Guanfacine Extended Release for the Reduction of Aggression,Attention-Deficit/Hyperactivity Disorder Symptoms,and Self-Injurious Behavior in Prader-Willi Syndrome—A Retrospective Cohort Study

Introduction

Prader-Willi Syndrome (PWS) is the most common genetic cause of morbid obesity in children, and is caused by the loss of expression of the imprinted genes in the paternally derived region of chromosome 15 (Cassidy and Driscoll 2009; Butler 2011). While the symptom that is most commonly associated with PWS is hyperphagia, behavioral disturbances are not uncommon. These symptoms can include aggression, oppositional behavior, and temper tantrums, which cause significant distress to patients and caregivers (Ogura et al. 2008; Arron et al. 2011; Tunnicliffe et al. 2014; Mazaheri et al. 2013). PWS also has a high prevalence of self-injurious behavior such as skin picking, as well as repetitive motor activity, impulsivity, and hyperactivity (Wigren and Hansen 2005; Greaves et al. 2006; Banga and Connor 2012; Ogata et al. 2014). Impulsivity and hyperactivity are well-known presenting signs of attention-deficit/hyperactivity disorder (ADHD), and as many as one out of every four PWS patients exhibit these symptoms (Wigren and Hansen 2005). Despite the high prevalence of behavioral disturbances, there have been a limited number of studies investigating drug therapy options to manage them in this complex genetic condition. Given the significant morbidity caused by these behavioral problems in this already vulnerable population, novel, evidence-based approaches to manage aggression, impulsivity, and self-injury are warranted.

Currently, selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics are utilized to manage aggression and skin-picking behavior in PWS (Bonnot et al. 2016; Soni et al. 2007). However, both classes of medications are associated with a potential for developing or worsening of metabolic syndrome (Warnock and Kestenbaum 1992; Hellings 1994; Kohn et al. 2001; Kraemer et al. 2011; Fjukstad et al. 2016; Almandil et al. 2013). Topiramate is another medicine utilized for self-injury and aggressive behavior (Bonnot et al. 2016). However, topiramate is known to cause cognitive side effects, which present a significant concern given that a majority of patients with PWS already suffer from intellectual disability (Javed et al. 2015; Laurier et al. 2015). Since PWS is strongly associated with obesity, prevention of metabolic syndrome is paramount to improving morbidity and mortality in these patients. In addition to the established metabolic side effects of these agents, there have been reports of development of psychotic symptoms such as auditory/visual hallucinations and paranoid delusions with the use of SSRIs and serotonin agonists, making serotonergic agents less than ideal, since PWS has a close association with development of psychotic symptoms (Vogels et al. 2004; Herguner and Mukaddes 2007; Dennison et al. 2013). In the case of impulsivity and hyperactivity, stimulants are commonly utilized to manage these symptoms. However, this class of medication sometimes worsens mood, irritability, and chronic use of stimulants may lead to an increase in skin-picking behavior (Kara and Akaltun 2018). While some medications such as N-acetylcysteine and oxytocin have been suggested for management of skin-picking behaviors, safe and effective modalities remain sparse for the management of behavioral symptoms in PWS (Tauber et al. 2011; Miller and Angulo, 2014; Kuppens et al. 2016; Miller et al. 2017).

Guanfacine extended release (GXR) is approved by the Food and Drug Administration (FDA) and is widely used for the management of ADHD (FDA Website). Guanfacine is a postsynaptic α2-adrenoceptor agonist that works by moderating prefrontal cortex activation associated with the coordination of executive functioning and consequent reduction in impulsivity (Schulz et al. 2013; Faraone et al. 2013). Medications that operate as α2-adrenoceptor agonists such as guanfacine have been shown to be beneficial in treating disruptive and aggressive behaviors, in addition to effectively treating symptoms of ADHD in children (Biederman et al. 2008; Connor et al. 2014; Pringsheim et al. 2015). In addition, GXR has been demonstrated to be safe and effective for reducing hyperactivity, impulsivity, and distractibility in patients with autism, another patient population that commonly presents with ADHD symptoms (Davis and Kollins 2012; Scahill et al. 2015). Most significantly, GXR has had no reports of significant weight gain, worsening hyperphagia, or other metabolic side effects. Despite these advantages, to date there is only one case report demonstrating a reduction in aggression with GXR in a patient with PWS (Singh et al. 2015; Hervas et al. 2014; Newcorn et al. 2016).

This retrospective cohort study aims to examine whether treatment with GXR can lead to a reduction in key behavioral symptoms of aggression, hyperactivity, and self-injury in individuals with PWS, while demonstrating an acceptable tolerability and safety profile.

Methods

This is a retrospective cohort study with PWS patients who were evaluated in an outpatient general psychiatry setting. Charts of patients with genetically confirmed PWS seen during a 4-year period were reviewed by a psychiatrist (D.S.) and neuropsychologist (C.F.) in the clinic. Collected data include demographic information, reasons for referral, whether or not GXR was used, behavioral symptoms being managed, side effects, and response to treatment. Patients referred for aggression/agitation, skin picking, or symptoms of ADHD (inattention and/or hyperactivity) were included in this study. Side effects that were closely monitored during the cohort study included sedation, hypotension, insomnia, weight gain, and worsening aggression/agitation and self-injury. Blood pressure, heart rate, and the weight of the patients were monitored for any significant clinical changes. Patients taking other psychotropic medications were included in the study as long as there were no other changes in dosage or treatment regimen within 1 month of GXR initiation. The severity of the patients' behavioral symptoms was monitored over the duration of GXR treatment, and response to treatment was categorized as improved, unchanged, or worsened based on clinician observation as well as patient and caregiver reports. The primary outcome of this study was the percentage of the PWS patients whose behavioral symptoms improved with GXR treatment. Necessary Institutional Review Board approvals were obtained.

