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Buspirone for the treatment of anxiety-related symptoms in Angelman syndrome

a case series

Balaj, Kaylaa; Nowinski, Lisab,c; Walsh, Briannab; Mullett, Jenniferb; Palumbo, Michelle L.b,c; Thibert, Ronald L.b,c,d; McDougle, Christopher J.b,c,d; Keary, Christopher J.b,c,d

doi: 10.1097/YPG.0000000000000218
ORIGINAL ARTICLES
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Objectives Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the ubiquitin-protein ligase E3A gene on chromosome 15. AS results in intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and problematic behavior which may include anxiety. Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders and may, therefore, have a treatment role for patients with AS.

Methods We describe three patients who were given open-label buspirone for the treatment of behaviors thought to be related to anxiety.

Results We found significant improvement in symptoms of anxiety with buspirone. Patients tolerated long-term usage of the medication.

Conclusion The findings of this study suggest that buspirone may be effective for the amelioration of behaviors related to anxiety in patients with AS, and well tolerated. Limitations include the open-label nature of these treatments, the small sample size and the absence of a control group.

aDepartment of Psychiatry, Central Michigan University Health, Saginaw, Michigan

bDepartment of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Lexington

cHarvard Medical School

dDepartment of Neurology, Angelman Syndrome Program, Massachusetts General Hospital for Children, Boston, Massachusetts, USA

Correspondence to Christopher J. Keary, MD, Lurie Center for Autism, One Maguire Road, Lexington, MA 02421, USA Tel: +1 781 860 1700; fax: +1 781 860 1766; e-mail: ckeary@partners.org

Received May 17, 2018

Received in revised form October 22, 2018

Accepted December 21, 2018

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Introduction

Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the maternally inherited ubiquitin-protein ligase E3A gene (UBE3A) on chromosome 15 (Albrecht et al., 1997). It is estimated to occur in approximately one in 12 000–20 000 live births (Williams et al., 2010b). Molecular subtypes of AS include a deletion of the 15q11.2–13.1 region, mutation of the maternal UBE3A gene, paternal uniparental disomy, and imprinting defects. These genetic abnormalities can result in a host of clinical features including intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and ophthalmic pathology (Thibert et al., 2013). Individuals with this condition often exhibit a specific behavioral phenotype including a high level of social interest and engagement with frequent smiling and paroxysms of laughter (Angelman, 1965; Williams et al., 2010b).

In addition, challenging behavioral symptoms are common among patients with AS. Problematic behaviors seen in this population can include hyperactivity, sensory stimulation, self-injury, aggression, and anxiety (Laan et al., 1996; Clayton-Smith, 2001; Williams, 2010a; Arron et al., 2011). Sleep problems, while likely multifactorial in etiology (Pelc et al., 2008), may also have a behavioral component, a possibility bolstered by a recent study showing improvement in sleep with behavioral intervention (Allen et al., 2013). While sleep problems sometimes improve in adulthood, other behavioral symptoms may become of increasing concern. This is especially true as adult care services diminish and patients with AS increase in size and strength, making effective limit-setting more difficult.

Multiple studies of individuals with AS have identified anxiety as a consistent concern (Clayton-Smith, 2001; Walz, 2007; Giroud et al., 2015; Larson et al., 2015). A study of adults reported that 46% of caregivers identified their family member with AS as ‘showing signs of anxiety (Larson et al., 2015).’ One study of a younger cohort (248 participants, ages 3–22 years) found 45% of participants became upset when routines were changed (Walz, 2007). Another study (68 participants, ages 1–22 years) found half of participants had a fear of crowds and a third had a fear of noise (Artigas-Pallarés et al., 2005).

