Donezepil for Emotional and Behavioral Symptoms of Alzheimer’s Disease

Abstract & Commentary

Source: Weiner ME, et al. Effects of donezepil for emotional and behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry 2000;61:487-492.

The cholinergic system is well known for its role in encoding memory, but less noted for its role in a variety of behaviors, including aggression, mania, and depression. Behavioral disturbances in patients with Alzheimer’s disease cause significant distress and possible injury to caregivers, and severely reduce the quality of life for all parties involved. Previous small studies have reported reduced anxiety, apathy, hallucinations, aberrant motor behaviors, and disinhibition in the context of treatment with cholinergic agents (e.g., tacrine) in patients with Alzheimer’s disease. In the current study, outpatients with Alzheimer’s disease were tested at baseline, one-, three-, four-, and 12-month follow-ups with the Mini-Mental Status Examination (MMSE) and a behavioral rating scale for dementia (CBRSD). The CBRSD is a 48-item scale, with subscales for depression, behavioral dysregulation, inertia, irritability/aggression, psychosis, and vegetative symptoms. Scores are 0 (none) to 4 (severe), with a maximal score of 168. Patients with a score of 25 and higher were openly treated with donezepil (Aricept)— 5 mg daily for three months, followed by a possible dose increase to 10 mg daily, based on the clinician’s judgment. Twenty-seven patients were enrolled and 25 completed a 12-month follow-up. Seventeen were increased and maintained on 10 mg of donezepil daily. Fifteen concurrently took psychotropic drugs (mainly SSRIs), with eight having a dose increase during the study. Eight of the 15 females were taking estrogen. Preliminary analyses found no differences in MMSE or CBRSD scores between those taking or not taking psychotropic drugs, those taking or not taking estrogen, or those at 5 mg vs. 10 mg of donezepil daily in relation to outcome; therefore, the data for these groups were analyzed together. Community-dwelling AD patients (n = 153) who completed a descriptive (nonintervention) 12-month Alzheimer’s study served as a reference group.

Following donepezil, MMSE scores were improved at 1, 3, and 4 months, and returned to baseline by month 12. Likewise, overall CBRSD scores were improved at months 3-4, and returned to baseline by month 12; specifically, the CBRSD depression and behavioral dysregulation subscales were significantly reduced (dysregulation was defined by restlessness, action without purpose, wandering, and attempting to leave the premises). The study group and the reference group were virtually identical in terms of demographics and MMSE scores at baseline. At the 12-month follow-up, the study group had only a 1.1 decline in MMSE, compared to the reference group’s 3.9-point decline; the former also had a 5.1-point decrease in the CBRSD compared to the reference group’s 0.2-point increase, which is consistent with donepezils’ effects on cognition.

Comment by Donald M. Hilty, MD

Donezepil appears to reduce problematic behaviors, particularly depression and behavioral dysregulation, associated with Alzheimer’s disease in a manner consistent with its effects on cognition (i.e., improvement followed by a return to baseline, which is better than constant decline without treatment). The study analysis did not include tests to control for the effect of cognitive improvement on behavioral problems, which deserves elaboration. If the two are intertwined, cholinesterase inhibitors would appear indicated in mild and moderate dementia, as currently prescribed. If however, the two are not intertwined, there is potential benefit of these drugs even in later, more severe stages of dementia. Controlled trials are indicated to attempt to answer some of these questions. Because of its favorable side effect profile, there appears to be minimal risk of using donepezil at a higher dose (10 mg daily) to target behavioral symptoms. When a comorbid disorder or more specific psychiatric symptoms (e.g., hallucinations) are present, low-dose treatment with other psychotropics is indicated (e.g., an SSRI for depression, antipsychotic for psychosis). Controlled trials are needed to evaluate the efficacy and safety of these other psychotropic drugs in this population.