Schizophrenia is a chronic psychiatric disorder associated with high noncompliance and discontinuation rates. Poor adherence to treatment guidelines increases the risk for relapse and both clinical and functional deterioration. Long-acting injectable (LAI) formulations of antipsychotics have been developed to increase compliance and to simplify the medication regimen. Risperidone-LAI was the first atypical antipsychotic drug with an LAI formulation used as a biweekly injection for the treatment of schizophrenia. Paliperidone palmitate (PP) is a recently developed LAI atypical antipsychotic that is hydrolysed to paliperidone (9-hydroxyrisperidone), the primary active metabolite of risperidone. It is administered once a month. There is no consensus on whether both LAI formulations differ in terms of efficacy, functionality or side effects (Nussbaum and Stroup, 2012).
A significant side effect of risperidone-LAI and PP is hyperprolactinaemia, which may cause sexual dysfunction. This side effect is an important cause of drug discontinuation, mainly in young patients (Yuan et al., 2008). There is limited information on whether these two LAI formulations differ in terms of hyperprolactinaemia or sexual dysfunction. A few studies have compared the rates of hyperprolactinaemia between these two compounds, with contradictory findings, as some trials favour risperidone-LAI, whereas others favour PP (Nussbaum and Stroup, 2012). There are no studies addressing whether the switch from risperidone-LAI to PP leads to an improvement in prolactin levels or sexual function. In clinical practices, some patients are switched from risperidone-LAI to PP because of the benefits of a once-monthly administration (instead of a biweekly administration for risperidone-LAI), which results in increased convenience for the patient and improved quality of life (Pandina et al., 2011). The main aim of our study was to assess whether the switch from risperidone-LAI to PP was followed by an improvement in prolactin levels or sexual function. Because there are no previous studies exploring this subject, we have designed a prospective, observational and pragmatic case series study.
Materials and methods
We studied 11 patients with a psychotic disorder (n=9 schizophrenia, one schizoaffective, one psychosis not otherwise specified) who attended the Early Psychosis Programme from Reus (HPU Institut Pere Mata, Spain) and who were switched from risperidone-LAI to PP. The 11 patients fulfilled the following inclusion criteria: (a) hyperprolactinaemia (defined as prolactin levels greater than 375 mIU/l for men and 632 mIU/l for women), (b) being treated with risperidone-LAI for at least the previous 6 months and (c) not having changed antipsychotic treatment (neither changes in antipsychotic doses nor the introduction of another oral antipsychotic) during the last 3 months. The dose conversion when switching from risperidone-LAI to PP was determined according to the technical specifications of the product, with the monthly paliperidone dose being double the fortnightly risperidone dose.
Our study was based on routine clinical practice and did not receive any industry support. Ethical approval was obtained from the institutional review board and all participants provided written informed consent.
A clinical assessment of psychopathological status was carried out at baseline and 3 months after the switch. The Positive and Negative Syndrome Scale (Kay et al., 1990) was used to assess positive, negative and general psychotic symptoms. The Calgary Depression Scale (Addington, 1990) was administered to rate depressive symptoms. The Arizona Sexual Experiences Scale (ASEX) (Mcgahuey et al., 2000) was used to assess sexual function. This scale is a five-item (scored from 1 to 6), self-administered scale that yields a total score ranging from 5 to 30, with higher scores indicating increased sexual dysfunction. A total score greater than 18, a score of at least 5 on any single item or any three items with individual scores of at least 4 is indicative of clinically significant sexual dysfunction.
Psychopharmacological treatment at baseline and at 3 months was assessed by a semistructured interview. There were no changes in antipsychotic treatment during the follow-up.
Prolactin and obesity measures
Two fasting blood samples (baseline and 3 months after switch) were obtained to determine the plasma prolactin levels. Prolactin concentrations were determined using a chemiluminescence immunoassay. We also obtained anthropometric data at both visits. BMI was calculated using the following formula: weight (kg) divided by height (m2).
The SPSS version 17.0 software (SPSS Inc., Chicago, Illinois, USA) was used to carry out statistical analyses. The Wilcoxon signed-rank test was used to explore the changes in continuous variables during the study period. The McNemar test was used to explore the changes in clinically significant sexual dysfunction after the switch. A P value less than 0.05 was considered to be significant. R and a ggplot2 package (http://www.r-project.org/) were used to plot changes in prolactin from the baseline to the end of the treatment period.
