Treatment with the antidepressant bupropion does not improve apathy in nondepressed patients with dementia of Alzheimer type (DAT), results of a multicenter, double-blind, placebo-controlled trial show.

Although safe in this patient population, bupropion was no better than placebo in reducing apathy, neuropsychiatric symptoms, or health-related quality of life, the researchers say.

"Bupropion will most likely not be effective in apathy in AD. It is important to study other drugs due to the negative impact of apathy on the disease course and the associated burden for patients and caregivers," first author Franziska Maier, PhD, Department of Psychiatry, University of Cologne, Germany, told Medscape Medical News.

The study was published online May 28 in JAMA Network Open.

Biologic Rationale

Apathy, a profound loss of motivation, is the most common behavioral problem in patients with Alzheimer disease and treatment options are limited.

Low levels of dopamine are associated with reduced motivational and reward-driven behavior and have been linked to apathy. Research has also shown an inverse association been dopamine and noradrenaline transporter binding in the ventral striatum and higher apathy scores in patients with Parkinson disease.

Bupropion is a norepinephrine/dopamine-reuptake inhibitor used for major depressive disorder, seasonal affective disorder, and smoking cessation.

The drug has been shown to increase psychomotor activity in a mouse model of DAT. Case reports in frontotemporal dementia and post-stroke apathy also support a potential benefit of bupropion for the treatment of apathy.

Against this backdrop, Maier and colleagues evaluated the safety and effectiveness of bupropion for apathy in 108 patients with mild-to-moderate DAT and clinically relevant apathy. Patients with clinically relevant depressed mood were excluded. The mean age of patients was 74.8 years and about two thirds were men.

Over 12 weeks, half of the patients were randomized to receive placebo and half bupropion (150 mg for 4 weeks plus 300 mg for 8 weeks). If the 300-mg dose was not tolerated, patients continued on 150 mg throughout the study.

The primary outcome was change on the Apathy Evaluation Scale–Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12.

At baseline, AES-C scores were comparable in the bupropion and placebo group (mean, 52.2 vs 50.4). 

Need for Better Measures?

After controlling for baseline AES-C score, study site, and comedication with donepezil or galantamine, the mean change in AES-C score was not statistically significant between the bupropion and placebo group (mean change, 2.22; 95% CI, –0.47 to 4.91; P = .11).

Additionally, there was significantly greater improvement in the placebo group in the secondary outcomes of total neuropsychiatric symptoms and health-related quality of life. 

There were no statistically significant changes between groups in activities of daily living or cognition. Adverse events and serious adverse events were comparable between study groups.

These findings are similar to those of a recent randomized clinical trial in which bupropion did not alleviate apathy in nondepressed patients with Huntington disease.

Maier and colleagues say it's important to note that at the time their study was planned (2008-2009), the AES-C was the standard measure for apathy in DAT. More recently, it has been shown that this scale is a one-dimensional test, with a substructure that does not include all dimensions of apathy.

"Therefore, further studies should use more advanced measures, such as the Dimensional Apathy Scale, that better discriminate between apathy and overlap symptoms of depression, as well as between different apathy subdimensions," they write.

Currently there is no standard treatment for apathy in Alzheimer disease. However, as previously reported by Medscape Medical News, there is some evidence that methylphenidate might be beneficial.  

"Besides medication, nonpharmacological treatment options such as occupational therapy are still first-line," said Maier.

The study was funded by a grant from the German Ministry of Education and Research. Maier has disclosed no relevant financial relationships.

JAMA Netw Open. Published online May 28, 2020. Full text

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Cite this: Antidepressant Fails to Improve Apathy in Dementia Patients - Medscape - May 29, 2020.