Community Research and Development Information Service - CORDIS

FP7

PERS Report Summary

Project ID: 241959
Funded under: FP7-HEALTH
Country: Netherlands

Final Report Summary - PERS (Paediatric European Risperidone Studies)

Executive Summary:
The last decade showed a strong prescription rise and extensive off-label use of atypical antipsychotics (in particular risperidone) in children and adolescents with various psychiatric disorders. However, a serious lack of information on efficacy and safety of these medications in paediatric populations may expose this vulnerable patient group to unknown and unwarranted risks. PERS (Paediatric European Risperidone Study) was designed to respond to a specific call of the FP7 Cooperation Work Programme “HEALTH- 2009-4.2-1: Adapting off-patent medicines to the specific needs of paediatric populations”. PERS is a knowledge-translation initiative to promote evidence-based prescribing practices related to atypical antipsychotics treatment. The originally granted PERS protocol aimed to improve the availability of information on the efficacy and safety of risperidone by authorizing its use for an in-label prescription in children and adolescents with Conduct Disorder and average IQ. The PERS project was thus originally designed within a regulatory framework for a Paediatric Use Marketing Authorization (PUMA) after consultation with the European Medicines Agency (EMA). The PUMA procedure depends on the participation of a pharmaceutical company in the PERS study. In the granted PERS proposal three clinical studies were planned to fit the PUMA requirements: two randomized controlled trials (RCTs; WP2, WP3), and one naturalistic observational study (WP4). WP4 explores the safety issues and adverse effects associated with long-term use of risperidone.
Since the costs associated with the proper conduct of the two RCTs were significantly higher than anticipated, WP4 had to be dropped from the EU’s financial support. Despite this decision, the PERS investigators applied for approvals wherever it was feasible and enrolled paediatric patients into WP4 on a voluntary, unpaid care-as-usual basis.
The risperidone tablets and placebo for WP2 and WP3 were manufactured by Wockhardt UK at its Indian production site at Waluj, Aurangabad. This manufacturer did not comply with the Good Manufacturing Practice requirements, and all products manufactured at this site became subject to a major recall, including the tablets which were manufactured for our paediatric investigational plans. The PERS consortium tried to encourage alternative risperidone-selling companies to participate in the PUMA process, but without success. In the absence of a pharmaceutical company that would be able to provide us with the study medication (active risperidone and matching placebo tablets) and that would apply for a PUMA, PERS had to conclude that to be unable to conduct WP2 and WP3 anymore, and that no clinical trial data will be generated that would support obtaining a PUMA for prescribing risperidone for the indication of conduct disorder in children and adolescents.
At the end, PERS has enrolled more than 400 participants in the observational study of WP4. The database, which is the main deliverable of PERS, is very rich and includes extensive clinical, lifestyle, endocrinologic, growth and laboratory measues. First analyses showed that risperidone treatment was associated with profound effects on BMI, prolactin, and ASAT. Risperidone treatment had no major effect on glycolated Hb, ALAT, fasting glucose, fasting cholesterol, fasting LDL, and fasting HDL. Full analyses taking into account all confounding variables and investigating at the various predictors, moderators and mediators with regard to lifestyle, medication dose and length, use of co-medication and various adverse events will be done over the next 18-24 months. Results will be published in peer-reviewed journals, communicated at national and international meetings, and feedback into guideline committees.

In the meantime, some member of PERS were able work on collateral projects on the efficacy and safety of antipsychotics (risperidone and others) in children and adolescents with psychiatric disorders (autism, schizophrenia, conduct disorder). This work showed that treatment with risperidone was related to hyperprolactinemia in about 50% of boys treated, and that hyperprolactinemia was associated with lower bone mineral density, sexual side effects and lower testosterone levels. We further reported that olanzapine, quetiapine, and risperidone increased body weight but had different cardiometabolic side effect profiles and different temporal side effect patterns. Finally, we examined in patients with intellectual disability the effects of discontinuation of long-term used antipsychotics on weight, body mass index (BMI). Discontinuation of antipsychotics led to a mean decrease of 4 cm waist circumference, of 3.5 kg weight, 1.4 kg/m2 BMI, and 7.1 mm Hg systolic blood pressure. In those participants who had not completely discontinued use of antipsychotics we found a decrease in weight and BMI and an increase in fasting glucose. The presence of the C-allele of serotonin 5-hydroxytryptamine receptor polymorphism rs141334 was associated with higher waist circumference and higher plasma levels of triglycerides and lower levels of high-density lipoprotein. Achievement of complete discontinuation predicted a larger decrease in waist circumference and BMI. This showed the beneficial effects of discontinuation of long-term used antipsychotics on metabolic outcomes.