Attempts to link the specific genetic abnormalities in AS and behavioral manifestations of the disorder, specifically anxiety, remain exploratory. The molecular deficit implicated in AS is a loss of function of the UBE3A gene in maternally inherited chromosomes (Kishino et al., 1997). The UBE3A gene encodes an ubiquitin ligase that marks proteins for ubiquitination, a process implicated in protein degradation. In Drosophila, the UBE3A equivalent gene may play a role in regulating monoamine synthesis, thereby controlling the concentrations of monoamine neurotransmitters such as serotonin (Ferdousy et al., 2011). Furthermore, the affected genetic region in maternal deletions (the most common genetic cause of AS in humans) includes three γ-amino-butyric acid type A (GABAA) receptor subunits, implicating GABAergic dysfunction in patients with AS (Tan and Bird, 2016). Dysfunction in the regulation of serotonergic (Griebel, 1995) and GABAergic neurotransmitter systems (Lydiard, 2003) have both been implicated in the etiology of anxiety disorders.

Despite these findings, there is little known about the scope and severity of anxiety in AS. Initial attempts to identify anxiety using standardized assessment tools have failed to demonstrate elevated anxiety levels (Wink et al., 2015). This may reflect the small number of participants in the study or the heterogeneous ways in which anxiety may manifest in AS that are not captured using current assessment tools for nonverbal populations. Case studies that describe behaviors concerning for anxiety in AS are needed to guide standardized assessment and distinguish anxiety from other problematic behaviors in AS. Perhaps, because of such challenges, little is known about the treatment of anxiety in AS.

Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders. It is proposed to enhance tonic activation of postsynaptic 5-HT receptors by desensitizing the 5-HT1A receptor on the presynaptic neuron (Blier et al., 1990). This blocks the negative feedback loop mediated by presynaptic 5-HT1A in modulating 5-HT release. It also has antagonist activity on presynaptic dopamine D2 receptors and α1,2 adrenergic receptors. Buspirone carries an indication for the treatment of generalized anxiety disorder in adults from the Food and Drug Administration. It is often used to treat anxiety in children and adolescents, due to an absence of documented withdrawal symptoms and a mild side effect profile (Riddle et al., 1999). Buspirone’s documented tolerability is particularly attractive for use among patients with developmental disorders for whom sensitivity to medications makes treatment challenging. Experts advise lower dosages and slower titration of psychotropic medications among individuals with intellectual disability due to the increased frequency of side effects as compared to the neurotypical population (Handen and Gilchrist, 2006). Despite clear clinical need, no conclusive evidence currently exists to support the use of any anxiolytic medications, including buspirone, as an effective treatment for anxiety in patients with AS.

We present three cases of the use of buspirone in adults with AS that describe the positive results of this treatment in ameliorating behaviors thought to be related to anxiety.

In each of the three cases, parent interview was conducted to obtain retrospective ratings of anxiety and other maladaptive behaviors before the initiation of buspirone and after the optimal dosage had been attained. The rating scales used included the Anxiety, Depression, and Mood Scale, a rating scale designed to measure anxiety in nonverbal populations (Esbensen et al., 2003), and the Aberrant Behavioral Checklist, a parent completed rating scale that assesses the severity of Irritability, Lethargy/Social Withdrawal, Stereotyped Behavior, Hyperactivity/Noncompliance, and Inappropriate speech (Aman et al., 1985).

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Case reports

Case 1

Mr A was a 28-year-old male diagnosed with AS, due to maternal deletion of chromosome 15 q11–q13, referred for evaluation and treatment of anxiety and sleep disturbance. He was the product of a full-term pregnancy complicated by maternal gestational diabetes. The labor began spontaneously and he was born vaginally, weighing five pounds, and six ounces. At one point, Mr. A. was diagnosed with failure to thrive. He did not walk until he was 5 years old. He never developed words, but uses specific vocalizations to refer to preferred caregivers and a picture board for understanding his daily schedule. During childhood, Mr A had frequent ear infections necessitating bilateral osteotomies at 10 years of age. Symptomatic generalized epilepsy was diagnosed at age 2 years and had been controlled with valproate for over 20 years. He transitioned from valproate to clobazam due to elevated liver function tests. He also presented with chronic constipation and gastroesophageal reflux disease (GERD).

