Analysis of SSRIs and gut microbiota in major depressive disorder


Mr. Richards is a 55-year-old white male with a 20-year history of recurrent and severe major depressive disorder (MDD) with psychotic features. During his outpatient visits, his mood is chronically depressed and he has a chronic delusion that he is suffering from gastrointestinal candidiasis. He takes a probiotic formulation that he orders online from an overseas supplier to treat candidiasis. He frequently reports various gastrointestinal symptoms.

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Mr. Richards is only partially adherent to his psychotropic medications and will often adjust his dose or stop medication altogether without consulting his psychiatrist. It reportedly failed 2 previous selective serotonin reuptake inhibitor (SSRI) trials. He asks his psychiatrist about other probiotics he can take for his major depressive disorder.

Many patients who have MDD do not respond to SSRI treatment.1 There is some evidence of alterations in the gut microbiota of patients with depression compared to controls.2.3 One study found that transplanting the feces of MDD patients into the entrails of mice could induce depression-like behaviors.4

Outside of depression, the gut microbiota can influence drug efficacy through pharmacokinetic changes.5 There is also some evidence in animal models that SSRIs can affect the gut microbiota.6.7

The current study

Gao and colleagues8 explored the association between the gut microbiome and response to SSRIs in patients with depression. They recruited 62 antidepressant-treated patients aged 18 to 55 years with first episode DSM IV MDD. Participants were followed up for 8 weeks of SSRI treatment. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17).

The study authors also recruited 41 matched healthy controls who had no history of mental disorders, an HDRS-17 score of less than 8, and were not treated with antibiotics or probiotics at the time. Exclusion criteria were acute or chronic illness or infection, pregnancy or breastfeeding, antibiotic or anti-inflammatory treatment in the previous month, and history of digestive diseases.

Patients were treated with such SSRIs as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram. SSRI response was defined as a 50% reduction in HDRS-17 score from baseline to week 8. Stool samples were collected prior to SSRI treatment. Gut microbial communities were identified using a 16S ribosomal RNA gene sequence analysis.

Correlation coefficients were calculated for gut microbiome and clinical data. Binary logistic regression and receiver operating characteristic curves (ROCs) were used to analyze the response to SSRIs and related bacteria.

There were significant differences in the gut microbiome composition of SSRI responders, SSRI non-responders, and controls in the alpha diversity analysis. The relative abundance of 12 genera was increased in the control group, by
5 increased in responders and 2 increased in non-responders (Table).

Table. Increased genders in control group, SSRI responders and SSRI non-responders

Regarding beta-diversity, there was a significant difference in gut microbial community between SSRI responders but not non-responders and controls. three genera (Blautia, Bifidobacteria, AND Coprococcus) were significantly correlated with the reduction in HDRS-17 scores. After controlling for age, gender, and education, the area under the ROC curve for SSRI response based on these genders was 0.93, with a sensitivity of 0.88 and specificity of 0.92.

Study conclusions

The authors concluded that the gut microbiota is gender-specific Blautia, Bifidobacteria, AND Coprococcuswas associated with greater response to SSRIs in MDD. These 3 bacterial groups are related to the production of short-chain fatty acids.9

Strengths of the study include that the participants were experiencing their first episode of depression and were on antidepressants. Limitations of the study include the small sample size, the absence of a placebo group, and the lack of control over dietary habits, which could affect the gut microbiome.

The bottom line

The diversity of the gut microbiome and the relative abundance of Blautia, Coprococcus, AND Bifidobacterium are potential biomarkers of response to SSRIs in patients with major depressive disorder.

Dr. Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is part of the editorial staff of Psychiatric Times and serves as the schizophrenia section chief. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Zhao B, Li Z, Wang Y, et al. Manual or electroacupuncture as adjunctive therapy to SSRIs for depression: a randomized controlled trial.J Psychiatr Res. 2019;114:24-33.

2. Chen Z, Li J, Gui S, et al. Comparative metaproteomic analysis shows alterations of fecal microbiota in patients with major depressive disorder. Neuroreport. 2018;29(5):417-425.

3. Jiang H, Lin Z, Zhang Y, et al. Altered faecal microbiota composition in patients with major depressive disorder.Brain Behavior Immun. 2015;48:186-194.

4. Kelly JR, Borre Y, OBrien C, et al. Transfer of the blues: Gut microbiota associated with depression induces neurobehavioral changes in the rat. J Psychiatr Res. 2016;82:109-118.

5. Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome.Intestine. 2020;69(8):1510-1519.

6. Ramsteijn AS, Jaarevi E, Houwing DJ, et al. Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression.Gut microbes. 2020;11(4):735-753.

7. Luki I, Getselter D, Ziv O, et al. Antidepressants affect the gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior.Translation psychiatry. 2019;9(1):133.

8. Gao M, Tu H, Liu P, et al. Analysis of the association of gut microbiota and efficacy of SSRI antidepressants in patients with major depressive disorder.J Affective disorder. 2023;330:40-47.

9. Sorbara MT, Littmann ER, Fontana E, et al. Functional and genomic variation among isolates of human origin of Lachnospiraceae reveal inter- and intra-species diversity.Cellular host microbe. 2020;28(1):134-146.e4.

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