Risperidone Treatment for Irritability in Fragile X Syndrome

Introduction

Fragile X syndrome (FXS) is the most common inherited form of both intellectual disability and autism spectrum disorder (ASD) (Bailey et al. 2008; Hagerman et al. 2009; Budimirovic and Kaufmann 2011). FXS results from an unstable trinucleotide repeat expansion resulting in gene methylation and associated silencing of the Fragile X Mental Retardation 1 (FMR1) gene. This, in turn, leads to deficient or absent expression of FMR protein. As an X-linked disorder, FXS is associated with a unique neurobehavioral phenotype with a more severe presentation in males (Bailey et al. 2001). Features of FXS include developmental disability, hyperactivity, inattention, impulsivity, learning disabilities, sensory issues, anxiety, high risk for comorbid ASD, and behavior problems, including risk for severe aggression and self-injury (Baumgardner et al. 1995; Bailey et al. 1998; Hatton et al. 2002; Symons et al. 2003, 2010; Cornish et al. 2004; Baranek et al. 2008; Schneider et al. 2009). Despite significant efforts, there are currently no treatments for the underlying pathology of FXS (Schaefer et al. 2015; see Davenport et al. 2016). Clinical pharmacologic treatment in FXS to date has focused on treatment of symptom clusters that interfere with daily functioning, including irritability marked by aggression, self-injurious behavior, and severe tantrums.

Irritability is common in FXS, particularly in males, with prevalence estimates ranging from 38 to 86 percent (Hagerman et al. 1986; Bailey et al. 2008, 2010; Hessl et al. 2008; Symons et al. 2010; Newman et al. 2015). Parents and caregivers of individuals with FXS report that irritability has a significant negative impact on quality of life, and cite this symptom cluster as their most pressing behavioral concern (Bailey et al. 2000; Hatton et al. 2000). Aggressive behaviors frequently result in the need for more restrictive educational and living environments and can result in injuries and stress for caregivers (Wheeler et al. 2016). Atypical antipsychotics are the most commonly used class of medications targeting irritability in FXS (Erickson et al. 2006), based on literature supporting their use in ASD and other related developmental disabilities (Jesner et al. 2007; Ching and Pringsheim 2012; Hirsch and Pringsheim 2016). Unfortunately, to date there is limited data supporting the use of atypical antipsychotics for treatment of irritability in individuals with FXS.

Retrospective reviews of large FXS clinical samples do provide some support for the use of atypical antipsychotics targeting irritability in this population. Amaria et al. (2001) surveyed 140 males with FXS younger than the age of 18 years. They demonstrated that the use of atypical antipsychotic medications was relatively common (14% of the sample), with risperidone being the most commonly prescribed atypical (∼93% of prescribed antipsychotics). Berry-Kravis and Potanos (2004) reported that risperidone was the most frequently prescribed antipsychotic medication in a survey of 176 individuals with FXS, and that treatment resulted in a relatively high response rate. A more recent analysis examining 257 patients with FXS treated between 1991 and 2005 found that aripiprazole and risperidone were the most commonly prescribed antipsychotics, with 70% of individuals responding to aripiprazole and 50% responding to treatment with risperidone (Berry-Kravis et al. 2012). The investigators also determined that risperidone was particularly helpful in younger males with autistic traits and older males with significant aggression.

To date, there has been only one prospective trial of an atypical antipsychotic in FXS. This open-label study, completed by Erickson et al. (2011), examined treatment with aripiprazole monopsychotropic therapy (mean dose, 9.8 mg/day) targeting irritability in 12 patients (aged 6–25 years) with FXS. Eighty-seven percent of participants demonstrated a significant treatment response, defined as a Clinical Global Impressions-Improvement (CGI-I) scale of “much improved” or “very much improved” and a ≥25% improvement on the Aberrant Behavior Checklist-Irritability subscale. Ten of the patients were able to complete the study with two discontinuing due to reported adverse effects (drooling, tiredness, and possible akathisia).

In this review of prospectively acquired clinical treatment data, we present data describing naturalistic risperidone treatment targeting irritability in 21 males with FXS. This study aims to add to the literature regarding the systematic use of risperidone in this population. In this study, we describe aspects of risperidone dosing, concomitant medication use, tolerability, and clinical response in a naturalistic longitudinal treatment setting.