Mr A had excessive swallowing and recurrent vomiting that was thought to be attributable to anxiety. Starting in his mid-teen years, he began having bouts of excessive swallowing that occurred every few seconds for hours at a time. These episodes increased when he went to school or a location where he was uncomfortable. The episodes worsened in his 20’s, resulting in recurrent vomiting, weight loss, and emergency room visits. Mr A was unable to eat, drink, or participate in activities when he was in the midst of a gastrointestinal (GI) episode. An extensive workup, including multiple evaluations by gastroenterologists and an otolaryngologist, assessment by a feeding team and an occupational therapist, and allergy (including food) workups did not reveal any clear etiology for the GI episodes. Treatments for GERD and allergy medications were ineffective. Transitioning from valproate to clobazam partially improved these episodes. Proceeding as though the excessive swallowing and vomiting may be anxiety-related, lorazepam 0.5 mg per day, clonazepam 0.5 mg per day and escitalopram 10 mg were tried sequentially. The benzodiazepines and the selective serotonin reuptake inhibitor (SSRI) escitalopram were discontinued, however, due to minimal benefit and overt sedation, respectively. In addition to these potentially anxiety-related GI manifestions, Mr A had long shown significant anxiety whenever he was separated from his mother. His anxiety increased significantly as he got older. There was also a family history of anxiety and depression on both the maternal and paternal sides.

In addition to the interfering GI episodes, Mr A also presented with a significant sleep disturbance. He was taking clonidine 0.2 mg at bedtime which was helpful for falling asleep but not maintaining sleep throughout the night. When Mr A would wake up in the middle of the night, if his parents were not awake to intervene, he would rip out his fingernails, scrape the skin off the back of his heel with the opposing toenail, scratch the back of his neck until the skin broke, rub his toes together to the point of excoriations, and bite himself. Mr A also picked at his gums to the point where he required gum grafts. On very rare occasions, Mr A also became aggressive towards others. Otherwise, his mood was generally good during the day; he remained active and socially engaged. He enjoyed supervised work experiences and participated in social clubs including yoga, swimming, and dance.

On initial psychiatric evaluation, Mr A was given the Diagnostic and Statistical Manual of Mental Disorders, Fifth ed. (DSM-5) diagnoses of Unspecified Anxiety Disorder and Intellectual Disability. At the time of initial evaluation, his medications included clobazam 15 mg in the morning, 15 mg in the afternoon and 40 mg at night for maintenance of seizure control. Additionally, he was prescribed ranitidine 150 mg at bedtime for GERD. To target the anxiety and possibly associated behaviors, treatment with buspirone was initiated at the dosage of 2.5 mg every morning for 1 week, then increased to a dosage of 2.5 mg in the morning and 2.5 mg at night for 1 week with a plan to increase by 2.5 mg a week, in this manner, until anxiety was controlled. After 2 weeks of treatment with buspirone, Mr A had a complete cessation of excessive swallowing behaviors and a significant reduction in vomiting. Once he reached a dosage of 5 mg twice a day, his sleep improved significantly and the self-injurious behaviors that occurred primarily when he awoke in the middle of the night were eliminated entirely. He appeared calmer and happier and he more easily acclimated to new social settings outside the home. Mr A was more agreeable and playful with his caregivers, as well. There has been no significant change, however, in Mr A’s need for near-constant reassurance when he is around his mother or the worsening of symptoms of anxiety when he is separated from her. Over the past 2 years, the dosage of buspirone has been increased by 2.5 mg approximately every 6 months to maintain this degree of symptom improvement. Mr A’s current dosage of buspirone is 10 mg twice a day. There have been no observed adverse events.