Project Context and Objectives:
Project context
The prescribing of psychotropic medication has become an increasingly important component of comprehensive treatment programs of child and adolescent psychiatric disorders. One class of psychotropic medication that is increasingly being prescribed to children and adolescents is the second-generation antipsychotics. Data from the United States indicate a six fold increase in prescriptions of antipsychotics for children and adolescents from 1993 to 2002 (Olfson et al., 2006). Between 2000 and 2002 9.2% of all mental health visits and 18.3% of visits to child and adolescent psychiatrists included antipsychotic treatment, and 92.3% of visits with prescription of an antipsychotic included a second-generation antipsychotic. In the United States, antipsychotics appear to be prescribed for a wide range of disorders, including psychotic disorders (responsible for 14.2% of prescriptions of an antipsychotic in persons of 20 or younger), mood disorders (31.8%), conditions characterized by aggression such as Conduct Disorder (CD) (37.8%), and irritability associated with autism (17.3%; Olfson et al., 2006). In the United Kingdom, the prescribing prevalence of antipsychotics for patients 7 to 12 years of age in general practices almost tripled between 1992 and 2005. Atypical antipsychotic prescribing increased 60-fold from 1994 to 2005 (Rani et al., 2008). In the Netherlands, prescribing prevalence of antipsychotics doubled from 1997 to 2005. Prevalence was highest among 10 to 14-year-olds, especially among boys. This increased prevalence was mainly attributable to both increased use and a longer duration of use of second-generation antipsychotics (Kalverdijk et al., 2008). Virtually all of the prescriptions of second-generation antipsychotics within Europe are off-label. In the United States risperidone and aripiprazole have been approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in adolescents and adults and for additional indications, including the treatment of children and adolescents with autistic disorder and bipolar mania (Safer, DJ., Calarge, CA & Safer, AM., 2013).
Risperidone is the most widely prescribed antipsychotic agent in children and adolescents. Aripirazole is a newer antipsychotic possibly associated with fewer adverse effects, such as weight gain and sedation (Almandil et al, 2013). However, currently, there is insufficient data available about long-term safety of atypical antipsychotics in the paediatric population. Most studies are limited to one year, while treat¬ment in clinical practice is typically longer. Thus, over the last years there has been a clear increase in the exposure of children and adolescents to incompletely understood risks, in particular risks for weight gain, metabolic syndrome, cardiovascular adverse events and prolactin-relate ad¬ver¬se events (Vitiello et al., 2009; Correll, 2009; Correll, 2008; Cohen and Correll, 2009; Roke et al., 2009; Kuehn, 2009; Ross, 2008; Calarge et al., 2009).
Recent studies on the metabolic effects of risperidone in children and adolescents suggest that paediatric populations may represent a vulnerable group, in which metabolic side effects are greater than in adults. There is a lack of knowledge about the factors that make some children and adoles¬cents more vulnerable than others to short-term and long-term adverse effects of risperidone (Vitiello et al. 2009; Calarge et al.,2009; Hrdlicka et al., 2009; Cohen and Correll, 2009; McIntyre and Jerrell, 2008; Jensen et al., 2008). Dose might be one important mediator and recently, some evidence has also pointed to genetic vulnerability factors. More systematic work should also focus on the degree of reversibility of adverse reactions, and neurobiological mechanisms.

Overall aim
PERS (Paediatric European Risperidone Study) was designed to respond to a specific call of the FP7 Cooperation Work Programme “HEALTH- 2009-4.2-1: Adapting off-patent medicines to the specific needs of paediatric populations”. PERS is a knowledge-translation initiative to promote evidence-based prescribing practices related to atypical antipsychotics treatment. The originally granted PERS protocol aimed to improve the availability of information on the efficacy and safety of risperidone by authorizing its use for an in-label prescription in children and adolescents with Conduct Disorder and average IQ. The PERS project was thus originally designed within a regulatory framework for a Paediatric Use Marketing Authorization (PUMA) after consultation with the European Medicines Agency (EMA). The PUMA procedure depends on the participation of a pharmaceutical company in the PERS study. In the granted PERS proposal three clinical studies were planned to fit the PUMA requirements: two randomized controlled trials (RCTs; WP2, WP3), and one naturalistic observational study (WP4). WP4 explored the safety issues and adverse effects associated with long-term use of risperidone.

The risperidone tablets and placebo for WP2 and WP3 were manufactured by Wockhardt UK at its Indian production site at Waluj, Aurangabad. This manufacturer did not comply with the Good Manufacturing Practice requirements, and all products manufactured at this site became subject to a major recall, including the tablets which were manufactured for our paediatric investigational plans. The PERS consortium tried to encourage alternative risperidone-selling companies to participate in the PUMA process, but without success. In the absence of a pharmaceutical company that would be able to provide us with the study medication (active risperidone and matching placebo tablets) and that would apply for a PUMA, PERS had to conclude that to be unable to conduct WP2 and WP3 anymore, and that no clinical trial data will be generated that would support obtaining a PUMA for prescribing risperidone for the indication of CD in children and adolescents.

Thus, PERS was able to collect data only through WP4, an observational, non-interventional and non-commercial open-label pharmacovigilance study. All PERS recruitment sites observed relatively few new prescriptions for risperidone and a strong shift towards prescriptions of aripiprazole over the study period. This observed shift from risperidone to aripiprazole seems to be a general phenomenon in whole Europe. Our clinicians noticed good responses to aripiprazole in children and adolescents with aggression and conduct problems associated with emotional dysregulation.
Aripiprazole is a partial dopamine agonist and, as risperidone, an atypical second-generation antipsychotic drug. It is in the top 5 of the “best-selling“ prescription drugs in the US (Friedmann 2012). The US Food and Drug Administration (FDA) approved aripiprazole in November 2002 (treatment of schizophrenia in adults), the European Medicines Agency (EMA) in June 2004 (schizophrenia and bipolar disorder in adults). At present, it is used for a variety of indications, including psychotic and mood disorders in adolescents. It represents a prescription medicine used to treat schizophrenia in adolescents and adults (in Germany age 15 and older), bipolar disorder (in Germany age 13 and older), major depressive disorder in adults (as add-on treatment), irritability associated with ASD in children and adolescents (in the USA), and agitation associated with schizophrenia or bipolar disorder.
As a consequence of the shift in prescribing practices PERS has collected data on possible adverse events associated with risperidone or aripiprazole treatment in a large paediatric European cohort, as collected in clinical practice within a number of European child and adolescent psychiatry centres. These centres have agreed on systematic monitoring (through clinical and laboratory measures), in accordance with international recommendations (Panagiotopoulos & Davidson, 2011). Close monitoring of adverse events as part of normal clinical care is essential to prevent or minimize metabolic or endocrine adverse events (Correll, 2008, Pringsheim et al, 2011). Clinicians have also collected relevant lifestyle behaviors (including diet, activity, sleep, and substance use).
All assessments have been part of normal structured clinical procedures, and performed in accordance with current guidelines for careful monitoring of children and adolescents treated with antipsychotics. As such, the study has solely collected records from patients’ medical records, without imposing any impact on choice and duration of treatment.