Methods

As part of a larger ongoing comprehensive assessment of medication management in developmental disabilities, data describing individuals with FXS, who were evaluated and treated at the Indianapolis Fragile X Research & Treatment Center (Indianapolis, IN) between 2004 and 2012, were collected. Data were prospectively collected during clinical treatment and retrospectively reviewed, extracted, and coded into a REDCap database. This study was approved by the local Institutional Review Board.

From our database, we identified patients with FXS who received longitudinal monoantipsychotic treatment with risperidone (two or more data points). For each subject, demographic data, including age, sex, race, ethnicity, and concomitant diagnoses, were collected. We additionally gathered data describing concomitant medications, previous atypical antipsychotic treatment trials, duration of risperidone treatment, final dose of risperidone, and body mass index (BMI) at initial and final risperidone treatment time points. Dosing for risperidone was determined clinically by the treating physician (C.A.E). Treatment response was measured using the CGI-I scale (Guy 1976). The CGI-I is designed to measure global change from baseline anchored in target symptoms, in this case, irritability. It is rated from 1 to 7 (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no improvement, 5 = minimally worse, 6 = much worse, 7 = very much worse). All CGI-I were assigned prospectively by the treating physician (CAE) anchored to the core symptoms of irritability. For the purposes of this study, patients were considered treatment responders if they were assigned a final CGI-I rating of 1 = “very much improved” or 2 = “much improved.” Given the wide age range of patients in this data set, an exploratory analysis was completed assessing the effect of age on response. Pearson chi-square was used to compare the percentage of responders younger and older than 12 years of age.

Diagnosis of FXS was confirmed by southern blot and polymerase chain reaction results consistent with a ≥200 cysteine-guanine-guanine (CGG) repeat expansion in the FMR1 gene with at least partial gene methylation. Autism diagnoses were made by clinicians with significant experience in autism, using diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association 2000). Intellectual disability diagnosis was based upon review of neuropsychological testing and/or school reports when available. All diagnoses of intellectual disability were given by psychologists based upon testing completed at Riley Hospital for Children at Indiana University of Health or testing completed by school psychologists. Change in BMI with treatment was analyzed using a paired t-test.

Results

Of the 74 patients with FXS in our medication management database, 35 (47.30%) were prescribed risperidone at any time (this includes those only prescribed risperidone at one visit, or in combination with other antipsychotic medications), and 21 (28.38%) received longitudinal risperidone treatment without cotreatment with another antipsychotic medication. Mean age of study participants at risperidone initiation was 14.0 years (SD 8.5). All participants were male, 95.2% were Caucasian, 85.7% were diagnosed with ASD, and 90.5% (n = 19) had documented intellectual disability. The level of intellectual disability for the other two participants was undocumented or unknown (Table 1). Ten (47.6%) of the 21 patients had a previous treatment trial with at least 1 antipsychotic medication before starting risperidone, and 6 (28.6%) had failed prior trials of 2 or more antipsychotic medications, thus, meeting criteria for drug-refractory irritability (Adler et al. 2015). There were only two participants who had not been treated with any psychotropic medications before starting risperidone. Concomitant medication use was common, with antidepressants and alpha-2 agonists being the most frequently prescribed classes of medications (Table 2). Nearly half of the participants (47.62%) were prescribed a concomitant antidepressant, and one individual received treatment with two antidepressant medications (paroxetine and mirtazapine). Four participants (19.05%) were prescribed risperidone alone.

Risperidone treatment duration ranged from 22 days to 122 months, (mean duration 22.1 ± 28.2 months, Table 3). Risperidone dosage ranged from 0.05 to 12 mg per day. The average daily dose at last data point for each subject was 2.50 ± 2.64 mg/day. The mean CGI-I score at time of treatment cessation or the last collected data point was 3.28 ± 1.16 (“minimally improved,” n = 18). Seven patients (33.33%) were deemed treatment responders at the final recorded visit. Four patients (19.05%) had CGI-I of 5 (minimally worse) and none had a CGI-I score of 6. Nine of the 12 patients who initiated treatment before age 12 had CGI-I data available, and all the 9 patients who initiated treatment after age 12 had CGI-I data available. Five of the 9 patients younger than the age of 12 years (56%) were considered treatment responders, and 2 of the patients older than the age of 12 years (22%) at the time of treatment initiation were responders (see Fig. 1, X²  = 2.10, p = 0.15). Weight gain was the most commonly reported side effect for risperidone (47.6%). Other side effects reported included sedation (14.29%), drooling (4.76%), and increased appetite (4.76%).

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FIG. 1.

