Probiotics may be a promising treatment for depression

Probiotics may be efficacious either as an adjunct to antidepressants or as a standalone treatment for major depressive disorder (MDD), according to results of a meta-analysis and network systematic review.

Most clinical guidelines on MDD focus on pharmacotherapy and psychotherapy. [VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, Version 4.0 – 2022; Ann Intern Med 2023;176:239-252] “However, recent research on the gut microbiota–brain axis has suggested that microbiota-targeted therapies could be promising,” wrote the researchers.

Therefore, researchers from the Chinese University of Hong Kong (CUHK) pooled data from 42 double-blind, randomized controlled trials (n=13,050) examining antidepressants (ie, serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants, and ketamine/esketamine) and microbiota-targeted interventions (eg, prebiotics, probiotics, and synbiotics) for treatment of MDD in adults. The included trials were published between 2015 and 2022. [Nutr Rev 2025;83:72-82]

Second highest ranking

Probiotics were found to be superior to brexpiprazole (standardized mean difference [SMD], -0.42; 95 percent credible interval [CrI], -0.68 to -0.17), cariprazine (SMD, -0.44; 95 percent CrI, -0.69 to -0.24), citalopram (SMD, -0.37; 95 percent CrI, -0.66 to -0.07]), duloxetine (SMD, -0.26; 95 percent CrI, -0.51 to -0.04), desvenlafaxine (SMD, -0.38; 95 percent CrI, -0.63 to -0.14), ketamine (SMD, -0.32; 95 percent CrI, -0.66 to -0.01), venlafaxine (SMD, -0.47; 95 percent CrI, -0.73 to -0.23), vilazodone (SMD, -0.37; 95 percent CrI, -0.61 to -0.12), vortioxetine (SMD, -0.39; 95 percent CrI, -0.63 to -0.15]), and placebo (SMD, -0.62; 95 percent CrI, -0.86 to 0.42), and noninferior to other antidepressants.

“Escitalopram, followed by probiotics, ranked the best among all interventions [surface under the cumulative ranking curve (SUCRA), 0.98 and 0.92, respectively],” pointed out the researchers.

Among the 16 interventions evaluated, probiotics as an add-on intervention were superior to brexpiprazole, cariprazine, desvenlafaxine, venlafaxine, and vortioxetine, with SMDs ranging from -0.32 to -0.38.

Only one trial investigated the efficacy of probiotics as a standalone treatment, which demonstrated the same efficacy as first-line (eg, escitalopram) and novel (ie, ketamine, esketamine) antidepressants for MDD.

“Due to a lack of available evidence, we were unable to determine the efficacy of prebiotics and synbiotics in adults with MDD,” noted the researchers.

“Our results are consistent with the majority of individual trials and pooled analyses, suggesting that there is indeed potential for the use of probiotics as an add-on treatment in MDD,” said the researchers.

Potential mechanisms

Probiotics may exert potential synergistic and additive effects by regulating the same neurotransmitters as antidepressants. Certain probiotic strains, such as Lactobacillus helveticus, can produce serotonin, which plays an important role in bidirectional communication between the gut and the brain. Lactobacillus species also produces other neurotransmitters, including glutamate, histamine, and gamma–aminobutyric acid, which may alleviate depressive symptoms.

“Leaky gut” is a condition characterized by weakened gut barrier, which can lead to gut microbiome disruptions. This has been linked to MDD as it triggers a peripheral proinflammatory response. Antidepressants may exacerbate this gut microbiota dysbiosis through antimicrobial effects. In contrast, probiotics may potentially restore gut microbiome homeostasis and improve gut barrier function.