While experts in mainstream psychiatry may place varying degrees of credence in the potential that nutrition has to prevent or manage symptoms of mental illness, large-scale clinical studies are setting a framework for when and where dietary intervention and supplementation should be investigated.

According to Dr. Joseph Firth, a UKRI (United Kingdom Research Initiative) research fellow from University of Manchester, evidence is beginning to generate momentum and interest among clinicians.

At Vitafoods Europe 2022, Firth discussed several studies and meta-analyses that he and his team have been a part of in order to shed light on promising trends in nutrition interventions for a host of mental illnesses.

Population Data

Firth first pointed to a study of data sets sourced from 70,000 participants of the UK Biobank published in 2018. Using 24-hour dietary recall across multiple time points from these participants, the researchers found that pro-inflammatory diets were linked to the prevalence of a host of mental disorders.

“Diet emerged as a very pertinent factor in mental illness in this study,” Firth said. “We utilized a dietary inflammation score system based on the intakes of 18 pro-inflammatory or anti-inflammatory nutrients which have already been validated against biological measures of inflammation. More severe mental illnesses, namely bipolar and psychosis, had the strongest connection to dietary inflammation compared to the general population. Even depression was linked to significantly higher inflammation scores.

“It could be that pro-inflammatory diets are increasing the risk of mental health conditions, however, these conditions could be making people more likely to eat a poor diet, which is something we’ve seen a lot in our research,” Firth continued. “Metabolic conditions appear to be a big risk factor for mental illness, so it’s really hard to tease out the cause and effect.”

Dietary Intervention

Firth noted a meta-analysis his team conducted in 2019 which evaluated 16 randomized, controlled, human clinical studies comprising a total of over 40,000 participants. The study looked at the outcomes of improvements in dietary quality against controlled conditions.

All of the common, health-promoting diets used in the study, which included the Mediterranean diet, weight loss diets, and diets that boosted nutrient intakes, were all linked to better depression outcomes, Firth said. Those who were most likely to benefit from diets were women and participants with obesity at baseline who lost a significant amount of weight.

“While there were no significant effects on anxiety, significant improvements were observed in depression,” Firth said. “Most of the evidence was from sub-clinical or sub-threshold depression, which is how we refer to people without major depressive disorder. Since we’ve published this study, the Mediterranean diet has been shown in studies to reduce symptoms in major depressive disorder.”

Notably, weight loss diets appeared to have a negative impact in men when it came to depression symptoms, Firth said. However, the Mediterranean diet was shown in males with major depressive disorder to have a positive effect on mental health outcomes.

Supplementation

“This is a field that’s gaining incredible attraction at the moment,” Firth said. “Mental health is coming to the forefront in the media and across the population as an outcome, and it stands to be a great place of innovation. Quite encouragingly, another group that found it quite interesting is the World Psychiatry Journal, who commissioned our group to create a special review bringing together all of the information on supplements in the treatment of mental illness.

“It’s such a massive evidence base that it’s impossible to look at studies individually,” Firth continued. “We aggregated several meta-analyses and reviews, and put together 33 meta-analyses testing all sorts of different nutrients in 10,000 individuals with mental illness.”

Firth said that supplementation with omega-3 fatty acids, particularly EPA, appeared to hold the most promise for more positive outcomes in people being treated for depression. The strongest correlation appeared to be with total doses of EPA as opposed to any particular ratio of EPA and DHA.

The researchers also found clinical significance was achieved in folic acid supplementation. “This seemed to be driven from high-dose methylfolate supplementation, a form of the nutrient which is more bioavailable and rapidly-absorbed,” Firth said.

He characterized evidence on the potential benefits of NAC as “emerging,” and the evidence on vitamin D and probiotics as “preliminary.” While clinical significance seems to be waning for vitamin D supplementation, he said that trials on probiotics in the context of depression appear to be advancing this ingredient category.

When it comes to ADHD, omega-3s were the most widely tested ingredient class, showing small but statistically significant effects on ADHD symptoms, but no effect on actual cognitive performance in children, Firth said. A similar case was made for Bipolar Disorder; omega-3s seemed to be the only supplement with a substantial enough evidence base to warrant further, large-scale investigations.

There are many unexplored areas and a huge amount of research which still needs to be undertaken on simply evaluating supplementation, especially with more novel ingredients, Firth said. But, where might the literature be going next remains an important question.

In Practice

While a multi-nutrient approach seems to be an intuitive next step for testing nutrients that hold promise, Firth said that recently-published trials seem to indicate a lack of support.

Targeted, high-dose nutrient supplementation could offer potential, he said, pointing to a clinical trial appearing in Molecular Psychiatry as an example. In this study, researchers found that high-dose supplementation of l-methylfolate in a population of 55 patients with schizophrenia resulted in significant improvements to PANSS (Positive and Negative Syndrome Scale) scores, as well as convergent changes in brain physiology which warranted further clinical trials.

“Another potential option which is gaining a lot of traction is combining nutrition with other lifestyle and medicine factors,” Firth said. “This is my main area of research, and we published a review last year in which we looked at lifestyle psychiatry—a number of modifiable factors relevant to mental health. We found top-tier evidence for exercise, diet, smoking status, and sleep in both recovery and prevention in a broad spectrum of mental health conditions.”

This review included the results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized, controlled clinical trials. Participants were evaluated for prevention and treatment outcomes in depression, anxiety, stress-related disorders, schizophrenia, bipolar disorder, and ADHD.

Fundamentally, questions remain about how much diet should be considered among mental health professionals, and how dietary changes actually exert their actions upon the brain.

“We were asked by BMJ to conduct a review on how diet and nutrition affect well-being. The one we’re probably most interested in today are these hormonal, inflammatory, neural, and microbiological pathways—all direct pathways. What we mean by the term ‘mental health’ is also an important question. There is a lot of preliminary evidence and not much certainty on these direct pathways at the moment.

“Where there is a great deal of certainty, however, is that diet can improve mental health through these indirect pathways, such as cardiometabolic diseases,” Firth continued. “Physical and mental health affect one another in a bidirectional way, and these direct pathways might not be a realistic picture.”

Firth noted that a case could be made that we often treat mental health at the expense of physical health, as highlighted by a review he and a team of researchers conducted which appears in The Lancet.

“The largest health disparity we see at the moment is in Americans with mental illnesses. They die between an estimated 15 and 30 years earlier than the general public, not due to suicide, but due to cardiometabolic diseases. This inequity is growing as time goes on, and that premature mortality gap grows even as the healthy population’s life expectancy increases,” Firth said.

“Some key actions we suggested are to tackle high rates of smoking, poor diet, and suboptimal prescriptions, along with fragmented, inaccessible care. We need to find some novel methods of promoting physical health for mental wellbeing, and increase utility in clinical services […] Some facilities are on the cutting edge and have a gym and dietitian present, and, compared to other clinics in the same area, we’re already seeing better outcomes. It’s not something that’s taken seriously at the moment, but where it happens, it works.”