CGI-I Scale score by age group. Older group is aged 12 years and older. Younger group is younger than the age of 12 years. CGI-I, Clinical Global Impressions-Improvement.

Participants were overweight at study initiation, with mean BMI of 23.33 ± 6.50. For participants who had BMI measurements available at both treatment initiation and cessation (n = 11), the average change in BMI was not significant (t[10] = 1.71, p = 0.11). The range of change in BMI was from −0.86 to 4.58. Over half of the cohort (52%) stopped risperidone treatment during the data analysis period. The most common reason for treatment cessation was loss of effectiveness (n = 4). Weight gain led to treatment cessation in only 9.5% (n = 2) of patients.

Discussion

This report examined risperidone monoantipsychotic treatment targeting irritability in 21 individuals with FXS over nearly 2-year mean treatment duration in a naturalistic tertiary care setting. Participants demonstrated improvement with risperidone, however, on average, the improvement was graded as minimal (mean CGI-I = 3.27) with only one third of the sample demonstrating significant clinical response. Despite this relatively low clinical response rate, nearly half of participants continued on risperidone at the end of data collection, suggesting that while treatment response did not meet our definition of clinically significant, families were seeing some degree of desired results.

The response rate in our study is significantly lower than the 50–85% response rates described in previously published FXS treatment (Berry-Kravis et al. 2002, 2012), although there are several differences between our study and previous reviews, which may, in part, explain these rate differences. First, risperidone response rates in previous reviews were based on interpretation of clinical notes (i.e., Berry-Kravis et al. 2012) rather than prospectively assigned CGI-I scores extracted from clinical records. Specifically, a positive response was defined as documented clinical improvement in irritability in at least two settings sustained over six months (Berry-Kravis et al. 2012), which is not directly comparable to CGI-I scores. Second, our cohort of patients may have suffered from relatively more severe and treatment-resistant irritability than those in previous FXS treatment reviews, as 74.0% of individuals with FXS in our database have history of treatment with an antipsychotic medication in contrast to only 22.6% in the review by Berry-Kravis. It is interesting that treatment response was higher in patients younger than the age of 12 years. This is consistent with previous work by Berry-Kravis et al. (2012), who found that risperidone was particularly effective in males younger than the age of 12 years with autism. However, this difference was not significant and must be considered with caution given the small sample size.

Our results differed from previous work in some other notable ways. Our sample had relatively limited change in BMI over the course of risperidone treatment and a less than 10% discontinuation rate due to weight gain. In contrast, problematic weight gain was cited as a common reason for treatment cessation in the study of Berry-Kravis et al. (2012). However, BMI data in this sample were notably limited with BMI at both initiation and cessation of treatment, only available for 11 patients. In addition, previous studies have included very little information regarding concomitant use of psychotropic medications, whereas the majority of our study participants were treated with at least one concurrent psychiatric medication, indicating that perhaps our sample suffered from more significant psychiatric symptomatology.

The results of our study must be considered on the context of several limitations. Most notably, all participants in this study were male, and the majority suffered from comorbid autism and intellectual disability. In comparison, 21% of those patients in the clinic-based analysis by Berry-Kravis et al. (2012) were female, and level of intellectual disability is not noted. The severity of impairment in our study group limits the generalizability of our results. Other limitations include study design and small sample size. Neither the clinician nor the subject was blinded to treatment, and additional objective measures of irritability such as the Aberrant Behavior Checklist (Aman et al. 1985a, 1985b) were not available. Many of these weaknesses are a function of the naturalistic clinical setting, in which the analysis was completed. However, this setting does offer the significant advantage of providing insight into the effectiveness and tolerability of the drug in real-world clinical practice.

Conclusions

Risperidone was, on average, minimally effective in the management of irritability with one third of patients demonstrating a more pronounced effect in this group of males with FXS and predominantly treatment-resistant irritability. We believe our findings warrant future prospective study of risperidone for irritability in FXS. Such studies would benefit from standardized dosing schedules, complete metabolic information, and other safety laboratories, as well as use of standardized outcome measures such as the Aberrant Behavior Checklist modified for use in FXS (Sansone et al. 2012).

Clinical Significance

Our report offers additional evidence that risperidone may be effective in the treatment of irritability in males with FXS, although the effect may not be as pronounced as that seen in persons with idiopathic autism. The overall effectiveness of monoantipsychotic treatment with risperidone was limited in this study compared with previous published reports; however, this may be the result of differences in response measurements as well as the reflection of the severity of irritability in this sample.