TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

Introduction Over 5.8?million people in the US are currently living with Alzheimeru0027s disease (AD), the most common form of neurodegenerative dementia. More than 90% of individuals with AD experience neuropsychiatric symptoms (NPS), such as agitation, apathy, and depression. Agitation is one of the most common NPS, which not only accounts for 12% of health and social care costs but also increases the risk of mortality and caregiver burden. The most common treatments for agitation include psychotropic medications, used off-label, along with behavioral management strategies. Though the prevalence of AD is projected to rise to 13.8?million by 2050, there are no FDA-approved treatments for the severe agitation associated with this condition. Recent case series and prospective naturalistic reports have demonstrated evidence that electroconvulsive therapy (ECT), used widely for severe episodes of Major Depression in older adults, may be effective for reducing severe agitation in moderate to severe stages of Alzheimeru0027s dementia. We describe an NIA funded study comparing the efficacy of ECT plus usual care (ECT + UC) versus simulated ECT plus usual care (S-ECT + UC) in decreasing agitation symptoms for individuals with AD. In order to minimize the potential for adverse cognitive effects associated with ECT, such as memory impairment, the present study has taken into consideration treatment modality, treatment modification, and treatment discontinuation to minimize adverse effects of ECT on cognition and the development of delirium. Methods The ECT-AD study aims to randomize 200 patients with a diagnosis of AD, severe agitation and a history of at least three prior failed trials of psychotropic medication. The patients will be admitted to the inpatient psychiatry units at Emory Wesley Woods Hospital, McLean Hospital, Mayo Clinic, Pine Rest Christian Mental Health Center, and Northwell Health. The consent will be provided by an authorized health care representative and assent will be obtained from patients. Subjects will be randomized to up to 9 ultra-brief pulse Right Unilateral (UB-RUL) ECT treatments plus usual care or simulated ECT plus usual care, blinding the inpatient treatment team to the study arm allocation. Previous research has not only established the comparability in regards to the safety and efficacy of UB-RUL ECT with more commonly practiced treatment modalities (i.e., brief pulse bitemporal (BP-BT) or BP-bifrontal (BP-BF)), but also demonstrated that there is reduced evidence for memory impairment associated with UB-RUL ECT than with either BP-BT or BP-BF. To mitigate the risk of cognitive side effects, this study will initiate UB-RUL for all patients. Seizures threshold will be established at treatment one, and subsequent treatments will be given at 6 x seizure threshold. Treatment modifications for this study include a switch from UB-RUL ECT to BP-BT ECT after the 6th ECT treatment if the patient has not demonstrated improvement. The treatment parameters will be switched to BP-BT for sessions 7 through 9, and charge dose would be determined using the half-age method. We established discontinuation procedures to minimize cognitive side effects, such as discontinuation due to change in eligibility (i.e., no longer meets agitation criteria on Cohen Mansfield Agitation Inventory (CMAI), development of delirium measured by the Confusion Assessment Method (CAM), or development of a cognitive adverse event as determined by persistent decreases on measures of the Severe Impairment Battery (SIB-8) or the Barthel Index (BI). Results A recent retrospective chart review of sixty patients with dementia and agitation from Emory suggests that UB-RUL ECT is safe and effective in reducing agitation in AD as measured by the Pittsburgh Agitation Scale (PAS), Global Assessment of Functioning (GAF) and number of psychotropic medications. The baseline PAS total was 9.3+/-3.7 and it decreased significantly after three (2.5+/-2.8) and six (1.5+/-2.3,) ECT treatments. No significant ECT-related medical complications were observed except transient confusion. There was a reduction in the number of psychotropic medications prescribed along with an increase in the global assessment of function (GAF) score after the ECT treatment course. We hypothesize that ECT+UC will be more efficacious in reducing severe agitation in AD subjects than S-ECT+UC. The primary efficacy outcome measure is the CMAI. The secondary efficacy outcome measures are the Neuropsychiatric Inventory – Clinician Version (NPI-C), Alzheimeru0027s Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC), and PAS. Safety and tolerability will be assessed with the Severe Impairment Battery – 8 items (SIB-8) for cognitive decline, the CAM for the development of delirium, and adverse event monitoring. For subjects who exhibit floor effects on the SIB-8 at baseline, the Barthel Index (BI) will be used as a proxy measure of cognitive function. Conclusions The present study aims to demonstrate the safety and efficacy of ECT for treating severe agitation in individuals with AD using a randomized-controlled method while minimizing cognitive side effects through established baseline treatment parameters and treatment modification protocols. Results from this study will likely guide further research and help clinicians more effectively address severe agitation in patients with AD, including an improvement in quality of life for individuals with AD while decreasing caregiver burden and healthcare costs. This research was funded by: National Institute of Aging R01 AG061100-01