Objectives
The key objectives of PERS WP4 were to:

1. Investigate the efficacy and safety of risperidone and aripiprazole in children and adolescents with psychiatric disorders.
2. Address scientific questions about the moderating and/or mediating factors. Identify mechanisms of treatment and of tolerability; under which circumstances treatment have different effects or side effects (e.g. initial conditions, life style, co-medication).
3. Disseminate the extension of knowledge acquired by the proposed studies to medical and mental health professionals, to patients and their families and society in general.

Key objective 1 included the following aims:
Aim 1. To study the long-term safety of risperidone and aripiprazole in a 1-year longitudinal naturalistic prospective pharmacovigilance study. This study will include children and adolescents treated with risperidone or aripiprazole for any indication, including conduct disorder (CD), schizophrenia, bipolar disorder, and autism spectrum disorders.
Aim 2. To ensure that when performing this clinical study due consideration is being paid to medical ethical issues.

Key objective 2 included the following aims:
Aim 3. It is unclear which child or adolescent is likely to benefit from treatment with atypical antipsychotics. We have examined the role of the following potential moderating factors of the clinical response to risperidone and aripiprazole: (i) presence or absence of comorbid psychiatric conditions as Attention-Deficit/Hyperactivity Disorder (ADHD) and the mood disorders; (ii) presence of risk factors arising from the family-environment (Loeber et al. 1468-84); (ii) life style factors.

Aim 4. There is a lack of knowledge about factors that make some children and adolescents more vulnerable than others to adverse effects of risperidone and aripiprazole. We have examined the influence of (i) medication factors (average daily dose; cumulative antipsychotics dosage; pre-treatment history of medication; use of co-medication); (ii) patient factors (age: children versus adolescents; initial body weight / Body Mass Index; genetic vulnerability factors; clinical indication), and (iii) lifestyle factors.

Aim 5. To study mechanisms which mediate tolerability of risperidone and aripiprazole. Specific pathophysiological pathways for adverse events, including weight gain and metabolic factors, associated with treatment with these antipsychotics in adolescents remain unclear and will be investigated.

Key objective 3 included the following aims:
Aim 6. Publish the results of these studies as peer-reviewed papers in international journals, and in leading national medical and mental health journals.
Aim 7. Present the data in national and international meetings in the form of symposia, workshops and clinical training sessions. We will pay particular attention to knowledge transfer to new EU states and associated and candidate states.
Aim 8. To translate the results of the proposed studies into evidence for developing new and updating existing clinical guidelines and practice parameters for the treatment of psychiatric disorders with risperidone or aripiprazole, such as schizophrenia in adolescents and children and adolescents with autism spectrum disorders.

Project Results:
1. The main direct scientific result of PERS is the establishment of a database that contains information on baseline and multiple follow-up visits of about 400 children and adolescents with psychiatric disorders and treated with Risperidone or Aripiprazole in the context of an observational study. In our initial analyses, we have focused on the possible effects of risperidone on body mass index (BMI), Glycolated Hb, prolactin, ASAT, ALAT, Fasting Glucose, Fasting cholesterol, fasting LDL, and fasting HDL, between baseline and 12 months of treatment. These initial analyses indicate that treatment had no major effect on Glycolated Hb, ALAT, Fasting Glucose, Fasting cholesterol, fasting LDL, and fasting HDL.

However, there was a significant increase in BMI after 12 months of treatment, as well as a significant increase in prolactin and ASAT. On average children gained 1.55 kg/m2 BMI; 0.140 u prolactin and 3.00 u ASAT. The increase in BMI correlated significantly with medication dose.
This indicates that treatment with risperidone has profound and significant effects on BMI, liver functioning and prolactin.

Full analyses taking into account all confounding variables and investigating at full the various predictors, moderators and mediators with regard to lifestyle, medication dose and length, use of co-medication and various adverse events will be done over the next 18-24 months and will result in a number of journal publications. These analyses will also allow for more fine-tuned analyses of the various metabolic parameters in relation to treatment, by making use of all available data time points (the initial analyses have only focused on a comparison between baseline and 12 months and have not yet taken into account the sizeable number of children that have prematurely discontinued the medication, probably to a large extent due to adverse metabolic events. Thus, while the initial results already point to very profound effects on BMI, prolactin, and ASAT, the full metabolic picture will become available upon fine-tuned analysis of the full data set, considering all available data and time points.

Ethics aspects. We obtained ethics approval to conduct the planned RCTs in WP2 and WP3 of PERS in all sites. However, due to the problems with the study medication supplied by Wockhardt, these studies were not implemented. The observational study did not need specific ethics approval, since this was considered to be part of care-as-usual.

