The Way to the Head May Be Through the Gut: Probiotics for Depression

gut brain connection
gut brain connection
Although the theory of the gut-brain axis has existed for more than a century, recent studies are now examining how gut microbiota influence mood.

Despite the ubiquity of selective serotonin reuptake inhibitors (SSRIs) for depression, not everyone benefits from their use.1 Approximately one-third of patients with depression do not respond to medication.2-4 Also, SSRIs are not without risk for adverse events, and adherence to antidepressants is <50% within 6 months of initiation. 2

Depression affects more than 300 million people globally and is the leading cause of disability worldwide. Each year, approximately 800,000 people die by suicide.5 Given that the disease is so prevalent and increasing, the World Health Organization cites depression as one of its priority conditions.5

The Case for Probiotics

For more than a century, the theory of the gut-brain axis has existed.6 More recent studies, however, are examining how gut microbiota influence mood.6 Probiotics and other dietary supplements are an area of study as substitutes for drugs and as adjunctive therapy.

Ng and colleagues found in a 10-study meta-analysis of 1349 patients that probiotics did not significantly improve mood in patients with clinical depression (standardized mean difference [SMD] −0.128; 95% CI: −0.261 to 0.00463; P =.059).1 However, in a subgroup analysis comparing patients without depression with those with mild to moderate depression, the improvement was significant (SMD −0.684, 95% CI: −1.296 to −0.0712, P =.029).1

“The effects of probiotic supplementation on depressive symptomatology are probably modest, even in depressed individuals,” explains lead author Qin Xiang Ng, MBBS, of KK Women’s and Children’s Hospital in Singapore. “Although generally safe and palatable, in clinical settings it cannot be recommended that probiotics replace antidepressant medications as the primary treatment for depressed patients. However, they could be potential (and palatable) adjunctive therapies.”

The probiotics in the meta-analysis studies included yogurt with Lactobacillus acidophilus and Bifidobacterium bifidum, powders, milk drinks, and tablets. Just as the dosages and the type of probiotics were wide-ranging, so were the diagnostic criteria for depression. More than half the studies did not specify the instrument used to determine depression for study inclusion.1 The outcome measures were pooled using scores from the Hospital Anxiety and Depression Scale or change in the Beck Depression Inventory from baseline.1

While the efficacy of probiotics in the meta-analysis was less than stellar, none of the patients in the 10 studies reported any adverse events.1 Given that patients often discontinue their antidepressant medications due to adverse effects, clinicians are seeking alternatives providing more tolerable therapies for patients with treatment-resistant depression.2

Earlier meta-analyses assessing the effect of probiotics on mood regulation concluded that probiotics were beneficial for patients with depression.7 In a systematic review by Huang and colleagues of 5 studies (N=458), probiotics demonstrated statistically significant efficacy in reducing the depression scale score (-0.30, 95% CI: -0.51 to -0.09; P =.005). However, in subgroups stratified by age, patients <60 years benefited more from probiotics than did older patients.7

Alternatives to Antidepressants

In addition to probiotics, researchers are also examining the efficacy of vitamins and minerals to combat depressive symptoms. In a small study of 12 patients, an adjuvant combination of probiotics and magnesium orotate was administered with SSRIs for treatment-resistant depression for 8 weeks.4 At the end of the study, two-thirds of the patients demonstrated significant improvement (P<.001), but all of the patients experienced relapse 8 weeks after the adjuvant therapy was discontinued.4

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“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,” notes Matthew Bambling, PhD, of the University of Queensland, in Brisbane, Australia. “At least for a proportion of treatment-resistant depression cases, this approach may address some of the pathophysiological mechanisms affecting treatment response. However, like most things it is not a panacea, as some patients do not respond.”

Dietary changes are also on the table of inquiry to alleviate mood disorders. Bruce-Keller and colleagues are examining the effect that a high-fat/low-fiber diet has on decreasing gut microbiome diversity.8 She and her team are also studying the effects of prebiotics, or indigestible plants, in maintaining a healthy balance of beneficial microbes in the gut.8

“Many probiotics (ie, live microbial cultures) are Generally Recognized as Safe (GRAS) with relatively few adverse effects beyond mild stomach upset or diarrhea,” says Annadora J. Bruce-Keller, PhD, associate professor from the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, Louisiana. “The risk of adverse effects can be essentially eliminated by dietary approaches to combat intestinal dysbiosis (increased fruits/vegetables/fiber, decreased saturated fats/processed foods/food additives). Contrast this pattern to the adverse effect profile of traditional antidepressants, which can include suicidal ideation, weight gain/metabolic syndrome, and sexual dysfunction. However, any decision on treatment alterations for mood disorders must be made in conjunction with a physician–so I always caution individuals against making abrupt or radical changes to their treatment plan without an extended dialogue with their physicians.”

Beyond probiotics, other studies include the interplay of mood and gastrointestinal dysfunction. Researchers are examining the role that feeding behavior has on stress, anxiety, and depression.9 To gain a better understanding of this relationship, researchers have studied how the lack of gut microbiota affects germ-free mice, who became motionless and registered high levels of stress (hypothalamic–pituitary–adrenal axis activity, greater inflammation, and increased intestinal permeability) in a forced swim test.9

Brittany L. Mason, PhD, assistant professor in the psychoneuroendocrine research program at UT Southwestern Medical Center in Dallas, Texas, concurs that probiotics show promise, but more research is needed. “Nutritional guidance and sleep interventions can go far to help patients suffering with 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,” she said.

Summary and Clinical Applicability

Probiotics show some promise in offering symptom relief for patients with depression, though the evidence base is weak. Future studies need to better elucidate the gut-brain relationship and determine which type of probiotics are most efficacious.


  1. Ng QX, Peters C, Ho CYX, Lim DY, Yeo WS. A meta-analysis of the use of probiotics to alleviate depressive symptoms. J Affect Disord. 2018;228:13-19.
  2. Keene MS, Eaddy MT, Nelson WW, Sarnes MW. Adherence to paroxetine CR compared with paroxetine IR in a Medicare-eligible population with anxiety disorders. Am J Manag Care. 2005;11(12 suppl):S362-S369.
  3. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17(2):111-126.
  4. Bambling M, Edwards SC, Hall S, Vitetta L. A combination of probiotics and magnesium orotate attenuate depression in a small SSRI resistant cohort: an intestinal anti-inflammatory response is suggested. Inflammopharmacology. 2017;25(2):271-274.
  5. World Health Organization. Depression fact sheet. Accessed February 10, 2018.
  6. Schmidt C. Mental health: thinking from the gut. Nature. 2015;518(7540):S12-S15.
  7. Huang R, Wang K, Hu J. Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials.Nutrients. 2016;8(8).
  8. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Harnessing gut microbes for mental health: getting from here to there. Biol Psychiatry. 2018;83(3):214-223.
  9. Mason BL. Feeding systems and the gut microbiome: gut-brain interactions with relevance to psychiatric conditions. Psychosomatics. 2017;58(6):574-580.