Probiotics Help Depression Only If It’s of Clinical Severity

Why some (including me) don’t get happier with probiotics.

Shin Jie Yong
Jan 31 · 7 min read
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Image by José Augusto Camargo from Pixabay

A healthy gut equals a healthy brain. That’s what researchers and the media inform us. So I figured I would take some probiotic supplements (see picture below) back in my difficult times. I did not feel any benefits; increasing the dosage did not change anything either. I found out why as I writing an academic review which was later published in the Frontiers of Neuroscience.

Academics in this field classify depression into major depressive disorder (MDD) and depressive-like symptoms. The former is much more severe, requiring clinical attention while the latter doesn’t. In this sense, researchers say “MDD patients” and “healthy individuals with depressive-like symptoms.” They are said to be healthy as they can perform daily activities independently. Whereas MDD is disabling, meeting criteria A to C below.

Excerpt from page 160–161 of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) from the American Psychiatric Association, 2013:

A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.)

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation).

3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.)

4. Insomnia or hypersomnia nearly every day.

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

6. Fatigue or loss of energy nearly every day.

7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. The episode is not attributable to the physiological effects of a substance or to another medical condition.

With such diverse symptoms arising from different biological reasons, MDD is challenging to treat. Standard antidepressants only work at about half of the time. And about 60% of its users experience side effects such as blunted emotions, suicidality, sexual dysfunction, and addiction. That’s why many fall under the category of treatment-resistant MDD. In a 2018 US national survey and interview, MDD affects 10–20% of the population. It is also projected to outrank heart disease as the leading cause of disease burden by 2030. Given such cause, scientists and funding bodies are desperately looking for new treatments for MDD.

“There is growing openness among practitioners to consider nonpharmacologic adjunctive treatments when all else fails or more importantly as a preferable approach due to greater tolerability and fewer adverse effects,” says Matthew Bambling, Ph.D. from the University of Queensland, Australia.

Probiotics are suitable for this cause. “Many probiotics are Generally Recognized as Safe (GRAS) with relatively few adverse effects beyond mild stomach upset or diarrhoea,” adds Annadora J. Bruce-Keller, associate professor from Louisiana State University in Baton Rouge, Louisiana.

Owing to the rapidly growing field of the microbiota-gut-brain axis, scientists discovered that MDD and a dysbiotic gut often co-occur. This means that certain harmful bacterial populations are overwhelming the beneficial ones. Gut dysbiosis is a known inducer of systemic inflammation that could mess with the brain neurotransmitter circuitries. This explains why the theory of “chemical imbalances in the brain” is not the only story. It is worth the effort and resources to try to treat MDD via the gut microbiota with, for example, probiotics.

Do probiotics have antidepressive effects? Research heretofore suggests it do, but only for MDD patients and not healthy people with depressive-like symptoms. In 2018, a team of Singaporean academicians synthesized data from 10 clinical trials to form a meta-analysis. They calculated that probiotics did not affect mood in general. But subgroup analyses revealed “significant improvements in the moods of individuals with mild to moderate depressive symptoms and nonsignificant effects in healthy individuals.” The good news is that none of the 10 studies reported any side effects of probiotics.

Another 2019 meta-analysis from the Warren Alpert Medical School of Brown University, United States combined 34 controlled clinical trials also agreed that probiotics provide “small but significant effects for depression and anxiety.” Sub-group analyses reveal that, again, “probiotic effects were larger for clinical than community samples for depression.” They also examined prebiotics and concluded that it did not differ from placebo in improving depression and anxiety symptoms. “In general, the largest effects were found for probiotics and major depression,” the authors wrote.

It appears that the severity of depression determines whether probiotics are effective or not.

To date, five studies had tested probiotics on MDD patients. All five have shown positive findings, with only one reported some side effects:

Probiotics (L. acidophilus, L. casei, and B. bifidum) for 8 weeks improved depression symptoms by >3-fold versus placebo (n = 40 MDD patients).

Probiotics (L. helveticus and B. longum) for 8 weeks lessened the severity of depression by nearly 3-fold compared to placebo and prebiotics (n = 81 MDD patients)

Probiotics (L. acidophilus, B. bifidum, and S. thermophiles)+antidepressant for 6 weeks alleviated depression modestly, in relative to the antidepressant alone (n = 40 MDD patients). Side effects: 10% had diarrhea; 15% had an abdominal cramp; 20% had bloating and/or nausea.

Probiotics (L. casei, L. acidophilus, L. bulgarigus, L. rhamnosus, B. breve, B. longum, and S. thermophilus)+magnesium supplement+antidepressant for 8 weeks improved depression severity drastically in treatment-resistant MDD patients (n = 12, a pilot study). Participants relapsed at the 16th week after stopped consuming probiotics).

Probiotics (C. butyricum)+antidepressant for 8 weeks resulted in >50% reduction in depression symptoms in 70% of treatment-resistant MDD patients (n = 40), of which 35% achieved full recovery.

Either as standalone or adjunct, research on probiotics as an antidepressive has been encouraging for the MDD population. Limitations remain. For one, no large cohort study has been done. Second, all studies used different probiotic formulations. In this sense, each study has not been replicated. There are, however, common species — i.e., those belonging to the Lactobacillus and Bifidobacterium genera.


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The probiotics I previously took also contain some of these species, but it did not benefit my mental well-being. Why do probiotics only work for depression of clinical severity?

One reason is that probiotics do not necessarily colonize the gut. Some people are more resistant to colonization attempts of probiotics while others are more permissive. This depends on the baseline levels of that probiotic species. Lactobacillus species, for example, only colonizes the gut of people who had low lactobacilli counts, to begin with. In those with preexisting high levels of lactobacilli, the probiotics did not provide any health benefits. The same applies to Bifidobacterium species in humans. In mice, the antidepressive effects of probiotics (lactobacilli + bifidobacteria) manifested only when it successfully colonized the gut. In ‘non-responders’ mice, the probiotics did nothing.

The following reasoning is that MDD patients have lower levels of lactobacilli and bifidobacteria in their gut. Indeed, research data concurs. “Individuals with lower Bifidobacterium and/or Lactobacillus counts are more common in patients with MDD compared to controls,” writes the Japanese authors from the National Center of Neurology and Psychiatry, Japan. This suggests that the inner physiology of MDD patients are maladjusted to the point where the gut microbiota is also affected. They could, thus, benefit from probiotics. Whilst for healthy individuals with depressive-like symptoms, probiotics probably wouldn’t have any job to do.

“Nutritional guidance and sleep interventions can go far to help patients suffering from mental illnesses and I think that probiotics and other supplementation will become tools in the arsenal that clinicians will become more comfortable using once science can get a better grasp of which products may be more helpful than others,” says Brittany Mason, assistant professor of psychoneuroendocrine research at UT Southwestern Medical Center, Texas. Meanwhile, research needs to conduct larger clinical trials and more consistent probiotic formulation to move forward for an FDA approval.

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

Shin Jie Yong

Written by

Published academic author | 20 y/o neurobiology postgrad in Malaysia | 60+ curated articles on Covid | shinjieyong@gmail.com | Support me at ko-fi.com/sjyong

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

Shin Jie Yong

Written by

Published academic author | 20 y/o neurobiology postgrad in Malaysia | 60+ curated articles on Covid | shinjieyong@gmail.com | Support me at ko-fi.com/sjyong

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

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