Successful risperidone treatment for behavioral disturbances in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is characterized by perinatal muscular hypotonia, dysmorphic features and infancy feeding problems, followed by overeating and being excessively overweight and other symptoms related to hypofunctioning of the hypothalamus (i.e. hypogonadism, short stature and hypopigmentation) including learning disorders.1,2 PWS represents the most common diagnosable genetic obesity syndrome. It occurs in approximately one in 15 000 births, and it is associated with chromosomal paternal deletion or maternal disomy at 15q11–q13.3 In addition to physical features such as obesity, PWS also includes behavioral disturbances such as stubbornness, impulsiveness, aggressiveness, self-mutilation, skin picking, and temper tantrums.1,2 Behavioral disturbances (i.e. hyperphagia, morbid obsession, reduced satiety, stealing money to buy food), decreased energy expenditure and reduced physical activity may lead to morbid obesity accompanied by life-threatening cardiac-respiratory complications. Therefore, various modes of psychotropic medications have been suggested, among them selective serotonin reuptake inhibitors, central nervous system stimulators, lithium, anticonvulsant medications (valpro acid, carbamazepine, etc.) and classical neuroleptics.4 However, to date, no proven and efficient management modality for the behavioral manifestations in PWS has yet been established. Risperidone, an atypical antipsychotic agent, is a highly potent antagonist against both dopamine D2 and serotonin 2A receptors.5 Our decision to choose risperidone for the treatment of PWS was motivated by a recent report6 that described risperidone as being effective for children suffering from autism with behavioral disturbances including stubbornness and impulsiveness, which are similar to those of PWS. We herein report a case of PWS, in which risperidone improved the behavioral disturbances and also resulted in weight loss due to the introduction of cognitive behavioral therapy without any side-effects. The case is an 11-year-old boy, who was born at 39 weeks' gestation with a bodyweight of 2720 g. After birth, he was admitted to the neonatal intensive care unit of the University of Occupational and Environmental Health, Kitakyushu, Japan, because of muscular hypotonia, a poor sucking reflex. A chromosomal test (the fluorescence in situ hybridization method) carried out at the age of 8 months detected deletion of chromosome (15q11–q13), so he was diagnosed as having Prader–Willi syndrome. Overeating appeared at the age of two, and his bodyweight rapidly increased. After his parents divorced, the patient discontinued visiting the hospital and he therefore no longer received any intervention to prevent his overeating. When he visited the hospital again two years later at the age of 11, hepatic function disorder, hyperinsulinemia and severe sleep apnea syndrome were observed with extreme obesity (Fig. 1, Table 1) with 143 cm height and 126 kg bodyweight (body mass index [BMI] 61.6 kg/m2). The patient had mild mental retardation, although an intelligence test had not been accurately carried out. After admission, the calories of food was restricted to 1600 kcal daily, but symptoms characteristic of PWS such as impulsiveness and stubbornness soon appeared, and problems such as food snitching and violence toward other children and staff were frequently observed. Initially we administrated mazindol and fluvoxamine (a selective serotonin reuptake inhibitor) was attempted as drug therapy, but did not improve the behavioral disturbances at all. Because it had become difficult to manage the patient in the pediatric ward due to those behavioral disturbances, he was moved to the psychiatric department of St. Lucia's Hospital one month later. After being moved, oral administration of risperidone (maximum 1.5 mg/day) was initiated with the family's consent, and behavioral disturbances especially impulsiveness and aggressiveness, did improve. As a result, cognitive behavioral therapy was then started. With the cognitive behavioral therapy, he learned to calculate his caloric intake each day, including snacks, to control his bodyweight, and he was praised for success, after which he could cope with the dietary restrictions by himself. At the time of his discharge from hospital, his weight decreased to 108 kg. He continues to take 0.5 mg/day of risperidone orally, and at 18 months after he was discharged, his bodyweight has decreased to 80.4 kg (BMI 37.1) without exhibiting any severe behavioral disturbances (Fig. 1). Furthermore, the complications due to obesity (i.e., hepatic dysfunction, hyperuricemia, hyperinsulinemia and sleep apnea syndrome) and hyperleptinemia observed before the initiation of the therapies, have also disappeared and the Retrospective Overt Aggressive score, assessing the frequency of verbal aggression and physical aggression against an object, self or others,7 also declined (Table 1). The growth chart of the patient. The Prader–Willi Syndrome Association (USA) recommends, in the behavioral management guidelines for PWS patients, praising sufferers for appropriate behavior, as it reduces inappropriate behavior.8 In addition, cognitive behavioral therapy is reported to be a useful approach for patients diagnosed as having mental retardation such as PWS.9 In this case, it is also believed that compliance with cognitive behavioral therapy was successful in changing the negative environment (in which the patient was only warned or prohibited from activity) to a positive environment (in which he was praised for correct behavior that he could accomplish during the cognitive behavioral therapy in the psychiatric ward). Risperidone, the atypical anti-psychotic drug used in this study, shows efficacy by inhibiting both serotonin receptors and dopamine receptors, and it has been reported to be associated with fewer side-effects than classical antipsychotic drugs, such as haloperidol. It has currently become a first-line drug for adult cases of schizophrenia.5 Although safety and efficacy for children has not been established, a randomized double-blind trial was carried out recently for children suffering from autism.6 Moreover, Durst et al. reported that administration of risperidone in seven cases of children with PWS for 37 weeks improved behavioral disturbances such as impulsiveness, aggressiveness, and stubbornness with no obvious side-effects in any of the cases.10 Weight gain due to increased food intake is one of the side-effects of risperidone,5 but following the administration of the drug for PWS by Durst et al.,10 weight loss was observed in five of seven cases, and in this case, as well, bodyweight was able to be reduced by over 40 kg because the overeating could be controlled. The precise pathological mechanisms of overeating in PWS are unknown. In this case as well, risperidone is not considered to have directly controlled the overeating, however, we believe that the bodyweight decreased because risperidone relieved the patient's temper tantrums, impulsiveness and stubbornness, thus facilitating the effective implementation of cognitive behavioral therapy, and finally resulting in a good control of the patient's tendency to overeat. On the other hand, this case presented with mild growth retardation after we began administering risperidone. To date, there have been no reports of growth retardation due to risperidone, so it will therefore be necessary to further observe the clinical course carefully to determine whether such a side-effect occurs. There are many commonalities between autistic symptoms and the behavioral disturbances of PWS, such as impulsiveness and temper tantrums. Dysfunctions of serotonin and dopamine systems have been reported as a cause of behavioral disturbances in autism or PWS. The effectiveness of risperidone for both disorders supports the hypothesis that dysregulation of central serotonin and dopamine transmitters may play a role in both disorders. In addition, it has been reported that the maternal duplication of 15q11.2–q13 is observed in autistic patients,3 and the deletion at the same site or maternal disomy of chromosome 15 is observed in PWS, thus indicating the possibility of a genetic commonality as a cause of the behavioral disturbances in these two disorders.3 The fundamental treatment of PWS is to improve lifestyle habits, including controlling overeating by early intervention, but it is often difficult to manage in reality due to behavioral disturbances and complications of obesity from overeating. However, according to this case and previous reports, the administration of risperidone for PWS appears to be effective for the treatment of behavioral disturbances characteristic of PWS and it is therefore expected to be useful for weight loss by controlling overeating. This paper is a single case report. Further studies involving more subjects with a systematic measurement of behavioral changes are thus needed to confirm the safety and effectiveness of risperidone in the treatment of PWS.