Probiotics to alleviate depression

Depression is more common than many might think; it affects 4.4 percent of the US population and 3.8 percent of the global population (1, 2). It also disproportionately affects women, who experience it about 50 percent more frequently than men (2). Despite its prevalence, effective treatment remains elusive for many. Current antidepressant treatments come with a plethora of unwanted side effects, from nausea to insomnia. Even with treatment, about a third of people with depression don’t experience improved symptoms (3).

However, a new and promising area of research may offer hope for those seeking alternative treatments. Researchers are delving into the world of probiotics, investigating their potential to serve as a harmless yet effective treatment for depression.

“The link between the gut and the mind has been known forever. We always say, ‘I feel it in my gut,’” said Roumen Milev, a psychiatrist at Queen's University. “There is this link that we never paid attention to because our way of differentiating portions of science we study did not necessarily cut it in the right way.”

Depression is a particularly difficult disorder to define. Each patient has their own somewhat unique constellation of symptoms that can vary widely from those of other patients. Some diagnostic criteria are even opposites, like weight loss and weight gain or loss of sleep and sleeping too much (4).

The link between the gut and the mind has been known forever. We always say, ‘I feel it in my gut.’
- Roumen Milev, Queen's University

This was especially frustrating for Anna-Chiara Schaub, a psychologist at the University of Basel, who recently decided to move away from this research area. “Depression and in general, mental disorders are so heterogeneous that when you just put depressed patients together, they have so many different etiologies and different patterns, so you can’t just put them in one group,” she said.

Recent advances have shed light on the intricate communication network between the gastrointestinal tract and the central nervous system known as the gut-brain axis. This bidirectional pathway involves the autonomic nervous system, which drives involuntary body functions such as breathing and heart rate; the enteric (gut) nervous system; the neuroendocrine system; and the immune system (5). Over the last decade, many mental health researchers have turned their attention to the gut-brain axis, specifically the microbiome, to uncover the underlying mechanisms and potential new treatments for a variety of disorders (6).

Based on early research into the microbiome's role, researchers suggested that a lack of microbial diversity might be a hallmark of depression. However, scientists recently used more nuanced meta-analyses to point to specific microbial imbalances underlying the disorder rather than overall microbial diversity. Depression and other psychiatric disorders generally go hand-in-hand with fewer anti-inflammatory bacteria and more pro-inflammatory bacteria within the gut compared to controls (7,8). In one study, researchers investigated the effect of fecal transplants from depressed humans to rats and found that symptoms of depression, like the inability to feel pleasure, became more common in the rodents (9).

“The understanding on the gut-brain is still at the early stage,” said Hein Tun, a microbiome researcher at the Chinese University of Hong Kong. “The gut-brain axis is always bidirectional ... so in the microbiome, there’s always this chicken or egg issue.”

Probiotics versus antidepressants

Results from meta-analyses and clinical trials have begun to illustrate probiotics’ potential as a viable treatment for mild-to-moderate depression, whether as standalone therapies or adjuncts to traditional antidepressants (10-12). These studies suggest that probiotics may not only improve depressive symptoms but also do so with fewer side effects and greater tolerability than many pharmacological alternatives. Many people already take probiotics in their daily lives, so unlike antidepressants, there is little to no stigma associated with them.

After noticing how many university students showed signs of mild depression, Tun was motivated to find a stigma-free treatment for depression. “We found that more than 45 percent of students experience depression, anxiety, or stress,” he said. “I became very interested in understanding why our next generation is suffering from so many mental health problems.”

He led a meta-analysis comparing probiotic treatments to prescription medications and found that probiotics were as effective as most common antidepressants (13). “I was very skeptical about it at first,” Tun said. Because the studies that he and his team analyzed used different compositions and doses of probiotics, he didn’t expect to see an effect. But “all the probiotics were working well,” he said. “This was shocking to me.”

A man holds a yellow pill in his hand above a table with a glass of water and a pill pack.

Many people already take probiotics in their daily lives, so unlike antidepressants, there is little to no stigma associated with them.

