Vortioxetine's Effect on Cognitive Function in Older Adults With Major Depressive Disorder

CLINICAL CONVERSATIONS

A recent study sought to understand the impact of vortioxetine on cognitive function and depressive symptoms in older adults with major depressive disorder (MDD). Investigators found that vortioxetine was consistently associated with improvements in depressive symptoms, though improvements in cognitive symptoms were inconsistent, with neutral-to-positive, predominantly domain-specific effects.¹

To learn more, Psychiatric Times sat down with one of the study’s authors, Ibrahim Makki, MD.

Psychiatric Times: Talk to us about your recent study on vortioxetine targeting cognitive function in older adults with MDD. What was the most important takeaway?

Ibrahim Makki, MD: During my geriatric psychiatry training, I remember a colleague saying that vortioxetine “improves cognition.” It was a very broad statement, but it caught my attention because cognitive symptoms are such an important issue in older adults with depression, particularly in patients who may already have some degree of cognitive impairment. I started reading more about it and realized that several important studies had been published since the last systematic review focused specifically on older adults. That was really where the idea for this review came from.

The main takeaway is that the mood findings with vortioxetine were generally favorable, while the cognitive findings were more nuanced. We found encouraging signals in specific domains, particularly processing speed, attention, executive function, and verbal learning. However, effects on global cognition were inconsistent in controlled studies, and vortioxetine was not consistently superior to placebo or other antidepressants. So I would describe the cognitive findings as promising, but not yet established.

PT: Your review found that vortioxetine's cognitive benefits showed up mainly on domain-specific tests, such as processing speed, attention, executive function, and verbal learning, rather than on global measures like the MMSE or MoCA. What do you think explains that gap? What should clinicians make of it when they see little change on a routine screen?

Makki: In late-life depression, cognitive difficulties often involve specific areas such as processing speed, attention, executive function, or memory, and domain-specific tests are better designed to detect changes in those areas. In contrast, tools such as the MMSE and MoCA are broad screening measures. They are very useful clinically, but they may be less sensitive to subtle changes in specific cognitive domains. So if a patient reports clearer thinking or shows improvement in day-to-day functioning but there is little change on a routine cognitive screen, I would not necessarily interpret that as meaning there has been no cognitive improvement.

That said, we still need to be cautious. Our review suggests that vortioxetine may have benefits in selected cognitive domains, but we do not yet have strong evidence that it produces broader improvement in global cognition.

PT: The broadest cognitive gains came from single-arm observational studies, while the controlled trials showed no consistent advantage over placebo or other antidepressants. How much weight should psychiatrists give the real-world data, given practice effects, placebo response, and regression to the mean?

Makki: The real-world data are useful, but I think we need to give them the right weight. They show that cognitive improvement can be seen in older adults treated with vortioxetine in routine clinical practice.However, without a control group, we cannot confidently say that those improvements were caused by vortioxetine itself. Some of the change may come from improvement in depression, repeated exposure to the same cognitive tests, expectancy effects, or regression to the mean. For questions about whether vortioxetine has a specific procognitive effect, I would therefore give greater weight to the controlled trials, and those results were much more mixed. So I see the observational findings as encouraging and clinically relevant, but not sufficient on their own to establish a cognitive benefit. They support further study rather than a firm conclusion.

PT: Many of the included patients had comorbid Alzheimer disease or mild neurocognitive disorder, and results in that group were mixed. How should clinicians approach vortioxetine in an older adult with depression when it is unclear whether the cognitive symptoms come from depression or early neurodegeneration?

Makki: I think including patients with Alzheimer disease or mild neurocognitive disorder was important because this reflects what we often see in clinical practice. In an older adult with depression and cognitive symptoms, the relationship between the 2 can be difficult to determine. Cognitive difficulties may be part of the depressive illness, may persist even as depression improves, or may occur alongside an emerging neurocognitive disorder.

From a clinical perspective, I would still treat the depression according to usual evidence-based recommendations, while continuing to assess the cognitive symptoms over time. Our review did not show a clear superiority of vortioxetine over other antidepressants in patients with neurocognitive disorders, and the findings in these populations were mixed.

However, when cognitive symptoms are prominent, particularly when the antidepressant response is incomplete or when a change in antidepressant is otherwise being considered, vortioxetine may be a reasonable option. The evidence is not strong enough to recommend it over other antidepressants, but the signals we saw in specific cognitive domains make it an option worth considering in selected patients.

PT: What are the most important gaps in the evidence? What would you want the next randomized trial to measure, and for how long?

Makki: The main gap is that the studies were quite different from one another. They included different patient populations, used different cognitive tests, and followed patients for different lengths of time. We also had relatively few well-controlled randomized studies, and many of the more positive cognitive findings came from observational studies.

For the next randomized trial, I would want cognition to be measured more systematically. That would include sensitive tests of specific domains such as processing speed, attention, executive function, and memory, together with a broader measure of cognition. Mood should be assessed at the same time so we can better understand whether cognitive improvement is independent of improvement in depression. I would also include functional outcomes, because ultimately we want to know whether any cognitive change makes a meaningful difference in everyday life.

In terms of duration, I would want both an early assessment and longer follow-up. One randomized study in our review showed a significant between-group difference on a cognitive measure at 12 weeks, but that difference was no longer significant at 26 weeks. This highlights why future trials need both early assessments and longer follow-up to determine whether any benefit is sustained.

PT: Based on what we know now, how would you advise a psychiatrist choosing an antidepressant for a patient over 65 whose family reports "brain fog," slowed thinking, or trouble concentrating?

Makki: For a patient over 65 with depression and complaints such as brain fog, slowed thinking, or difficulty concentrating, I would still follow the usual evidence-based approach to treating late-life depression. Cognitive symptoms are important, but based on the current evidence I would not choose an antidepressant solely on the expectation that it will improve cognition.

Vortioxetine is a reasonable option to consider, particularly when cognitive symptoms are prominent and you are choosing among otherwise appropriate antidepressants, or when the response or tolerability with another antidepressant has been inadequate. Our review found encouraging signals in areas such as processing speed, attention, executive function, and verbal learning, but the controlled evidence does not establish that vortioxetine is superior to other antidepressants for cognition. I would also continue to follow the cognitive symptoms over time rather than assuming that they will resolve simply because depression improves.

PT: Anything else you would like to share?

Makki: One practical point I would add is that we should pay close attention to cognitive symptoms in late-life depression and follow them over time, just as we do with mood symptoms. Families may notice slowing, poor concentration, or forgetfulness even when changes are not obvious on a brief cognitive screen.

For me, the treatment goals should go beyond improvement in mood. We also want to know whether the patient is thinking more clearly, functioning better, and getting closer to their previous level of independence. We still need well-designed studies in older adults to understand the cognitive effects of treatment, whether those effects are independent of mood improvement, and whether they translate into meaningful and sustained improvement in everyday functioning.

Dr Makki is a psychiatrist at St. Joseph’s Health Care London, and an assistant professor in the geriatric department of Schulich School of Medicine & Dentistry at Western University.

Reference

1. El-Kassem M, Ali M, Madani MT, et al. The effect of vortioxetine on cognitive function in older adults with major depressive disorder: a systematic review. J Affect Disord. 2026;415:122421.