High-Dose Propranolol for Severe and Chronic Aggression in Autism Spectrum Disorder: A Pilot, Double-Blind, Placebo-Controlled, Randomized Crossover Study.

BACKGROUND: Despite the use of behavioral interventions and psychotropic medications, many individuals with autism spectrum disorder (ASD) who engage in severe aggression remain refractory to conventional treatment. Propranolol, a beta-blocker, has accumulated much anecdotal evidence as a promising option. However, well-designed studies are rare, and the apprehension about cardiovascular side effects from large doses continues to exist. PURPOSE: The aims of this study were (1) to demonstrate the feasibility of treating aggression with high-dose propranolol using telehealth study visits and (2) to document cardiac safety. METHODS: This study utilized a randomized, double-blind, placebo-controlled, crossover design. Dosing was titrated up in a flexible but stepwise fashion until therapeutic response was obtained or up to 200 mg tid. Following washout, those who were assigned propranolol were crossed over to placebo and vice versa. Six participants between the ages 12-19 participated. The primary outcome measures were the final Clinical Global Impression Improvement Scale (CGI-I) and the Aberrant Behavior Checklist-Community Irritability (ABC-C/I) scores at 200 mg tid. RESULTS: The CGI-I indicated a 50% reduction in symptoms in the propranolol phase, while the ABC-I indicated a 37% reduction in comparison to placebo. The effect sizes ( r ) for the CGI-I and the ABC-C/I were large, -0.74 and -0.64, respectively. The average blood pressure was 122/68 during the placebo phase and 109/72 during the propranolol phase. All Holter monitor exams were unremarkable. CONCLUSION: These results suggest that propranolol is an effective option in decreasing aggression in individuals with ASD. As this was a small study, a larger clinical trial is needed.

The Safety and Effectiveness of High-Dose Propranolol as a Treatment for Challenging Behaviors in Individuals With Autism Spectrum Disorders.

PURPOSE/BACKGROUND: Individuals with autism spectrum disorders present with social communication deficits and a rigid adherence to sameness. Along with these symptoms, many individuals also present with severe challenging behaviors that place themselves as well as their families and communities at risk for injury. For these individuals, new and effective treatments are acutely needed. Propranolol has been used worldwide for over 50 years. Its primary indication is for hypertension, but there is evidence that, at higher doses, propranolol inhibits rage and anger through its effects on the central nervous system. This effect has been demonstrated in a variety of neuropsychiatric disorders. METHODS/PROCEDURES: Here, we present 46 retrospective analyses of clinical cases that were followed by a psychiatrist. Propranolol was prescribed as an add-on to the patients' existing medications. The doses ranged from 120 to 960 mg per day (mean = 462 mg). FINDINGS/RESULTS: Thirty-nine (85%) of 46 patients were found to be much improved or very much improved on the physician-rated Clinical Global Impression Improvement scale. There were few side effects noted, with only 2 subjects unable to tolerate the propranolol. IMPLICATIONS/CONCLUSIONS: It appears that high-dose propranolol can be given safely with minimal adverse cardiovascular problems, provided that close clinical monitoring is maintained. A more rigorous clinical trial is needed to elucidate and verify its clinical utility, clinical practice parameters, and the effects of propranolol as a monotherapy versus as an add-on to the patient's existing medication regimen.

Neuromodulation and a Reconceptualization of Autism Spectrum Disorders: Using the Locus Coeruleus Functioning as an Exemplar.

The Autism Spectrum Disorders (ASD) are a heterogeneous group of developmental disorders. Although, ASD can be reliably diagnosed, the etiology, pathophysiology, and treatment targets remain poorly characterized. While there are many atypical findings in anatomy, genetics, connectivity, and other biologic parameters, there remains no discreet hypothesis to explain the core signs as well as the very frequent comorbidities. Due to this, designing targets for treatments can only be done by assuming each symptom is a result of a discreet abnormality which is likely not the case. Neuronal circuity remains a major focus of research but rarely taking into account the functioning of the brain is highly dependent on various systems, including the neuromodulatory substances originating in the midbrain. A hypothesis is presented which explores the possibility of explaining many of the symptoms found in ASD in terms of inefficient neuromodulation using the functioning of the locus coeruleus and norepinephrine (LC/NE) as exemplars. The basic science of LC/NE is reviewed. Several functions found to be impaired in ASD including learning, attention, sensory processing, emotional regulation, autonomic functioning, adaptive and repetitive behaviors, sleep, language acquisition, initiation, and prompt dependency are examined in terms of the functioning of the LC/NE system. Suggestions about possible treatment directions are explored.

Categorical diagnosis: a fatal flaw for autism research?

The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect. Neuroscientists would benefit from attending to nosological difficulties to formulate meaningful research bridging basic biological systems and human disease. I propose a diagnostic schema that could translate more efficiently between the clinical and the neuroscience perspective as a step to improve the effectiveness of this type of research.