ELECTROCONVULSIVE THERAPY FOR THE TREATMENT OF ACUTE AGITATION AND AGGRESSION IN ALZHEIMER'S DEMENTIA (ECT-AD)

Abstract

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, affecting approximately 5.4 million individuals in the US, and predicted to increase to 13.8 million by 2050. Occurring in over 90% of AD patients, neuropsychiatric symptoms such as agitation, depression and apathy, contribute to caregiver burden and increase patient morbidity and mortality. With no FDA-approved options available, treatments for severe agitation in people with advanced dementia are limited, with modest evidence for efficacy and substantial safety concerns. Behavioral therapies are recommended as first-line treatments for agitation in AD; however, they require substantial time to take effect and may be less efficacious for the most severely agitated patients. Psychotropic medications, especially antipsychotics, are widely used off-label to treat agitation in AD even with documented limitations in efficacy and safety concerns. Therefore, new treatments for severe agitation in AD refractory to standard interventions are timely and warranted. Randomized controlled trials have demonstrated the safety and efficacy of electroconvulsive therapy (ECT) for the treatment of severe psychiatric disorders of late life, including depression, mania and psychosis. Recently, small open label studies suggest efficacy and safety of ECT for agitation in individuals with AD who are refractory to standard therapies. The present randomized controlled trial builds upon prior work and aims to determine the efficacy and safety of ECT for severe agitation in moderate to severe stage AD, while also examining the durability of the acute treatment effect in an exploratory maintenance naturalistic design. Methods We describe an NIA-funded multi-site, single blind, randomized trial of ECT plus usual care (UC) versus Simulated-ECT (S-ECT) plus UC. We will enroll 200 inpatients with severe agitation and moderate to severe dementia, who have not responded well to prior trials of psychotropic medications. Our primary efficacy outcome measure is the Cohen Mansfield Agitation Inventory (CMAI), and the Neuropsychiatric Inventory – Clinician Version (NPI-C), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC), and Pittsburgh Agitation Scale (PAS) will be secondary measures. Safety and tolerability will be assessed with the Severe Impairment Battery – 8 item (SIB-8), the Confusion Assessment Method (CAM), and adverse event monitoring. Results Preliminary open-label data from our team suggests acute ECT treatment is safe and effective in reducing agitation in this population as measured by the CMAI, PAS, CGI, and adverse event monitoring. A multi-site, prospective case series investigated ECT treatment in 23 consecutive inpatients with dementia and severe agitation who did not benefit from standard behavioral interventions and pharmacotherapy. Eighteen of the 23 subjects experienced a significant reduction in agitation from baseline to discharge on the CMAI. In a retrospective chart review study of 16 patients undergoing ECT for agitation related to AD, only two experienced more than transient confusion post-ECT that required treatment, and no other clinically significant adverse events were noted in this group. We hypothesize ECT+UC will be more efficacious in reducing severe agitation in AD subjects than S-ECT+UC, as measured by our primary and secondary efficacy measures, and that there will be no difference in tolerability/safety outcomes for ECT+UC and S-ECT+UC as measured by cognitive decline (SIB-8), development of delirium (CAM), and serious adverse event monitoring. Conclusions This innovative study will fill a gap in the current clinical practice of treating severe agitation in AD using a rigorous methodological approach thus providing evidence for a new therapeutic application (severe agitation in AD) of a well-studied, established, and safe treatment (ECT). Study findings may demonstrate support for a new therapeutic use of ECT for severe agitation in AD. Successful management of neuropsychiatric symptoms reduces long-term care placement, decreases the risk of mortality, and enhances patient and caregiver quality-of-life. Such an approach has the potential to offer enormous relief to the substantial socioeconomic burden of AD-related behavioral disturbances. This research was funded by National Institute of Aging R01 AG061100-01