Results

Discussion

This retrospective cohort study examined the effects of GXR in patients with PWS, in particular, looking at tolerability and efficacy in reducing aggression, self-injury, and ADHD symptoms. The results of this study showed reduction in the symptoms of aggression/agitation, ADHD, as well as skin picking. In addition, no significant weight changes were observed in patients who were treated with GXR, which is consistent with results found in prior studies with children and adolescents (Huss et al. 2018). The results of this retrospective cohort study suggest that GXR warrants a closer look as a treatment for behavioral disturbances in patients with PWS.

As GXR belongs to a class of α-agonist medication and is widely used in the management of ADHD symptoms, its usefulness in these symptoms in PWS patients is not surprising. In our study, 15 out of 16 patients who initially presented with complaints of symptoms of ADHD reported improvement, with additional benefits demonstrated in skin-picking behavior and aggression/agitation, with improvements reported in 81.8% and 82.3% of the cases, respectively. This finding is in line with a previously completed clinical trial of GXR use in children and adolescents with ADHD, where all treatment groups showed statistically significant improvement in their symptoms (Biederman et al. 2008). A clinical trial has also been completed on the use of GXR in patients with autism spectrum disorder, who presented with symptoms of impulsivity, where the rate of positive response was 50% in the treatment group (Scahill et al. 2015). As impulsivity is a commonly seen behavioral disturbance in patients with PWS, this may explain why GXR showed efficacy in the PWS patient population (Ogata et al. 2014).

GXR was discontinued only in two patients who presented with prior history of psychosis, including auditory hallucinations and delusions, due to lack of efficacy in treating these psychotic symptoms and aggression related to the psychotic episodes. This finding suggests that GXR should not be considered a treatment for psychotic symptoms in patients with PWS. As mentioned above, GXR appears to reduce behavioral disturbances in PWS patients whose symptoms originate from impulsive behavior; therefore, if behavioral disturbances are driven by an underlying psychotic etiology, GXR may not be able to target the symptoms appropriately. Otherwise, GXR was relatively well tolerated in this study, with increased fatigue and sedation being the most commonly reported adverse effects, which were transient and self-limited when adjusting the dosage.

Moreover, PWS patients commonly have GH deficiency, which contributes to the short stature and the central-obese body habitus. GH replacement therapy has shown beneficial effects in aiding linear growth, restoring normal body composition, bone density, as well as lipid profile values (Sipila et al. 2010; Bakker et al. 2017). Clonidine is an α2-adrenoceptor agonist similar to GXR, and both medications have been shown to increase GH levels in a dose-dependent manner (Gil-Ad et al. 1990; Halperin et al. 2003). However, GXR is less sedating compared to clonidine and therefore may be better tolerated (Balldin et al. 1993). This advantage is especially important to note, given the high prevalence of excessive daytime sleepiness in patients with PWS (Driscoll et al. 1998; updated 2017). Although not measured in this study, the possible physical benefits of increased GH could indicate an additional advantage of GXR in comparison to other medications used for behavioral management of patients with PWS. This could be further elucidated in prospective trials.

This retrospective cohort study has several limitations. It is challenging to establish external validity in a single site study, due to limitations of accounting for the variance in environmental and practitioner-based factors. Furthermore, although subjects were excluded if there were changes in other psychotropic medications within 1 month of GXR initiation, the average treatment duration of GXR was 8.5 months, and determination of treatment effect was made over the entire treatment duration. Any change made in other psychotropic medications during that time may have influenced the effect.

As PWS is a rare disease, a multicenter prospective trial with access to a larger patient population is desirable to further demonstrate the feasibility of GXR use. Because this is a retrospective cohort study with no control group available, we cannot compare symptom progression with and without the treatment of GXR. Therefore, this study is not able to provide a statistical significance, but rather provides a narrative based on the observation of these patients and their response to treatment in a naturalistic environment. Another limitation was that no standardized scales were used to quantify response to treatment. The use of conventional behavioral scales such as the Clinical Global Impressions - Improvement scale in future studies can provide a clearer clinical picture in how effective GXR can be in this patient population.

Despite these challenges to the study, GXR seems to provide promise in the management of PWS patients and warrants prospective, randomized controlled trials.

Conclusions

This retrospective cohort study aimed to provide a supporting framework toward the utilization of GXR in the management of behavioral symptoms comorbid with PWS. These disabling symptoms include aggression, irritability, inattention/hyperactivity, and skin picking. In this study, GXR demonstrated improvement in these symptoms, while maintaining a safety profile with very limited side effects. The results of this study suggest that GXR may be an effective and relatively safe treatment modality for behavioral problems in patients with PWS. Future prospective research is warranted to confirm the findings of this study.

Clinical Significance

Patients with PWS often present with challenging behavioral disturbances such as aggression/agitation, skin picking, and ADHD symptoms like impulsivity and inattention. Current management strategies for behavioral disturbances in PWS patients show limited efficacy and/or can have significant side effects. The results of this retrospective cohort study demonstrated that GXR may be effective in the management of behavioral disturbances in PWS, while demonstrating limited side effects.