2. There are also results and lessons from PERS outside the scientific domain. These relate to the various problems and complications of conducting pharmacological clinical trials in the context of an EU grant with the ultimate goal of achieving a Pediatric Use Marketing Authorisation (PUMA). The latter requires that the clinical studies are conducted according to the highest standards of good clinical practice, use a central lab, Interactive Voice Responsive System (IVRS) to appropriate randomization across multiple sites and are monitored by and supported by a Clinical Research Organization (CRO). In addition, provisions are needed for packaging and labeling of the medication, and for insurance of all sites.
In PERS, the academic sites were able to agree with Wockhardt to provide the study medication (tablets of Risperidone and matching placebo) for free, and in exchange would get access to all data to obtain a PUMA for risperidone in the treatment of conduct disorder in children and adolescents with IQ in the normal range. Wockhardt was not willing or able to provide financial support for the packaging and labeling of the medication.
It turned out soon after the start of PERS that the allocated budget of 5.6 M€ was by far insufficient to cover all of the costs linked to the originally planned three clinical studies. Informal contacts with pharmaceutical companies learned that they estimated a budget at least 10M€ would be needed to conduct these studies according to professional and good enough standards.

3. Another lesson is the strong dependency on the pharmaceutical company. In PERS, the risperidone tablets and placebo for the blinded clinical studies (WP2 and WP3) were manufactured by Wockhardt UK at its Indian production site at Waluj, Aurangabad, India. This manufacturer however did not comply with the Good Manufacturing Practice requirements, and all products manufactured at this site became subject to a major recall, including the tablets which were manufactured for our paediatric investigational plans. We tried to invite and encourage alternative risperidone-selling companies to participate in the PUMA process, but without success. Janssen-Cilag, the original licence holder, was initially interested but later turned out to be unable to act as study sponsor. In the absence of a pharmaceutical company that would be able to provide us with the study medication (active Risperidone and matching placebo tablets) and that would apply for a PUMA, we had to conclude that we cannot conduct WP2 and WP3 anymore, and that no clinical trial data will be generated that would support to obtain a PUMA for prescribing Risperidone for the indication of conduct disorder in children and adolescents. Obviously, for pharmaceutical companies the prospect of obtaining a PUMA for Risperidone in the treatment of conduct disorder in children and adolescents with IQ in the normal range was not sufficiently rewarding to decide about investing financially in PERS.

4. Collateral projects.

4.1 Collateral / spin-off project: observational study of boys with ASD – treated with antipsychotics versus medication naïve (Roke et al., 2009, 2012a,b,c, 2013). We conducted an observational study in 56 boys with autism spectrum disorder (ASD) of disruptive behavior disorder (DBD) treatment with any antipsychotic medication continuously for more than 16 months) and 47 boys with autism spectrum disorder (ASD) of disruptive behavior disorder (DBD) who were medication-naïve. The main aim was to study the short-term and long-term consequences of hyperprolactinemia associated with antipsychotic prescription in children and adolescents with ASD and/or DBD. In a descriptive review of 29 treatment studies, we reported that after weighted average mean treatment duration of 35 weeks, 62% of the children and adolescents were hyperprolactinemic (Roke et al., 2009). This descriptive review documents that maintenance treatment with risperidone is associated with persistent elevation of prolactin levels for periods up to two years. The very limited long-term data for pimozide, olanzapine, and quetiapine prohibit drawing conclusions for these antipsychotics (Roke et al. 2009). Based on the high prevalence of AP-induced hyperprolactinemia in children and adolescents, the clinical consequences of AP-induced hyperprolactinemia should be investigated through systematic long-term observational studies including specific questionnaires as well as physical examinations and age and gender-matched reference values for prolactin levels. Our main findings were (Roke et al., 2009, 2012a,b,c, 2013):
• Hyperprolactinemia is a common side effect (49%) in boys treated long-term with risperidone.
• Boys with antipsychotic-induced hyperprolactinemia were also more likely to report diminished sexual functioning (erectile and/or orgasm dysfunction, and loss of sexual interest) than boys not treated with antipsychotics.
• Antipsychotic-induced hyperprolactinemia had no prolactin-related side effects in 46% of these boys.
• Antipsychotic-induced hyperprolactinemia is related to significantly lower testosterone levels though within the normal reference range corrected for age and gender.
• LH, FSH and Inhibin B levels and the Tanner stages of puberty were the same for the boys with and without AP-induced hyperprolactinemia.
• The mean volumetric lumbar spine bone mineral density (BMD) z-score was lower in the antipsychotic -treated boys with hyperprolactinemia than in the antipsychotic -treated boys without hyperprolactinemia. The volumetric BMD of the lumbar spine is a good predictor of future fractures (especially wrist and forearm fractures), and therefore our findings suggest that antipsychotic -induced hyperprolactinemia may have a negative influence on BMD, especially of trabecular bone, such as of the lumbar vertebrae.
• 7–11% of the antipsychotic -induced hyperprolactinemic boys had low BMD of the lumbar spine (a z-score < -2). In adult patients a z-score of < -2 is defined as osteoporosis. The International Society for Clinical Densitometry has decided to use the phrase “low BMD” for pediatric patients because children and adolescents are still in the dynamic process of attaining their peak bone mass; however it remains a potential serious side effect, and may increase the risk of fractures (Lewiecki 2008, Bianchi 2008).

We also studied genetic risk factors. the Taq1A A1 allele of the DRD2 gene and the activity of the CYP2D6 enzyme complex as possible risk factors for the development of hyperprolactinemia. Our main conclusion was that the presence of at least one Taq1A A1 allele of the DRD2 gene was positively associated with higher prolactin levels. Furthermore, the prolactin levels and 9-hydroxy risperidone levels increased with reduced or no activity of CYP2D6. However our study lacked power to draw firm conclusions about the influence of the activity of the CYP2D6 enzyme complex on prolactin levels. Screening for genes relevant to the effect and side effects of pharmacological treatment may improve the effectiveness of the treatment and reduce side effects, thereby increasing patient quality of life and reducing the costs of treatment (Chou 2000).