Of all 11 participants, eight (72%) were men. They had a mean age (SD) of 26.6 (5.9) years. The mean (SD) duration of illness was 56.6 (30.1) months, and they were treated with risperidone-LAI for 21.45 (12.5) months. The mean BMI value was 26.5 (4.4) at baseline and 26.2 (4.7) 3 months after the switch. This difference was not significant. The demographic and clinical characteristics for each participant are shown in Table 1.
There was a significant reduction (25.5%) in prolactin levels from baseline over the 3-month assessment period (P=0.041). Those patients with higher prolactin levels at baseline seemed to show a greater reduction (Fig. 1). All three women from our sample (cases #2, #6 and #11 from Table 1) showed a decrease (35.2%) in serum prolactin levels during the follow-up period. None of them had amenorrhoea, and only one participant reported galactorrhoea (case #2 from Table 1) at baseline, which did not disappear 3 months after the switch. In terms of sexual dysfunction, although some cases showed a notable improvement in their ASEX scores (e.g. case #4 from Table 1), the average reduction for all patients was not statistically significant. We found that four out of the 11 cases (36.4%) fulfilled the criteria for clinically significant sexual dysfunction at baseline, and only one (9.1%) fulfilled the criteria after the switch. Although this reduction is suggestive of benefit, with these small numbers, significance testing was uninformative. Interestingly, the patient who continued to fulfil the criteria for clinically significant sexual dysfunction 3 months after the switch (case #1 from Table 1) was the only one who did not show a decrease in serum prolactin levels. In terms of changes in psychopathological status, none of the patients reported worsening of psychotic symptoms or depressive symptoms.
In a sample of 11 patients who were switched from risperidone-LAI to PP, we observed an improvement in prolactin levels. To our knowledge, this is the first study to find a reduction in prolactin levels after switching from risperidone-LAI to PP. Several participants reported clinical improvement in sexual function, which can be related to a reduction in prolactin levels as well as improvement in depressive or psychotic symptoms. The majority of cases did not report significant changes in ASEX scores. These findings could be explained by several factors: (a) the duration of the follow-up period (3 months), as it may not be long enough to detect clinical changes after the decrease in prolactin levels; (b) although prolactin levels decreased in most cases, a significant proportion of patients did not have fully normalized prolactin levels at the end of the study; and (c) most patients were taking other psychopharmacological drugs, including oral antipsychotics, antidepressants and/or mood stabilizers, which may have also affected sexual function. None of the patients experienced an increase in psychotic symptoms after the switch, nor did they report severe side effects that required changes in psychopharmacological treatment.
Our results are in contrast with other double-blind studies that have not reported differences in prolactin levels between risperidone-LAI and PP (Pandina et al., 2011). However, these studies are methodologically different because they compare two long-acting formulations but do not assess the switch from risperidone-LAI to PP.
Risperidone-LAI and PP differ in their pharmacokinetics, as PP is excreted renally, with limited hepatic metabolism. We wonder whether this pharmacokinetic difference may explain the greater reduction in prolactin levels after the switch. As we did not determine 9-hydroxyrisperidone levels before and after the switch, we do not know whether changes in prolactin levels could be explained by changes in 9-hydroxyrisperidone levels because of a different metabolism of risperidone-LAI and PP. It has been suggested that hyperprolactinaemia in patients treated with risperidone-LAI or PP is driven by 9-hydroxyrisperidone and the higher occupancy of D2 at the pituitary level compared with the striatum (Madaan et al., 2011).
Several limitations of our study need to be addressed. We have designed an open-label study under pragmatic conditions; therefore, blinding was not available. Patients received other psychopharmacological treatments, which could limit the potential benefits on sexual function after the switch to PP. Generalization of the results to paliperidone alone is difficult, as only three out of 11 patients were on monotherapy. The follow-up period of 3 months may be insufficient to detect changes in sexual function over time. The sample size is also small, which limits the possibility of comparing prolactin changes in subgroups (e.g. sex differences).
The main strength of our study is that it is the first to assess the potential changes in prolactin levels and sexual function after switching from risperidone-LAI to PP. Our results should be considered preliminary. Further prospective studies that extend the duration of the follow-up period are required to confirm whether the reduction in prolactin levels is followed by an improvement in sexual function.
This work was supported in part by grants from Fundació La Marató TV3 (092230/0922431). There was not support from industry. Javier Labad has received an Intensification of Research Activity grant (Programme I3SNS-INT 11/323) from the Instituto de Salud Carlos III (Spain) during 2012.
Conflicts of interest
There are no conflicts of interest.
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