Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study

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Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study"


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Prader–Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled


trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12–45 years) had genetically confirmed PWS and severe


irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50–200 mg/day)


for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour


Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the


CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved


significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose–effect relationship. DHK scores were also significantly associated


with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had


therefore a significant effect on eating disorders, with a dose–effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic


option within the global care of obesity in individuals with PWS.


Prader-Willi syndrome (PWS) is a rare genetic syndrome occurring in 1/21000 newborns in the general population1. This genetic abnormality is located in the 15q11-q13 region, a region with


genomic imprinting, and lead to an absence of expression of a paternal gene due to a micro-deletion (65%) or a maternal disomy (30%). Very few cases are due to a defect of the imprinting


centre (5%). The clinical presentation is heterogeneous, but some trends can be observed. First, the syndrome follows a developmental course. This is particularly clear for feeding


disorders: infants with PWS have poor feeding and social skills along with severe hypotonia that switches to uncontrolled hyperphagia around the age of 2 years. Second, cognitive impairments


(mild intellectual disabilities) and psychiatric impairments are common. Third, endocrine dysfunctions are likely to occur via growth hormone (GH) deficiency and hypogonadism. Adults with


PWS exhibit numerous challenging behaviours (irritability, aggression, hyperphagia, alimentary compulsions and skin lesions) and psychiatric disorders (mood disorders, obsessive-compulsive


disorder, brief psychotic episodes, hallucinations and delusional ideas)2. Feeding disorders are severe in 2/3 of cases, and the consequences of them can include obesity, somatic and


metabolic disorders and temper outbursts caused by frustration over alimentation or misunderstandings of social situations. Irritability and aggression are particularly challenging for


families and institutions. Skin lesions due to skin picking can lead to infections or chronic inflammation and severe anaemia.


The therapeutic approach to PWS has seen tremendous improvements during the last two decades and includes (i) the early use of GHs to improve short stature and body composition3, (ii) strict


behavioural measures during childhood to control food access and food intake to prevent obesity4, and (iii) the possible use of oxytocin for infant feeding deficits, which have shown


promising results5. However, despite the prevalence of psychiatric disorders and challenging behaviours among those with PWS, to date, no specific treatments have been approved, and very


little research has been conducted6. Antidepressants (IRS) and antipsychotics seem to be the most frequently used medications6. However, antipsychotics can lead to an increase appetite7 and


are responsible for a worsening of weight gain and irritability as well as temper outbursts related to eating disorders. So far, only two double-blind randomised placebo-controlled studies


have been conducted, but they had small sample sizes (n = 15). The first trial reported on the efficacy of fenfluramine compared to a placebo on improving eating and aggressive behaviours


(skin picking) and inducing weight loss8. However, this treatment was withdrawn from the market because of serious cardiac side effects. The second trial reported on the efficacy of


rimonabant on eating behaviours compared to a placebo9. This treatment was also withdrawn from the market due to its serious psychiatric side effects (anxiety, dysthymia and delusion).


An alternative therapeutic approach has been proposed with topiramate (TOP), an antiepileptic drug that has also been used as an anti-impulsive and mood stabiliser10. In addition, this


antiepileptic treatment, unlike other ones, does not promote weight gain and instead results in a decrease in appetite and, consequently, weight loss10. Topiramate has previously been


prescribed for the treatment of eating disorders. In a meta-analysis that pooled five randomised controlled trials of bulimia nervosa (n = 128) and binge eating disorder (n = 528) patients,


topiramate was more efficient in reducing the quantity of binges, the frequency of ‘loss of control’ (binging), and weight compared with a placebo11. Two prospective open trials that


included 8 patients with PWS each explored the efficacy of topiramate. The first reported an improvement in skin picking and aggressive behaviours but no change in eating behaviours12. The


second reported improvements in eating behaviours, skin picking and aggressive behaviours, and no side effects were reported13. Up to now, no double-blind randomised placebo-controlled


trials have been conducted in patients with PWS.


The objective of this double-blind randomised placebo-controlled trial was to study the efficacy of topiramate on eating disorders, skin picking, and irritability/impulsivity in patients


with PWS and its tolerance by patients. Given the large spectrum of symptoms, we chose the Clinical Global Impression Scale’s Improvement measure as the primary variable. Secondary variables


included symptomatic scales focusing specifically on eating behaviours, skin picking or irritability/impulsivity.


The TOPRADER study was approved by the local ethical committee of the principal investigator (Comité de Protection des Personnes d’Ile de France VI under number CPP/104-11). It was also


registered with the French regulatory authorities (Agence Nationale des Produits de Santé under the number EUDRACT: 2011-003432-32) and the ClinicalTrials.gov international registry under


number NCT02810483. All of the subjects received complete information regarding the protocol before enrolment and gave written consent. Regarding minors or adults under guardianship, either


the parents or legal guardian also received this information and gave written consent


The TOPRADER study was a multicentre double-blind randomised placebo-controlled trial. The objective was to evaluate the efficacy and tolerance of topiramate on irritability/impulsivity,


eating disorders and self-mutilation in patients with PWS over an 8-week period. The subjects were randomly allocated into two groups, one taking topiramate, and one taking a placebo. The


dosage of topiramate was 50 mg/day initially with increases of 50 mg per week up to 200 mg/day. Visits for inclusion and monitoring occurred at inclusion, baseline and at 2, 4, 6 and 8 weeks


(the endpoint).


Participants were outpatients and inpatients from the French reference centre for PWS, which encompasses 3 sites (Pitié-Salpêtrière University Hospital in Paris, Marin Hospital in Hendaye


and Children University Hospital in Toulouse), and the French reference centre for rare psychiatric disorders (Pitié-Salpêtrière University Hospital in Paris). The inclusion criteria were as


follows: a genetically confirmed diagnosis of PWS, being between 12 and 45 years of age inclusive, being over 50 kg in weight and presenting with one of the following symptoms1:


irritability/impulsivity2, eating disorders and/or obesity, or3 self-harm. The exclusion criteria were as follows: the presence of hallucinations, meeting the diagnostic criteria for


schizophrenia according to the DSM IV, suicidal risk, severe depression, comorbid organic conditions (epilepsy, the use of anticonvulsants or mood stabilisers, unbalanced diabetes (HbA1C > 


10%), type 2 diabetes treated with metformin or gibenclamide, a history of nephrolithiasis or glaucoma, hereditary fructose intolerance problems, glucose malabsorption or sucrose-isomaltase


insufficiency), current use of an effective dose of topiramate for a sufficient time without efficacy, the introduction or change in dose of a psychotropic medication within the previous 3


months, hypersensitivity to sulphonamides or to any of the components of topiramate or its placebo, the use of a medication with St John’s Wort, pregnancy or breastfeeding, a lack of


effective contraception in females of childbearing age, and no informative adult to provide feedback on subjects’ behaviour. Exclusion criteria also included biological abnormalities


indicating renal failure (serum creatinine greater than 1.5× normal), hepatic impairment (alanine aminotransferase greater than 2× normal), anaemia (haemoglobin 


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