and others. This research topic in clinical psychopharmacology is interesting and important. Although many studies target on the treatment effectiveness of shifting from FGA LAIs to SGA LAIs [13],[14], no studies have investigated the treatment effectiveness of shifting from SGA LAIs to FGA LAIs. In this study, we intended to investigate the treatment effectiveness of shifting from SGA LAIs to an FGA LAI (risperidone LAI).


  Methods Top


Study participants

Taoyuan Psychiatric Center is a major psychiatric hospital in northern Taiwan, which includes 282 acute inpatient beds, 380 rehabilitation inpatient beds, 300 day-hospital beds, 10 emergency department beds, and 4 intensive care unit beds. The catchment area of the study hospital includes Taoyuan City, New Taipei City, Hsinchu County, and Maoli County.

In this study, we collected outpatients with schizophrenia who had received treatment from January 2005 to December 2014 at this study hospital. The inclusion criteria of the study included patients with (a) age between 20- and 65-year-old, (b) owning a catastrophic illness cards which were issued by the Bureau of National Health Insurance of Taiwan, (c) having received at least a two-month risperidone LAI depot injection, and (d) having the dose of risperidone LAI being at least 50 mg per month. The exclusion criteria included those who had (a) other axis I psychiatric diagnoses rather than nicotine and hypnotic/sedative use disorder, as well as (b) major systemic illnesses or neurological disorders. This study was a retrospective chart review study and approved by the institutional review board of Taoyuan Psychiatric Center. Tauyuan Psychiatric Center. The IRB project number was B20170202, and was approved on March 14, 2017 without the stipulation of obtaining signed informed consent forms from all study participants.

Study variables

All of the study data were extracted from the chart records or electronic database of the study hospital. One experienced research assistant collected all the study data. One psychiatrist (CYC) trained the research assistant before data collection and rechecked the data. The study data had both demographic and clinical variables. Demographic variables included sex, age, marital status, residence status, and education level. Clinical variables included age of disease onset, age of the first treatment, pre-study number of hospitalization, physical comorbidity, Charlson comorbidity score, suicide history, violence history, psychiatric family history, a depot injection during the study, time to first antipsychotic discontinuation, total duration of depot injection, total dose of depot injection, average dose of antipsychotics per month, the ratio of prescribed daily dose/defined daily dose, two or more kinds of SGA use before study, combined oral antipsychotics during the study, concomitant anticholinergic agents, benzodiazepines, or propranolol treatment during the study.

The Charlson comorbidity score is a widely used comorbidity index. It contains 22 comorbidities (diabetes, renal disease, metastatic tumor, etc.). Each comorbidity has being weighted according to their potential influence on the risk of the outcome. A total score is calculated to provide for the outcome prediction [22]. The Charlson comorbidity score has been used for predicting the outcome and risk of death from many diseases [22].

Psychiatric family history of the study included the first, second, and third relatives. We also switched the dose of every kind of FGA LAIs to the equivalent dose of oral risperidone and then calculated the ratio of prescribed daily dose/defined daily dose. According to the data of the World Health Organization, the defined daily dose of oral risperidone is 5 mg/day [23].

Study groups

The aim of this study was to compare the effectiveness of shifting from an SGA LAI to FGA LAIs. If the patients met the study criteria, they were included in the study. Then, we divided them into two groups–the case group and the control group. The patients who were shifted to FGA LAIs (haloperidol decanoate, flupentixol decanoate, and fluphenazine decanoate) were classified as the case group. The patients who continued risperidone LAI treatment during the study were classified as the control group.

Measures

After at least a two-month risperidone LAI treatment, we observed the study outcomes for one year. The primary study outcome was time to hospitalization. The secondary outcome was whether side effects occurred during the study, according to the use of concomitant benzodiazepines, anticholinergic agents, or propranolol. Our study is a retrospective chart review study, and LAI injections were recorded in the medical record after patients had received treatment.

Statistical analysis

Categorical variables (such as gender, marital status, and living status) were analyzed using the Pearson's Chi-square test. Continuous variables (such as age, age of onset, Charlson comorbidity score, and others) were analyzed using the Student's t-test. We did survival analysis with log-rank test and used Cox regression model to analyze which variables influence time to hospitalization.

All statistical analyses were done using the Statistical Package for the Social Science software version 20 for Windows (SPSS, Inc., Chicago, Illinois, USA). The differences between groups were considered significant if p < 0.05.