Given the cross-sectional design of our study we compared the results of our total study population (N=113) of boys with ASD and/ or DBD with or without AP treatment with normative data on height, weight, BMI z-scores, Tanner stages, levels of 25-hydroxyvitamin D3, body composition, and BMD (Fredriks 2000). The findings were that:
• Our total study population took 1.6 years longer to attain the same Tanner stage compared to normative data with normal mean z-scores for height (0.40), weight (0.48), and BMI (0.44). When correcting for autism versus DBD, autism showed a trend towards significance for being later in attaining the same stage of puberty than healthy controls.
• Thirteen of the 113 (12%) boys had deficient levels of 25-hydroxyvitamin D3 (<30 nmol/L) and 37 (36%) had insufficient (<50 nmol/L) levels (Allgrove 2009. These are higher proportions than reported for Dutch young adult males without psychiatric disorders (4% and 22% respectively) (Boot 2011).
• Our total study population had a lower mean lean tissue mass, a higher percentage of total body fat than healthy controls; however the BMD of our total study population was not different when compared to normative data (Boot 2010).

These findings suggest first that future research should investigate the relationship between the disorder of ASD and a possible delay in the attainment of Tanner stages of puberty. Second, the higher prevalence of 25-hydroxyvitamin D3 deficiencies and insufficiencies is an important finding, since 25-hydroxyvitamin D3 is a major determinant of bone mineralization at school age (Pekkinen 2012). Supplements of 25-hydroxyvitamin D3 may prevent problems in the bone mineralization process. Third, our study population had a higher percentage of total body fat and lower lean tissue mass compared to normative data. This higher percentage of body fat may be a risk factor for future cardiovascular disease (Lavie 2012). Further, the lower lean tissue mass, which is mainly muscle mass, is highly related to bone mass in children and is important for the attainment of peak bone mass (Boot 2010). One explanation for the higher percentage of body fat and lower lean tissue mass in our study group could be that the boys with ASD participate less in organized outdoor sports activities, and their preferred leisure activities often involve an indoor setting. These preferred indoor activities and the consequent lack of sunlight are probably also the reason for the higher prevalence of 25-hydroxyvitamin D3 deficiencies and insufficiencies among this group.
In sum, these findings suggest that children and adolescents with ASD should be stimulated to take part in outdoor physical activities.
Considerations for the prevention and treatment of hyperprolactinemia. Our cross-sectional study and the study by Calarge et al. (2010) show a relationship between AP-induced hyperprolactinemia and diminished BMD in ANTIPSYCHOTIC-treated boys. These two studies are the first studies investigating the effect of ANTIPSYCHOTIC-induced hyperprolactinemia on bone mineral density in children and adolescents. Our study also showed that within the hyperprolactinemic group 7-11% of the boys had low BMD of the lumbar spine, which is a potential serious side effect and may lead to bone fragility (Lewiecki 2008). An earlier 2-year longitudinal study by Colao et al. (2000) investigated prolactinoma-induced hyperprolactinemia and the effect on bone mass in 20 adults and 20 adolescents and found that the adolescents had persistent irreversible bone loss, even after dopamine agonistic treatment, which restored normal prolactin levels. In the adult patient group the bone loss process was reversible after treatment with dopamine agonistic drugs. This study shows that adolescence is an important and vulnerable period for the attainment of peak bone mass and that disturbances during this process may be irreversible. It should be noted however that the prolactin elevation in prolactinomas is 2-4 fold higher than in ANTIPSYCHOTIC-induced elevations, and that we do not know at which threshold value of prolactin elevation the negative effect on bone mineral density begins. Because of the possible negative effect on bone mineralization in adolescence, we recommend active monitoring of prolactin levels and treatment of ANTIPSYCHOTIC-induced hyperprolactinemia until long-term follow-up studies indicate the otherwise. In the event of hyperprolactinemia, the dose should be reduced or another drug should be prescribed.
Bone mineral density and fractures in ASD. There are two previous studies, which investigated the effect of ASD on bone status (Hediger 2008, Mouridsen 2012). One study evaluated fracture prevalence and found this to be lower for patients with ASD, i.e. 12% for the patients with ASD versus 25% for the comparison group (follow-up for 30 years, N=118) (Mouridsen 2012). The other study investigated bone cortical thickness in children with ASD (mean age 7 years, N=75) measured on a hand-wrist radiograph. When compared with normative data, especially the boys with ASD with a dairy-free diet had reduced bone cortical thickness (Hediger 2008). The patients of our study had a normal calcium intake and a fracture prevalence rate of about 20% (19% for the ASD boys with hyperprolactinemia versus 21% for the ASD boys without hyperprolactinemia), which was also low, compared to the normative data fracture rate of 37% measured at a mean age of 23 years (Boot 2010). As mentioned before our study population had higher proportions of 25-hydroxyvitamin D3 deficiency and insufficiency compared to the normative data. 25-hydroxyvitamin D3 is a determinant of BMD in children and adolescents. One explanation could be that boys with ASD have less organized outdoor sports activities, and their preferred leisure activities often involve an indoor setting, which would protect them from sustaining fractures but also makes than susceptible for 25-hydroxyvitamin D3 deficiency or insufficiency’s (MacDonald 2011). It is reassuring from a clinical perspective that the psychiatric condition of ASD does not seem to lead to a higher fracture prevalence rate. In our study in boys with ASD or DBD bone mineral density was not significantly different from normal. However, one should be careful when prescribing antipsychotic with prolactin-elevating qualities because of the potential negative influence of hyperprolactinemia on BMD.