Credit: iStock.com/Vasil Dimitrov

Probiotics vary widely in their composition, with some targeting certain microbes more than others. They also differ in their concentration of bacteria by up to 50 times (14). However, “now that we know more about the gut-brain axis, hopefully we can develop the next generation microbiome-targeted intervention,” said Tun. He hopes to develop specific probiotics called synbiotics to contain the most influential microbes to speed up and maximize their effect. He also plans to conduct longitudinal studies to better understand whether probiotics make lasting changes to mood and microbiome composition.

While investigating probiotics as a depression treatment is one approach, Schaub was curious if probiotics could work in parallel to antidepressants as an add-on therapy. “When you are in the clinics working with patients, it’s very obvious that many of the patients have issues with nutrition,” said Schaub. “That’s one of the main reasons to look deeper into this.”

She and her team conducted the first randomized control trial of short-term, high-dose multi-strain probiotics for depression (15). They studied patients who were already being treated for depression with antidepressant medications. Half of the participants took a strong probiotic with eight different strains of bacteria for a month, while the other half took a placebo.

The gut-brain axis is always bidirectional ... so in the microbiome, there’s always this chicken or egg issue.
- Hein Tun, Chinese University of Hong Kong

After sequencing participants’ gut microbiota from stool samples, the team found that probiotics increased the abundance of the bacteria Lactobacillus and maintained microbial diversity. Participants in the treatment group also showed slightly decreased scores on the Hamilton Depression Rating Scale eight weeks after the intervention, suggesting that probiotics may help increase depression remission rates. Participants who received probiotics also showed a decrease in neural responses to neutral faces, which are typically heightened in people with depression (15). A further analysis of this data showed that participants in the probiotic group also performed better on a memory task and had normalized hippocampal function compared to controls (16).

While these findings point to a positive effect of probiotics on depression, researchers are still unsure about the mechanism behind it. “One hypothesis is that if probiotics reduce inflammatory processes, you could also see an effect on general health or more somatic symptoms like bad sleep,” said Schaub.

Milev did not seem to mind the ambiguity about probiotics’ mechanism. “If we don't show that it works, who cares how it doesn't work? The first step is to really show robust efficacy and good tolerability and safety, and once we show that and there is something in it, then the second step is how it does it,” he said.

Milev is working with the Canadian Biomarker Integration Network in Depression, a program aimed at gaining a holistic understanding of depression and its treatments using brain scans, clinical assessments, and blood samples. In a clinical pilot study of people with major depressive disorder who had never taken antidepressants before, his team found that probiotics alleviated symptoms after just four weeks and improved sleep quality after eight weeks (17). However, because the study was done on only 10 participants and had no placebo group, Milev hopes to conduct follow-up research with more people.

Future challenges

The burgeoning research into probiotics as a potential therapy for depression offers a glimmer of hope to researchers, medical professionals, and patients, but a few key challenges lie ahead. One is that many patients with depression are already on antidepressants or have a history of antidepressant treatment. In addition to disentangling the effect of antidepressants and probiotics on mood, researchers also struggle to account for how antidepressants affect the growth of certain microbes, sometimes stunting their growth (16). Tun and others emphasized the importance of testing probiotics on people who show signs of depression but who have never been treated to get a clearer idea of probiotics’ effectiveness.

Milev agreed with Tun that testing untreated patients is imperative. His ideal study would assess young adults soon after their depression diagnosis who have significant symptoms that interfere with their daily lives. With a strong dose of probiotics over the course of 12 weeks and follow up assessments, Milev believes that such a dream study “would definitively answer only one question: do they work?” Researchers would need to conduct additional studies to determine why and for whom probiotics have antidepressant effects.

The research community will continue to unravel the complexities of the microbiome and its relationship to depression to develop a new avenue for treatment without the side effects of traditional antidepressants. This new direction will hopefully encourage medical professionals to search for solutions outside of the traditional pharmacological box.

“It’s good to keep the gut in mind,” said Schaub. “It's nice to see the person more in a holistic way.”