  Results Top


[Figure 1] shows the participant flowchart of the study. There were 123 patients in the study at first. Eight patients were excluded from the case group because of the following reasons: (a) using combined risperidone LAI and FGA LAIs at the same time, (b) having interval of injection after risperidone LAI more than one month, and (c) re-using of risperidone LAI during the a one-year observation period. Two patients were excluded from the control group due to less than a two-month risperidone use before study and age being < 20 years. Nineteen patients in the case group had used risperidone LAI before switching to FGA LAIs. But the time gap between risperidone LAI injections and FGA LAI injections was more than one month. Therefore, those 19 patients did not meet the criteria of the case group because the interval between risperidone LAI discontinuation and the beginning of FGA LAI treatment was less than one month. But those 19 patients had received risperidone LAI for more than one year before switching to FGA LAIs. Therefore, we redistributed those patients into the control group. There were 113 patients left, 15 in the case group and 98 in the control group. In the 15 patients of the case group, the causes of switching from to risperidone LAI to FGA LAIs included patients' preference (7 patients), wishing a longer interval of injection (7 patients), and poor treatment response to risperidone LAI (1 patient). In the control group, only two patients re-exposed to risperidone LAI due to EPS.
Figure 1: Research flow chart. #1Fifty milligrams risperidone long-acting injectable less than two months, then shift to 1st long-acting injection. #2Fifty milligrams risperidone long-acting injectable less than two months, then continue 2nd long-acting injection. #3Combined risperidone LAI and 1st LAI at the same time. #4Interval of injection after risperidone LAI more than one month. #5Reuse of risperidone LAI during 1 year observation period in case group. #6Interval between risperidone LAI and 1st LAI was more than one month, and met the criteria of control group. #7Less than two-month risperidone LAI injection. #8Age less than 20 years old.

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[Table 1] shows the distribution of demographic data and clinical characteristics of the case group and the control group. No significant differences existed between the case group and the control group in most variables, except gender (p < 0.05), family history of schizophrenia (p < 0.05), and family history of other mental disorder (p < 0.05). The patients in the case group were male predominant (73.3%), and those in the control group were female predominant (60.2%). The patients in the case group had a higher proportion of family history of schizophrenia than those in the control group (20.0% vs. 4.1%). The patients in the control group had a higher proportion of family history of other mental illness than those in the case group (34.7% vs. 6.7%).
Table 1: Demographic data and clinical characteristics of the study participants

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[Figure 2] is the survival analysis of time to hospitalization. Log-rank test showed that no significant difference existed between the case group and the control group. Hospitalization rate was 20% in the case group and 25% in the control group.
Figure 2: Kaplan-Meier survival analysis. For the time to hospitalization, log-rank test showed no significant difference between the patients in the case group and those in the control group.

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[Table 2] compares depot injection between the case group and the control group. Most kind of depot injection was fluphenazine (80%) in the case group. No significant difference existed in patients with persistent depot injection for one year, time to first discontinuation, and total time of depot injection. But a significant difference (p < 0.01) existed in the ratio of prescribed daily dose/defined daily dose between the case group and the control group.
Table 2: The comparisons between case group and control group in long-acting injectables

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[Table 3] shows that no significant differences existed between the case group and the control group in concomitant anticholinergic agents, benzodiazepines, and propranolol treatment.
Table 3: Concomitant anti-side effects drugs among case and control groups

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[Table 4] shows risk factors of time to hospitalization in Cox regression. The results showed that more prestudy number of hospitalization (hazard ratio [HR] = 1.202, 95% confidence interval [CI] = 1.103–1.310, p < 0.001) had a significant difference. The case group was not the predictive variable in the Cox regression model (HR = 3.676, 95% CI = 0.833-16.222, not significantly different).
Table 4: The hazard ratios of survival analysis

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  Discussion Top


In our study, we investigated the effectiveness of shifting from SGA LAIs risperidone LAI to FGA LAIs in patients with schizophrenia. To the best of our knowledge, no studies existed on this topic in the past. Most of previous studies have investigated the effectiveness of shifting from FGA LAIs to SGA LAIs. The results of this study showed that no significant differences existed in the primary outcome – time to hospitalization [Figure 2], and secondary outcomes – concomitant benzodiazepines [Table 3], anticholinergic agents [Table 3], and propranolol treatment [Table 3] – between the case group and the control group. In our opinions, the results of this study are valuable with important clinical implications.

In a recent nationwide retrospective study comparing the effectiveness of risperidone and FGA LAIs [15], the investigators found that risperidone LAI is similar to FGA LAIs in time to hospitalization. The result is in line with that in our study, showing no significant difference in time to hospitalization between the case group and the control group [Figure 2]. In another nationwide study comparing the effectiveness of risperidone, haloperidol, and flupentixol LAIs [16], the investigators found that the effectiveness of risperidone LAI is not superior to that of haloperidol or flupentixol LAIs [16]. In another NIMH-funded study [17], the investigators have also not found any significant difference in the efficacy between paliperidone palmitate and haloperidol decanoate. But two studies [13],[14] have shown an improvement in the mean total score of positive and negative syndrome scale when patients with stable schizophrenia were switched from oral antipsychotics and FGA LAIs to SGA LAIs. Study participant selections and different study design may explain the divergent results. For example, patients in Hawley et al.'s study [14] have active psychotic symptoms, but patients in our study had only residual psychotic symptoms.

