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A diet high in ultraprocessed food (UPF), particularly artificial sweeteners, has been linked to increased depression risk, new data from the Nurses Health Study II (NHS II) suggest.

Nurses who consumed more than eight servings daily had about a 50% higher risk of developing depression than nurses who consumed four or fewer servings daily.

However, in a secondary analysis, in which the researchers tried to tease out specific foods that may be associated with increased risk, only artificial sweeteners and artificially sweetened beverages were associated with an increased risk of depression.

“Animal studies have shown that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” study investigator Andrew T. Chan, quetiapine lithium interaction MD, MPH, of the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital, Boston, told Medscape Medical News.

“Given this potential association between ultraprocessed food and multiple adverse health conditions, wherever possible individuals may wish to limit their intake of such foods. This may be a lifestyle change that could have important benefits, particularly for those who struggle with mental health,” Chan said.

The study was published online September 20 in JAMA Network Open.

Multiple Potential Mechanisms

The findings are based on 31,712 mostly non-Hispanic White women who were free of depression at baseline. The mean age of the patients at baseline was 52 years. As part of the NHS II, the women provided information on diet every 4 years using validated food frequency questionnaires.

Compared to women with low UPF intake, those with high UPF intake had greater body mass index (BMI). In addition, they were apt to smoke and have diabetes, hypertension, and dyslipidemia, and they were less apt to exercise regularly.

During the study period, there were 2122 incident cases of depression, as determined using a strict definition that required self-reported clinician-diagnosed depression and regular antidepressant use. There were 4840 incident cases, as determined using a broad definition that required clinical diagnosis and/or antidepressant use.

Compared with women in the lowest quintile of UPF consumption (fewer than four daily servings), those in the highest quintile (more than 8.8 daily servings) had an increased risk of depression.

This was noted for both the strict depression definition (hazard ratio [HR], 1.49; 95% CI, 1.26 – 1.76; P < .001) and the broad one (HR, 1.34; 95% CI, 1.20 – 1.50; P < .001).

“Models were not materially altered after inclusion of potential confounders. We did not observe differential associations in subgroups defined by age, BMI, physical activity, or smoking,” the researchers report.

In secondary analyses, they classified UPF into their components, including ultraprocessed grain foods, sweet snacks, ready-to-eat meals, fats, sauces, ultraprocessed dairy products, savory snacks, processed meat, beverages, and artificial sweeteners.

Comparing the highest with the lowest quintiles, only high intake of artificially sweetened beverages (HR, 1.37; 95% CI, 1.19 – 1.57; P < .001) and artificial sweeteners (HR, 1.26; 95% CI, 1.10 – 1.43; P < .001) was associated with greater risk of depression and after multivariable regression.

In an exploratory analysis, women who reduced their UPF intake by at least three servings per day were at lower risk of depression (strict definition: HR, 0.84; 95% CI 0.71 – 0.99) compared with those with relatively stable intake in each 4-year period.

“Ultraprocessed foods have been associated with several different health outcomes which may reflect an effect on common pathways that underlie chronic conditions,” said Chan.

For example, UPF intake has been associated with chronic inflammation, which in turns leads to multiple potential adverse health effects, including depression, he explained.

There is also a link between UPF and disruption of the gut microbiome.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” Chan said.

Association, Not Causation

Several experts weighed in on the study results in a statement from the UK nonprofit organization, Science Media Centre.

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading, United Kingdom, cautioned that the study only offers information on association ― not causation.

“It is very possible that people with depression change their diet and might decide to consume foods that are easier to prepare ― which would often be foods considered to be ultraprocessed,” Kuhnle said.

What’s most interesting is that the association between UPF intake and depression was driven by a single factor ― artificial sweeteners.

“This supports one of the main criticisms of the UPF concept, that it combines a wide range of different foods and thereby makes it difficult to identify underlying causes,” Kuhnle added.

“There are currently no data that link artificial sweetener use to mental health, despite most of them having been available for some time. It is also important to note that there are a wide range of different artificial sweeteners that are metabolized very differently and that there might be reverse causality,” Kuhnle commented.

Paul Keedwell, MBChB, PhD, consultant psychiatrist and fellow of the Royal College of Psychiatrists, said this is an “interesting and important finding, but one that raises more questions. At this stage, we cannot say how big an effect diet has on depression risk compared to other risk factors, like family history of depression, stress levels, and having a supportive social network.”

Keedwell noted that the investigators carefully excluded the possibility that the effect is mediated by obesity or lack of exercise.

“However, an important consideration is that a diet based on ready meals and artificially sweetened drinks might indicate a hectic lifestyle or one with shift work. In other words, a fast-food diet could be an indirect marker of chronic stress. Prolonged stress probably remains the main risk factor for depression,” Keedwell said.

Keith Frayn, professor emeritus of human metabolism, University of Oxford, noted that the relationship between artificial sweeteners and depression “stands out clearly” even after adjusting for multiple confounding factors, including BMI, smoking, and exercise.

“This adds to growing concerns about artificial sweeteners and cardiometabolic health. The link with depression needs confirmation and further research to suggest how it might be brought about,” Frayn cautioned.

The NHS II was funded by a grant from the National Cancer Institute. Chan reported receiving grants from Bayer Pharma AG and Zoe and personal fees from Boehringer Ingelheim, Pfizer, and Freenome outside this work. Keedwell and Kuhnle have disclosed no relevant financial relationships. Frayn is an author of books on nutrition and metabolism.

JAMA Netw Open. Published online September 20, 2023. Full text

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