Hypogonadotropic hypogonadism. High prolactin levels may inhibit the pulsatile secretion of gonadotropin-releasing hormone, which by reducing the release of gonadotrophic hormones can cause hypogonadism. The effect of antipsychotic-induced hyperprolactinemia on testosterone levels has not been investigated in adolescent boys before. The significantly lower testosterone levels in boys with antipsychotic-induced hyperprolactinemia compared to boys with ASD or DBD without antipsychotic treatment were still within age- and gender-matched reference ranges. The gonadotrophic hormones were in the normal range. We can only speculate that the lower testosterone levels may lead to delayed puberty and sexual functioning disorders. There is one retrospective study, which found no influence on the attainment of Tanner stages of puberty among youths treated with risperidone (Dunbar 2004); however follow-up was limited to one year and a delay in puberty may take longer to take effect (McKeever 2000, Rosen 2001). Our study was cross-sectional, had limited power, and used self-assessment to investigate Tanner stages of puberty; future studies should be longitudinal, have a larger sample size and thus more statistical power than our study, and should also investigate the attainment of Tanner stages of puberty with a physical examination instead of self-assessment and assess testes volume with an orchidometer. Hypogonadism is related to small testicular volume. More power and more precise measurement should clarify the relationship between low(er) testosterone levels and the possible negative influence on the progression of puberty.
Sexual functioning. Hyperprolactinemia was associated with sexual side effects. Fourteen percent of the boys in our study with antipsychotic-induced hyperprolactinemia experienced sexual side effect. An earlier study that used a specific questionnaire for adverse sexual events showed a prevalence of 25% sexual dysfunction among adolescents treated with risperidone (N=21), olanzapine (N=13) and quetiapine (N=6) irrespective of prolactin levels and type of antipsychotic used; however this study included 45% females and irregular menses, gynecomastia and galactorrhea were part of the questionnaire; no actual sexual dysfunction was reported (Saito 2004). In studies of adults with schizophrenia or mood disorders who were treated with risperidone, the rate of diminished sexual functioning due to hyperprolactinemia was about 40% (Bobes 2003, Knegtering 2004 and 2006). Since the boys included in our study could have been sexually inexperienced or inactive, they might have not been able to self-assess their sexual functioning as well as adult patients. Moreover boys with ASD have difficulties with communication skills, which could have biased our results. Therefore the results of studies in adults with schizophrenia cannot be directly compared to boys with ASD. The sexual functioning data in our study from the Antipsychotic Sexual Functioning Questionnaire (ASFQ) (Knegtering 2000) may have been biased by recall and time. The boys had to reflect back to the time when they did not use risperidone. Moreover, some of the boys may have started risperidone before puberty and may have become sexually mature thereafter, so that they might have considered their sexual functioning as unchanged (20% for the cases and 10% for the comparison group) or unknown (cases, 30% and comparison group, 40%) whereas it was, in fact, suppressed. Moreover, boys who were sexually inexperienced or inactive could not make a before and after comparison. Therefore the actual rate of sexual side effects may be higher than we measured in our study. Nevertheless a significant number of boys (1 in 8) experienced sexual dysfunction in relation to antipsychotic-induced hyperprolactinemia. Therefore the clinician should actively and systematically ask about the sexual functioning before the start and over the course of treatment.
Monitoring. Systematic longitudinal follow-up studies have not been performed to investigate the clinical consequences for children and adolescents of long-term antipsychotic-induced hyperprolactinemia on hypogonadotropic hypogonadism and bone mineral density. However, the data in this thesis and in earlier cross-sectional studies are sufficient cause for concern for us to advise active monitoring of prolactin levels and change of treatment in case of antipsychotic-induced hyperprolactinemia if clinically feasible. Another argument for active monitoring is that about half of our study population had antipsychotic-induced hyperprolactinemia without any obvious prolactin-related symptoms (e.g., gynecomastia, galactorrhea, sexual dysfunctioning). Therefore, we recommend assessment of serum prolactin levels before and during treatment with prolactin-elevating antipsychotics (Staller 2006, Citrome 2008, Ho 2011). To establish the diagnosis of hyperprolactinemia, the Endocrine Society recommends (in their practical guideline, Melmed 2011) a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis of hyperprolactinemia as long as the serum sample is obtained without excessive venipuncture stress. Previous short-term studies show a steep increase of the prolactin level within the first six weeks (Aman 2002, Biederman 2005, Snyder 2002) followed by a slow decline after one year of antipsychotic treatment (Anderson 2007, Croonenberghs 2005, Turgay 2002, Stevens 2005, Migliardi 2009). Average prolactin levels remained above the reference value after two (Staller 2006, Reyes 2006) and three years of continued antipsychotic use (Calarge 2010, Roke 2012) although two studies reported a tendency towards normalization of prolactin after respectively 12 months (Migliardi 2009) and 22 months (Anderson 2007) of antipsychotic treatment. Our results are based on a carefully performed study in a sample of adolescents with long-term treatment of antipsychotic and indicate that after a mean of 51.5 months, half of the adolescents still had antipsychotic-induced hyperprolactinemia.
Since prolactin levels rise steeply during the first six weeks of antipsychotic treatment and decline to a plateau phase after three months (Findling 2004), we recommend monitoring prolactin levels after the first three months of treatment and repeating the test every year. Whenever the dose of antipsychotic is increased, prolactin levels also increase because of the clear dose-response relationship (Knegtering 2005). Furthermore prolactin-related side effects such as sexual functioning disorders should be addressed before and during treatment, since these sexual side effects occurred in 14% of the boys in our study with ASD treated with prolactin-elevating antipsychotics. Since self-report is a less valid method to assess these side effects, we recommend using a standardized questionnaire, such as the ASFQ (Knegtering 2003). We also suggest investigating the presence of gynecomastia and galactorrhea before and during treatment. We recommend using a questionnaire to check for symptoms of gynecomastia or galactorrhea (Saito 2004) and also a physical examination of the breasts (Roke 2012). The physician may also interview the patient about the following topics: a (family) history of fractures, calcium intake, sun exposure, and exercise. This assessment of risk factors for future osteoporosis may help the physician to decide how to treat the hyperprolactinemia and to give the patient advice on exercise and dietary intake to minimalize the risk of future osteoporosis. Since 25-hydroxyvitamin D3 is a major determinant of bone mineralization and bone strength in children and adolescents (Boot 2011, Pekkinen 2012), we recommend assessment of serum 25-hydroxyvitamin D3 and starting supplementation when necessary.

