Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disease that affects 1.5% of children. ASD presents with impaired social communication and restrictive behaviors and interests (1). Social communication deficits include difficulties with eye contact, body language, and verbal language, while restrictive behaviors include motor stereotypies and fixed behavioral routines (2). A characteristic of ASD is onset of poor social communication and stereotypies before 2 years of age, though the mean age of diagnosis is 5 years. While the etiology is unknown, most studies suggest that a combination of genetic and environmental factors are responsible, with neuroanatomical abnormalities in the limbic system, cerebellum, and cortex (3).

While there is no cure, existing treatments can alleviate disease symptoms and increase the patient's social and occupational functioning. High-functioning patients can lead independent lives, while low-functioning patients may require lifelong care in a dedicated facility (4). The only Food and Drug Administration (FDA)-approved pharmacotherapies for irritability in ASD are the atypical antipsychotics risperidone and aripiprazole (5, 6), but other antipsychotics (alpha-2 agonists, stimulants, antidepressants, and N-acetylcysteine [7, 8]), can treat the behavioral alterations (see Table 1). We present a case of an adult male with ASD who was hospitalized for aggression and violence and improved with propranolol monotherapy. We discuss the role of the autonomic system in ASD and evidence for treatment with non-selective beta-blockers.

Methodology

The case is discussed in the context of the literature on the use of beta blockers in ASD. A literature review was performed through searches on PubMed using the keywords “autism,” “autism spectrum,” “beta-blocker,” “propranolol,” “autonomic,” and “sympathetic.” Inclusion criteria were use of a beta blocker for adult patients with ASD-related aggression. Articles addressing adrenergic function in ASD were also included.

Case

“Mr. C” is a 25-year old Caucasian man with ASD who was admitted to the hospital due to “getting angry at home” for over a month. Six weeks prior to presentation, the patient had expressed a desire to attend a prestigious university; his mother informed him that this was impossible because he had not completed his high school diploma. Discussions between the patient and his mother became increasingly heated, and the patient began to exhibit behavior that ranged from verbal insults to destruction of doors and windows in their shared home. Mr. C's previously fluent speech began to include stuttering and echolalia, which were mild prior to his exacerbation. His past medications included clomipramine, risperidone, and pemoline (a dopaminergic stimulant), but he had been stable off of medication prior to this exacerbation.

When initially evaluated, the patient refused to speak to the treatment team, paced the hallways, hit furniture, and shouted at staff and other patients. His heart rate was 102 beats per minute but normotensive. He displayed impulsive and inappropriate behaviors that included shouting jokes into the telephone handset, pacing the hallways, knocking on other patients' doors, and initiating loud conversations with inappropriate laughter. When playing board games, he would exhibit aggressive outbursts and sweep the game pieces off the board when he lost. Throughout his hospital stay, he stuttered during single sentences and experienced episodes of noticeable echolalia. A basic metabolic panel, lipid panel, and electrocardiogram obtained on admission were normal.

Monotherapy with the beta blocker propranolol 20 mg twice daily was started for behavioral and verbal control and its known benefit in the treatment of neuroleptic-induced akathisia, which was a possible contributor to Mr. C's agitation from prior antipsychotic use. Two days later, he impulsivity subsided, and he participated in group activities on the unit without disruption. Four days into treatment, he developed friendships on the unit, held quiet conversations, and engaged in board games without anger. He tolerated emotional conversations, such as discussion of delaying college plans, and the frequency of stuttering and echolalia decreased. He denied any side effects. His blood pressure remained at his baseline of 110/80 mmHg, and his heart rate decreased to 80 beats per minute. With the behavioral improvement on propranolol and stable vital signs, the patient was safely discharged without additional medications.

Discussion

The Adrenergic System in ASD

Along with social dysfunction and restricted behaviors, ASD is often accompanied by impulsivity, anxiety, and aggression that resemble states of autonomic arousal (9). Autistic children demonstrate monoamine-induced tachycardia and elevated electrodermal conductance (a measure of sweat production from autonomic activation) (10) at when baseline compared with children without ASD, similar to the tachycardia exhibited by our patient on admission (11), markers that are associated with aggression (9). While normal subjects demonstrate increased sympathetic arousal during active tasks, individuals with ASD may display paradoxically increased parasympathetic activity, as measured by heart rate variability, compared with controls (12). These findings may suggest that the repetitive behaviors of the disorder (echolalia in the above case) may be an adaptive response to this heightened autonomic activity.

Therapeutic Use of Beta Blockers in ASD

The findings of sympathetic activation in ASD suggest that sympatholytic drugs may improve the behavioral symptoms of the disorder, as demonstrated by the efficacy of alpha 2 agonists for aggression in placebo-controlled trials (13). Though there are myriad reports of beta blockers improving aggression in patients with brain damage, mental retardation, and adult-onset psychiatric conditions (14–16), only two studies from a single cohort of eight adult patients have addressed the use of beta blockers for ASD-associated impulsivity and aggression. Both were open trials without controls, and both demonstrated remission of tantrums, property destruction, and self-injurious behavior in one-half the patient samples after 6 weeks of treatment with the non-selective beta blockers propranolol or nadolol (17). These trials revealed subtler improvements in speech and social behavior in all eight subjects (18), consistent with controlled trials demonstrating improvement of word fluency (19) and conversational reciprocity (20) with propranolol in ASD. In comparison, the response of the above patient in the present case report during the first week of treatment was faster than that of the patients in these studies and at a lower dose of propranolol (40 mg per day versus at least 100 mg per day). Additionally, nadolol does not penetrate the blood-brain barrier (21), suggesting that peripheral beta blockade may be sufficient to ameliorate aggressive symptoms. No studies, to our knowledge, have examined the effects of β1-selective blocking agents on the symptoms of ASD, and this remains an avenue for further research.

Limitations

The trials discussed above and in our case involved the use of beta blockers in adult autistic patients. It is unclear whether children might benefit, and the risk of hypotension may be dangerous in this age group. The beta blockers used were non-selective β1 and β2 antagonists, and the results from the trials and our case report cannot be applied to β1-selective agents. Potential confounding factors in our case report include the controlled hospital environment, the absence of the patient's mother, and the therapeutic benefit of interaction with hospital staff.

Conclusions

Although the autonomic hyperactivity hypothesis of aggression in ASD partially explains the behavior of our patient, aggression likely stems from multiple sources beyond just peripheral autonomic arousal. The rapid improvement with propranolol at a fairly low dose suggests that a subpopulation of patients may benefit from non-selective beta blockers. As beta blockers have hemodynamic side effects that include hypotension and bradycardia, clinicians should record baseline vitals and monitor for orthostasis, dizziness, and syncope. Overall, beta blockers may serve as an important therapy for aggression but should not replace a multimodal interventional plan that encompasses pharmacology, psychotherapy, and social support. It will be beneficial to validate the utility of propranolol and other beta blockers for ASD in future randomized controlled trials.

Key Points/Clinical Pearls