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Case 2

Mr B was a 28-year-old male diagnosed with AS, due to maternal deletion of chromosome 15 q11–q13, referred for evaluation and treatment of anxiety and aggression. He was the product of a full-term pregnancy complicated by first-trimester spotting, maternal headaches, and cigarette smoking during the second half of the pregnancy. There were no other prenatal exposures to medication or substances of abuse. The labor began spontaneously and Mr B was born vaginally, weighing eight pounds and eight ounces. He had jaundice with signs of meconium staining at birth but had normal Apgar scores and went home soon after birth. Regarding developmental milestones, Mr B never walked independently and remains minimally verbal. He had his first grand mal seizure at 2 years of age and was diagnosed with a seizure disorder which has been managed with lamotrigine. His medical history also includes hypothyroidism and constipation. Mr B had recurrent streptococcal pharyngitis as a child and had surgical removal of his tonsils and adenoids at age 4 years.

Mr B’s parents were concerned about his anxiety which had worsened considerably as he had gotten older and now often escalated to aggressive behavior. He demonstrated long-standing anxiety with separation from his mother. Mr B’s anxiety was characterized by anxious affect, sweating, and loud vocalizations. These symptoms of anxiety were present nearly every day and, at times, progressed to aggression. Behaviors included pulling others’ hair, grabbing their shirts and hitting them; chewing on his fingers repetitively; and throwing objects at others. Episodes of property destruction were severe enough to include kicking the front window out of a car. His anxiety and aggression seemed to worsen when he was constipated. Previous medication trials included risperidone 2 mg per day, which reduced the frequency of aggressive outbursts but increased their intensity, and sertraline at an unknown dosage, which resulted in increased agitation. Outside of these episodes, Mr B was a sociable and typically happy individual. He lived with his parents and was very active, participating in multiple special needs sports teams. He attended an adult day program 5 days a week.

On initial psychiatric evaluation, Mr B demonstrated psychomotor agitation, an anxious affect, and near-continuous loud vocalizations. He was given the DSM-5 diagnoses of Generalized Anxiety Disorder and Intellectual Disability. At the time of initial evaluation, his medications included lamotrigine 100 mg in the morning and 100 mg at night for seizure control and 50 mcg of levothyroxine at night for hypothyroidism. Constipation was well controlled with polyethylene glycol 17 g every day and two tablets of Senna at night. To target the symptoms of anxiety and aggression, a trial of mirtazapine 7.5 mg at bedtime was initiated. Due to a five-pound weight gain in 4 weeks, the drug was stopped. Buspirone was then started at 2.5 mg daily for 1 week then increased to 2.5 mg twice daily for 1 week, and then subsequently increased by 2.5 mg per week to a total daily dosage of 10 mg twice a day. Since beginning treatment with buspirone, Mr B’s parents find that he is more easily redirected when he becomes anxious and upset. He is much calmer and less likely to become aggressive. Mr B has also stopped sweating excessively when he becomes anxious. He is able to enter a setting where a large number of people are present without becoming anxious and aggressive. His improvement in response to buspirone has been maintained for the past 3.5 years. There have been no observed adverse events. Mr B continues to demonstrate significant separation anxiety in relation to his mother which has not lessened with treatment with buspirone.

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Case 3

Ms C was a 30-year-old female diagnosed with AS, due to maternal deletion of chromosome 15 q11–q13, referred for evaluation and treatment of anxiety, aggression, and sleep disturbance. She was the product of a full-term uncomplicated pregnancy. Ms C was delivered through a scheduled caesarean section and weighed over eight pounds. At birth, she had neonatal jaundice treated with phototherapy. As an infant, she experienced significant problems sleeping and maintaining her weight. Her developmental milestones were delayed as she sat up at age 1 year and began walking at 3 years. She never babbled, cooed or developed meaningful language; however, she did express intermittent purposeful vocalizations. At 18 months of age, she had her first seizure with multiple subsequent antiepileptic drug trials. She was seizure-free for many years on clonazepam 0.25 mg twice daily, but experienced a likely withdrawal seizure at 28 years of age related to a very gradual reduction and discontinuation of this medication. Ms C’s medical and surgical history was also significant for frequent ear infections in childhood and chronic constipation.