Summary of recommendations. We recommend:
• monitoring the prolactin level before treatment, after three months of treatment and repeating this every year or three months after dose increase.
• using a standardized questionnaire, such as the ASFQ, to measure sexual side effects (Knegtering 2003).
• investigating the presence of gynecomastia and galactorrhea before and during treatment using a questionnaire (Saito 2004) and also a physical examination of the breasts (2Roke 2012).
• assessing serum 25-hydroxyvitamin D3 and start supplementation if necessary.
• assessing risk factors for future osteoporosis.
• changing treatment in case of antipsychotic-induced hyperprolactinemia.
Our results also provide further input to clinical considerations and discussions about whether a risk assessment (genotyping) for hyperprolactinemia should be performed before prescribing antipsychotics such as risperidone to children and adolescents with psychiatric disorders. A risk assessment may reduce treatment expenses and may reduce adverse events (Chou 2000). However, the variants of D2DR gene and CYP2D6 enzyme are not specific enough yet to be used in clinical practice (Kirchheiner 2010).
Challenges. The problem with antipsychotic-induced hyperprolactinemia is that we do not know at which threshold value side effects (e.g., gynecomastia, diminished sexual functioning, galactorrhea) and complications such as diminished BMD and hypogonadotropic hypogonadism may begin. Half of the patients with hyperprolactinemia experienced no side effects. The question is whether these patients, those with hyperprolactinemia without evident side effects, are at increased risk for future complications. In our cross-sectional study the boys with antipsychotic-induced hyperprolactinemia and low BMD (z-score < -2) had no other prolactin-related side effects. Low BMD, especially in children and adolescents, is a serious side effect (Lewiecki 2008), which may lead to future clinical consequences such as higher bone fragility and osteoporosis. Hyperprolactinemia seems to be a long-term side effect of antipsychotic in half the children and adolescents treated, and could potentially influence processes such as the attainment of the peak bone mass. BMD continues to increase during adolescence, and in boys peak bone mass reaches a plateau between 18 to 23 years of age (Boot 2010). Still, it is possible that once the prolactin concentration normalizes, bone mineralization increases to normal. The impact of hyperprolactinemia on BMD is clinically relevant only if it leads to increased bone fragility and fractures.

4.2 Collateral / spin-off project: Second-generation antipsychotic use in children and adolescents: a six-month prospective cohort study in drug-naïve patients (Arango et al., 2014). This study was designed to assess weight and metabolic effects of 6 months of treatment with second-generation antipsychotics in naïve/quasi-naïve youths. It was a nonrandomized, naturalistic, multicenter, inception cohort study of 279 patients aged 4 to 17 years (mean = 14.6 ± 2.9 years). Of those, 248 (88.8%) received a single antipsychotic (risperidone, olanzapine, or quetiapine) and completed 2 visits, and 178 (63.8%) completed the 6-month follow-up. Patients had schizophrenia-spectrum disorders (44.5%), mood-spectrum disorders (23.2%), disruptive behavioral disorders (17.3%), or other disorders (15.1%). Fifteen age- and gender-matched, healthy, nonmedicated individuals served as a comparison group.

From baseline to 1 month, 3 months, and 6 months, all anthropometric measures increased significantly with each antipsychotic, that is, 6-month changes with risperidone (n = 157; 7.1 kg and 0.66 body mass index [BMI] z score), olanzapine (n = 44; 11.5 kg and 1.08 BMI z score), and quetiapine (n = 47; 6.3 kg and 0.54 BMI z score), but not in healthy control participants (-0.11 kg and 0.006 BMI z score). Fasting metabolic parameters increased significantly with risperidone (glucose [3.8] mg/dL, insulin [4.9] mU/L, homeostasis model assessment of insulin resistance [HOMA-IR: 1.2], triglycerides [15.6] mg/dL), and olanzapine (glucose [5.0] mg/dL, total cholesterol [21.2] mg/dL, and low-density lipoprotein cholesterol [44.6] mg/dL), but not with quetiapine or in healthy control participants. The percentage of research participants considered to be "at risk of adverse health outcome" increased during the 6 months from 8.9% to 29.2% for risperidone (p < .0001), 6.8% to 38.1% for olanzapine (p < .0001), and 6.3% to 4.0% for quetiapine (p = .91).
In conclusion, olanzapine, quetiapine, and risperidone increase body weight but have different cardiometabolic side effect profiles and different temporal side effect patterns.

