Recruitment is underway for a two-phase trial building on novel study.

Late-life depression (LLD) in adults 60 years and older is characterized by poor antidepressant response and cognitive decline. Even with successful antidepressant treatment, cognitive performance in LLD patients often does not return to previous levels.

In a small but novel study published in the Journal of Clinical PsychiatryWarren Taylor, M.D., director of geriatric psychiatry at Vanderbilt University Medical Center, and colleagues found evidence that transdermal nicotine may improve both mood symptoms and cognitive performance in LLD.

Taylor is testing these findings in a larger, two-phase trial. Up to 90 participants will be enrolled across two study phases, the first of which is underway, adding more rigorous memory testing and brain imaging to the evaluation.

Targeting the nicotinic acetycholine receptor is a new way of approaching both depression and cognitive decline. “Acetycholine is the neurotransmitter that gets impaired early in the course of Alzheimer’s disease, so it is closely related to memory and attention performance,” Taylor said. “We will use fMRI to see how nicotine affects brain function in areas that are involved in depression and cognitive activity.”

Nicotine Improved Depression Symptoms

The prior study was a 12-week, open-label outpatient study. Transdermal nicotine was given to 15 older adults (≥ 60 years of age) who met criteria for major depressive disorder and who self-reported cognitive/memory decline. None had used tobacco or nicotine in the last year.

“We saw a robust improvement in depression severity,” Taylor said. “Thirteen of 15 participants had a clinically relevant response and eight reached remission. It didn’t matter if they took the nicotine with another antidepressant medication or if they had a history of smoking – both groups did well.”

“If our studies continue to show similar results, we envision this as an adjunct to antidepressants,” Taylor said. “We know that when we combine antidepressants that work differently, you can often get a better clinical response. This type of augmentation strategy is commonly used to treat depressed adults who have a poor or partial response to an initial antidepressant.”

“If our studies continue to show similar results, we envision this as an adjunct to antidepressants.”

After completing the initial study, participants were followed for several weeks to track withdrawal symptoms, cravings or other adverse effects. “Some of the patients continued with patches because they felt so much better, and in no case did we see evidence of addiction,” Taylor said.

LLD and Cognitive Function

In general, people with LLD score lower on memory tests and have a higher risk of developing dementia, Taylor said. “It’s unclear why people with depression are prone to dementia. But we know repeated periods of depression over your lifetime are not good for cognitive performance and make you more vulnerable to Alzheimer’s. If we can treat the depression earlier, maybe we can prevent some of the decline.”

In the first study, participants’ subjective cognitive performance significantly improved with nicotine treatment. They also showed improved performance on some secondary cognitive measures, including working memory, episodic memory and immediate recall.

The upcoming trial will incorporate more demanding cognitive tasks to combat the placebo effect, some using fMRI. The scans will help distill particular functions that are impacted by nicotine, such as focus, memory or problem solving. “It will also tell us how well the brain responds to different emotional stimuli and weeds out irrelevant information, something that can really be impaired in people with depression,” Taylor said.

The initial phase will take place over two years. If outcomes replicate those of the first study, Taylor says the next step will be a larger, more robust placebo-controlled trial. “That would give us a higher level of evidence to say, yes, maybe this patch will be helpful. It would really support more definitive, larger studies.”

About the Expert

Warren Taylor, M.D.

Warren D. Taylor, M.D., M.HSc., is James G. Blakemore Chair and Professor of Psychiatry and Behavioral Sciences and director, Division of Geriatric Psychiatry at Vanderbilt University Medical Center. His research focuses on elucidating the psychopathology of depression and factors influencing response to antidepressant medications. This work includes combining multimodal neuroimaging and genetic analyses to examine how functional genetic polymorphisms may affect the brain and in turn predispose individuals to depression.