Ms C experienced anxiety, characterized by body tensing, pacing, and loud vocalizations, multiple times per day. At least once a day, the anxiety escalated to include aggressive attempts towards others and hand-biting. Her parents expressed concern that the anxiety and subsequent aggression and self-injury were often triggered by her inability to communicate her needs. Aggression and self-injury also occurred when limits were set by staff and family around her excessive attempts to hug others. Ms C’s sleep was also disturbed. She would awaken at night with episodes of laughter or nocturnal enuresis and demand to sleep in her parents’ bed. An electroencephalogram did not reveal evidence of seizures. She was an otherwise social individual who preferred structure and following routines. She lived with her parents and attended an adult day program 5 days per week. Previous psychotropic medication trials included diphenhydramine and melatonin for insomnia with minimal benefit. A 1 week trial of aripiprazole (dosage unknown) targeting anxiety and aggression was stopped due to cognitive dulling. Clobazam at a dosage of 5 mg twice a day was administered for these behaviors/symptoms but led to increased irritability. In addition, guanfacine 1 mg twice a day for an adequate duration of time was ineffective for improving these maladaptive behaviors.

On initial psychiatric evaluation, Ms C showed a near persistent smile, moderate motor hyperactivity with persistent pacing throughout the evaluation, loud vocalizations and bilateral tremor in the upper extremities. She was given the DSM-5 diagnoses of Generalized Anxiety Disorder and Intellectual Disability, as well as Enuresis, nocturnal only. At the time of initial evaluation, she was started on buspirone 2.5 mg in the morning to target the anxiety and aggression. At her 3-month follow-up appointment, Ms C was calmer and showed less hyperactivity and pacing about the office. She was able to sit in a chair for more than half of the visit. Her parents reported that, while there was still anxiety and aggression, the episodes were much less frequent and it was easier for them and staff members to redirect Ms C away from aggression towards others and self-injury. Buspirone was increased to 2.5 mg in the morning and 2.5 mg at night. During a phone check-in 3 months later, Ms C’s parents described additional improvement in the target symptoms. She was reportedly less frustrated and as a result, was demonstrating significantly less anxiety and aggression. She was tolerating the buspirone without apparent side effects. Ms C’s improvement in symptoms of anxiety has been maintained for the past 2.5 years. During the course of treatment, Ms C was also started on trazodone 25 mg every night with good effect for insomnia, and desmopressin 0.1 mg every night which led to a near resolution of the nocturnal enuresis. Ms C had no reduction in anxious behaviors seen during separation from her mother with buspirone treatment.

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Discussion

This report summarizes the effective use of buspirone in the reduction of behavioral symptoms hypothesized to be anxiety-related among three adult patients with a common molecular inheritance of AS (maternal deletion of the 15q11.2–13.1 region). Reductions in the measures of anxiety and irritability were seen in all three participants as measured with the Anxiety, Depression, and Mood Scale general anxiety factor, and Aberrant Behavioral Checklist (Table 1). This study represents, to our knowledge, the first case series describing treatment of anxiety and aggression in patients with AS.

Table 1

Table 1

Anxiety and aggression can be debilitating symptoms in AS that limit educational, vocational, and community involvement and contribute to well-documented caregiver stress (Griffith et al., 2011). Impairment in expressive language skills may contribute to these behaviors. Supporting communication through augmentative and alternative communication technology may allow for effective communication of emotional distress, in turn helping to reduce problematic behaviors. Also, physical illness, such as gastrointestinal disorders, associated with pain and discomfort may manifest as anxiety, agitation, or aggression in those with limited communicative ability, highlighting the importance of multidisciplinary and collaborative care teams.