4.3 Collateral / spin-off project: Effects of controlled discontinuation of long-term used antipsychotics on weight and metabolic parameters in individuals with intellectual disability (Kuiper et al., 2013). Antipsychotics are frequently prescribed agents in individuals with intellectual disability, often for behavioral symptoms. Efficacy of antipsychotics for this is ambiguous, so discontinuation should be considered. Weight gain and metabolic dysregulation are well-known adverse effects of antipsychotics which increase the risk of the metabolic syndrome. We performed a discontinuation study in 99 adults with intellectual disability, living in residential facilities who used antipsychotics for behavioral symptoms for more than 1 year. The aim of the present study was to investigate the effects of discontinuation of long-term used antipsychotics on weight, body mass index (BMI), and parameters of the metabolic syndrome and to investigate the influence of genetic polymorphisms and medication factors on these outcomes. Discontinuation of antipsychotics led to a mean decrease of 4 cm waist circumference, of 3.5 kg weight, 1.4 kg/m2 BMI, and 7.1 mm Hg systolic blood pressure. In those participants who had not completely discontinued use of antipsychotics we found a decrease in weight and BMI and an increase in fasting glucose. The presence of the C-allele of serotonin 5-hydroxytryptamine receptor polymorphism rs141334 was associated with higher waist circumference and higher plasma levels of triglycerides and lower levels of high-density lipoprotein. Achievement of complete discontinuation predicted a larger decrease in waist circumference and BMI.
In conclusion, results of the study show the beneficial effects of discontinuation of long-term used antips

Potential Impact:
PERS was designed to address at least two significant mental health problems, namely the treatment of antisocial behaviour/Conduct Disorder, and appropriate use of antipsychotic medication in particular Risperidone. Evidently, there is no one-dimensional one-strike solution to the complex problem of antisocial behaviour/CD. However, the use of effective and safe medication such as risperidone is expected to make a major contribution to effective treatment of those children and adolescents with CD who present in various mental health settings and/or require efforts by societal agencies. At the end of the day, effective and safe medication will pay off by significantly lowering the burden for individuals with CD, their families as well as society in general.

However, since the two planned RCTs were not carried out, we have not been able to contribute to build a rich database on the efficacy of Risperidone in the treatment of antisocial behaviour/Conduct Disorder.

PERS was also expected to contribute to improving the treatment of other child and adolescent psychiatric disorders, such as Schizophrenia, and Autism Spectrum Disorders. In these disorders, atypical antipsychotics such as risperidone, are also increasingly prescribed. Schizophrenia and Autism Spectrum Disorders affect a rather small portion of the population, however, the individual and societal burden associated with the disorder is quite high. Effective and safe treatment with antipsychotic medication, in many cases over prolonged periods of time as continuous or maintenance therapy, will significantly contribute to a better long-term health outcome of patients with schizophrenia and autism spectrum disorders, and will concomitantly be associated with economic savings.

It was expected that the PERS would have the following concrete impact:
1. Changed regulatory status of risperidone in CD. Since no PUMA will be obtained, this impact has not been realized.
2. Better use of risperidone in CD and other psychiatric disorders as schizophrenia and autism spectrum disorders. Risperidone is the most often prescribed antipsychotic in children and adolescents, however, its frequent use is at variance with the available evidence-base. Although the present project has not delivered new RCT data about effective and safe use of risperidone in CD, our extensive dissemination activities (see below) at seminars, training schools, international and national symposia and meetings have had impact on the scientific community and a large group of child and adolescent psychiatrists and other potential prescribers of antipsychotics to children and adolescents. Partly supported by PERS, the academic sites were able to publish a series of papers on efficacy and safety of antipsychotics, based on data collected in other projects, in peer-reviewed journals (see below). These dissimination activities and scientific communications have substantially contributed to better knowledge about and greater awareness of the indications and pros and cons of prescribing of antipsychotics as Risperidone in pediatrioc populations.
3. Better assessment of long-term benefits versus long-term risks of the use of risperidone. CD and also schizophrenia and autism spectrum disorders are rather stable and chronic conditions, which necessitate long-term treatment in a sizable proportion of cases. The risks of long-term use of risperidone in children and adolescents however are strikingly unknown. There is a rather pessimistic outlook that in some cases long-term risks for metabolic syndrome, obesitas and diabetes mellitus may eclipse any therapeutic effect of risperidone. More precise knowledge about these long-term risks and the factors that make individual patients more or less vulnerable to these risks, would greatly enhance the effective prescription of risperidone in CD and other disorders. As described above under 2., our dissemination activities and publications have significantly added to knowledge and awareness of long-term benefits and risks. Moreover, the data collected in the observational study will be further analyzed and published, and provide further impact to the field.

We had anticipated to take the following steps to realize impact:
1. Prepare Paediatric Investigational Plans and submit requests for Paediatric Use Marketing Authorisations to EMA. The first has been realized in interaction with EMA, and approved by EMA, the latter not.
2. Contact the relevant professional societies, the European College for Neuropsychopharmacology (ECNP), and the European Society for Child and Adolescent Psychiatry (ESCAP) to get their support to establish an EU Clinical Guidelines Group for the Assessment and Treatment of Conduct Disorder. Since we did not collect RCT data (and no RCT data were published by either companies or academic investigators) this has not been realized yet.

List of Websites:
Website: http://www.pers-project.com
Contact details: coordinator Prof. Jan Buitelaar,
Jan.Buitelaar@radboudumc.nl
Tel -31-24-3610750

Related information

Contact

Maarten Van Langen, (legal advisor)
Tel.: +31-24-3619791
Fax: +31-24-3540529
E-mail
Record Number: 191752 / Last updated on: 2016-11-11
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