The secondary outcomes are whether side effect occurred during the study, according to concomitant use of benzodiazepines, anticholinergic agents, and propranolol. Although our results showed no significant differences in the secondary outcomes [Table 3], several studies showed that risperidone has fewer EPS in comparison with FGA LAIs [16] or switching from oral antipsychotics or FGA LAIs to risperidone LAIs [13],[14]. Small sample size with low statistical power of this study might produce this result. But risperidone also has a higher proportion of EPS than other SGA antipsychotic agents, explaining no significant difference in the secondary outcomes. We suggested that larger sample size with a higher statistical power may achieve significant difference. As shown in [Table 3], the case group had a higher proportion of concomitant propranolol treatment than the control group (50% vs. 26.7%); it is similar to the result of a previous NIMH-funded study, also showing that haloperidol LAI has more akathisia than paliperidone LAIs [19].

LAIs have some advantages such as having more stable plasma drug concentration, avoiding of first-pass metabolism in liver, not needing to take medications every day, having lower relapse and rehospitalization rate, and having better chance to monitor adherence [24]. In our study, there were three FGA LAIs (haloperidol decanoate, flupentixol decanoate, and fluphenazine decanoate) and only one SGA LAI (risperidone LAI). All of FGA LAIs have terminal hydroxyl (-OH) group. All of them can go through the process of esterification in vivo, with high oil solubility and low water solubility, and can be dissolved in vegetable oil. After intramuscular injection, ester drug slowly releases into the blood stream and rapidly hydrolyzes the parent drug. Differing from FGA LAIs, risperidone LAI is encapsulated into microspheres, which needs cold storage for release characteristics and slowly hydrolyzes in vivo. Another difference is that oil-soluble FGA LAIs have pain and other adverse reactions over injection site. But the injection interval is also different between risperidone LAI and FGA LAIs. Risperidone LAI needs to be injected once every two weeks whereas FGA LAIs need to be injected up to every one month. Those differences may contribute the effectiveness and acceptability of those medications for patients with schizophrenia.

Patients' nonadherence to take medications causes relapse and is the most important risk factor of rehospitalization. Many factors to cause nonadherence include history of previous nonadherence, recent psychiatric hospitalization, cognitive deficits, poor disease insight, persistent negative symptoms, adverse drug reactions, inadequate drug efficacy, hostility, substance use, younger age, and poor socioeconomic support [25]. Another study showed that risk factors related to relapse of psychotic symptoms include male, younger onset, longer duration of untreated psychosis, substance use, psychosocial support, and premorbid function [25]. In our study, we also analyzed what variables would influence time to hospitalization. The results [Table 4] showed that higher pre-study number of hospitalization had a significant difference (p < 0.001), and lower prescribed daily dose also had a significant difference (p < 0.05). Higher number of hospitalization may represent more symptom relapse, more medication nonadherence, or treatment-resistant population; those characteristics all increase the risk of symptom relapse and hospitalization [4]. Lower prescribed daily dose may be below the optimal therapeutic daily dose, which may induce a higher risk of psychotic symptom exacerbation and a shorter time to rehospitalization. Previous studies also illustrated that adequate antipsychotic dosages can prevent relapse and rehospitalization for patients with schizophrenia [26],[27].

In our study, 51.3% of patients with schizophrenia continued LAIs after one year of the study, and there was no significant difference between the case group and the control group. But the study by Wu et al. showed that only less than 10% of patients treated with LAIs continue their medications after one year [28]. We suggested that differences in patients' population, study design, and sample size can produce different results.

Study limitations

The readers are warned against over-extrapolating the study results because it has four major limitations:

  • This study is retrospective in nature
  • There were only 15 patients in the study group and 98 patients in the control group. Small sample size with inadequate statistical power may induce Type IIerror even we tried to get better statistical power by the ratio of the case group and the control group was near 1: 6.
  • Our study only included outpatients with schizophrenia. The results cannot generalize to other mental disorders and inpatient population.
  • We included the data of patients of only one single psychiatric center. The findings from this study may not be generalized to other studies because of differences in local practice patterns.


Summary

Our study showed no significant differences in treatment effectiveness and side effects between the study group and control group in patients receiving risperidone LAIs and FGA LAIs. Considering that SGA LAIs have a higher cost, and FGA LAIs may have better cost-effective ratio [21], we suggest that clinicians can choose LAIs according to patients' characteristics, preference, and other appropriate considerations, but not the generation of antipsychotic agents (FGAs vs. SGAs). But few study participants in our study indicate lower statistical power, and further larger sample size studies are needed in future to prove the results. We expect the appropriate LAI use for patients with schizophrenia, to improve the care quality for this population.


  Acknowledgment Top


The funding body played no rôle in study design, analysis, or interpretation of the study data in this paper.


  Financial Support and Sponsorship Top


This study was supported by a grant from the Taoyuan Psychiatric Center, Ministry of Health and Welfare of Taiwan (TYPC-10603).


  Conflicts of Interest Top


Both authors declared no conflicts of interest in writing this paper.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

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