Initial trials documenting the efficacy of buspirone for neurotypical adults with anxiety found improvement at mean daily dosages near 20 mg (Ansseau et al., 1990; Enkelmann, 1991). In our study, two participants were maintained on the dosage of 20 mg per day, whereas the third participant showed significant sustained improvement on a total daily dosage of 10 mg (Table 1).

There are multiple mechanisms by which buspirone may reduce anxiety due to its actions on the 5-HT1A and D2 receptors as well as corticosterone blood levels that may be particularly beneficial in individuals with AS. Firstly, it is important to note that in maternal UBE3A deficient mice, serotonin or 5-HT (5-hydroxytryptamine) levels are found to be significantly increased in the frontal cortex and striatum compared to wild type littermates with caudate nucleus, putamen and anterior cingulate cortex involvement (Farook et al., 2012). In the presence of elevated serotonin, the above neuroanatomical structures have been implicated in the development of increased, rather that decreased, anxiety (Frick et al., 2015). As buspirone is a partial agonist at the 5-HT1A receptor, it behaves as an antagonist in the presence of elevated serotonin and may reduce anxiety by decreasing serotonin in the cortex and striatum, particularly the caudate nucleus, putamen, and anterior cingulate cortex. In addition to mitigating anxiety in the serotongergic system, buspirone also has D2 antagonist properties which have been shown to reduce high-anxiety behaviors and accelerate extinction of conditioned fear (Pavlova et al., 2015). In low doses, buspirone has been linked to reduced blood corticosterone levels in rodent models reducing activation of the HPA axis (Urban et al., 1986). This may be of particular benefit to individuals with AS as data from rodent models of AS has found evidence of chronically elevated morning basal corticosterone blood levels (Godavarthi et al., 2012).

Also of note, buspirone use was tolerable in AS patients who experienced side effects with other psychotropic medications. One participant, who had side effects with benzodiazepines and an SSRI, was able to tolerate buspirone. Two participants, who could not tolerate atypical antipsychotic medication, also tolerated buspirone without adverse events. None of the participants experienced worsening of the neurologic sequelae of their AS (seizures, ataxia, tremor, or insomnia) that can be related to buspirone use. Participants took buspirone for 2, 3.5 and 2.5 years, respectively, at the time of this manuscript and all three remain on this medication. Tolerability is a particularly important factor for patients with AS where medications used to target behavioral problems may worsen tremor (i.e. valproate) or seizures (i.e. carbamazepine) (Thibert et al., 2009). Stimulants and SSRI’s may carry elevated risk for behavioral activation/worsening among patients with developmental disabilities as compared to neurotypical individuals (Research Units on Pediatric Psychopharmacology Autism Network, 2005; King et al., 2009).

Despite clear and consistent clinical improvement, this report has a number of limitations. The treatment described is open-label, with a small number of participants, and the lack of a control group. All participants were adults with deletion positive AS and results may not be generalizable to children with AS or patients with other AS genotypes. Given the complex nature of clinical treatment, we cannot fully rule out whether other medications played a role in behavioral improvement. However, no other antianxiety medications were started or stopped while buspirone’s effectiveness was being assessed. Changes in buspirone were conducted separately from any other medication change. While symptoms described in these cases are attributed to anxiety, this remains the clinician’s best hypothesis of the emotional state of the patients. Studies that use behavioral analysis to better understand the function and emotions underlying problematic behavior in AS (Strachan et al., 2009) are a welcome addition to the literature. Clinical response to buspirone was identified using a combination of clinical observation, parent report and the use of rating scales. Scores on rating scales were retrospective and therefore participant to possible recall bias. Furthermore, these rating scales have not specifically been validated for use in patients with AS. The identification or development of rating scales for symptoms of anxiety that are valid and reliable in this population will be essential for the design and implementation of prospective double-blind, placebo-controlled treatment trials in persons with AS in the future.

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Acknowledgements

This work was supported in part by the Nancy Lurie Marks Family Foundation.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

Angelman; anxiety; buspirone; treatment

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