A new study published in the Journal of Alzheimer’s Disease suggests that vortioxetine, an antidepressant with a unique multimodal mechanism, may offer greater benefits for both mood and cognitive function in people with Alzheimer’s disease who also experience depressive symptoms, compared to other commonly prescribed antidepressants. Over the course of a year, patients taking vortioxetine showed larger improvements in measures of memory, attention, and reasoning, as well as a greater reduction in depressive symptoms, than those taking escitalopram, paroxetine, or bupropion.
Alzheimer’s disease is a progressive neurodegenerative disorder that affects memory, thinking, and behavior. It is the most common cause of dementia in older adults, gradually impairing a person’s ability to carry out daily activities. Alongside cognitive decline, many people with Alzheimer’s also experience neuropsychiatric symptoms such as depression, anxiety, and apathy. Depression in Alzheimer’s is common and can intensify the difficulties posed by memory loss and disorientation, while also worsening quality of life for both patients and caregivers.
The high prevalence of depression in Alzheimer’s has led to increased prescribing of antidepressants in this population. Yet research on how these drugs affect cognitive function has been limited and sometimes conflicting. Certain antidepressants may worsen cognition due to side effects on neurotransmitter systems, while others could potentially support brain function.
Vortioxetine is of particular interest because, beyond its action on serotonin receptors, it also influences other neurotransmitter systems involved in learning and memory. Previous studies in people with depression and in those with mild cognitive impairment have hinted at cognitive benefits, but few have directly compared vortioxetine to multiple other antidepressants in patients with Alzheimer’s.
To address this gap, researchers Eduardo Cumbo and Daniela Migliore conducted a 12-month randomized, open-label study at the Neurodegenerative Disorders Unit in Caltanissetta, Italy. The analysis focused on 108 outpatients with mild Alzheimer’s disease and depressive symptoms. Participants were randomly assigned to receive either vortioxetine (n=36) or one of three other antidepressants—escitalopram, paroxetine, or bupropion (n=72 in total)—while continuing standard Alzheimer’s treatments such as cholinesterase inhibitors or memantine. Patients were assessed at the start of the study, after six months, and after twelve months.
Cognitive function was measured using several established tests. The Mini-Mental State Examination evaluated overall cognitive ability, including memory, orientation, and language. The Attentive Matrices test measured selective attention, while the Coloured Progressive Matrices assessed nonverbal reasoning and problem-solving. The Digit Span task tested verbal working memory. Depression severity was measured with the Hamilton Depression Scale and the Cornell Scale for Depression in Dementia.
By the end of the study, patients in all groups showed some improvement on cognitive tests, but gains were generally largest and most consistent in the vortioxetine group. On the Mini-Mental State Examination, vortioxetine-treated patients improved by nearly three points, a statistically significant change. They also showed significant gains in selective attention and nonverbal reasoning, while patients on other antidepressants tended to improve less, and in some cases, not significantly. Working memory scores improved slightly in the vortioxetine group but did not reach statistical significance.
When comparing groups directly, vortioxetine outperformed the other antidepressants on most cognitive measures. The difference was particularly notable when compared to paroxetine, which has anticholinergic properties that can impair cognition in older adults. Escitalopram and bupropion showed moderate improvements on some attention measures, but not to the same extent as vortioxetine.
The study also found that depressive symptoms decreased in all groups over the 12-month period, but the reduction was more pronounced in patients taking vortioxetine. On both depression scales, the vortioxetine group’s scores dropped by about seven points from baseline—an improvement considered clinically meaningful. Between-group comparisons showed that vortioxetine’s effect on depressive symptoms was statistically superior to that of the other antidepressants.
Side effects were relatively uncommon and generally mild. Nausea and headache were the most frequently reported with vortioxetine, occurring in about 8% of patients. Two participants—one on paroxetine and one on bupropion—discontinued treatment due to side effects. No serious adverse events or deaths occurred during the study.
The researchers note some limitations. The trial was conducted at a single site with a modest sample size, which may limit how well the findings apply to the wider Alzheimer’s population. It was also open-label, meaning patients and doctors knew which treatment was being given, which could introduce bias.
Importantly, only patients with mild Alzheimer’s were included, so the results may not extend to those with more advanced disease. The study also could not determine whether the observed cognitive improvements were due directly to vortioxetine’s pharmacological effects or indirectly through relief of depressive symptoms.
Despite these caveats, the findings add to a growing body of evidence suggesting that vortioxetine may have cognitive benefits beyond its antidepressant effects. The authors suggest that larger, longer-term, and double-blind studies are needed to confirm these results and to clarify how vortioxetine’s effects on neurotransmitter systems might influence both mood and cognition in people with Alzheimer’s.
If future research confirms these findings, vortioxetine could be considered a particularly useful option for Alzheimer’s patients who experience depression—addressing not only mood symptoms but also potentially helping to preserve certain cognitive functions.
The study, “Differential effects of antidepressants on cognition in Alzheimer’s disease with depression: A sub-group analysis of an open-label, observational study,” was authored by Eduardo Cumbo and Daniela Migliore.