Analyzing SSRIs and Gut Microbiota in Major Depressive Disorder

Psychiatric TimesVol 40, Issue 7

What is the association between the gut microbiome and response to SSRIs in patients with depression?




“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. At his outpatient visits, his mood is chronically depressed, and he has a chronic delusion that he suffers from gastrointestinal candidiasis. He takes a probiotic formulation that he orders online from an overseas supplier to treat the candidiasis. He frequently reports various gastrointestinal symptoms.

Mr Richards is only partially adherent with his psychotropic medications and will often adjust the dose of, or altogether stop, medications without consulting his psychiatrist. He has reportedly failed 2 previous trials of selective serotonin reuptake inhibitors (SSRIs). He asks his psychiatrist about other probiotics he can take for his MDD.

Many patients who have MDD do not respond to treatment with SSRIs.1 There is some evidence for alterations in the gut microbiota of patients with depression versus controls.2,3 One study found that transplantation of the feces of patients with MDD into the guts of mice could induce depression-like behaviors.4

Outside of depression, gut microbiota can influence the effectiveness of medications via pharmacokinetic changes.5 There is also some evidence in animal models that SSRIs can influence 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-naïve patients aged 18 to 55 years with first-episode DSM-IV MDD. Participants were followed for 8 weeks of treatment with SSRIs. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17).

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 being treated with antibiotics or probiotics at the time. Exclusion criteria were acute or chronic diseases or infections, pregnancy or lactation, 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. Response to SSRIs was defined as a ≥ 50% reduction in HDRS-17 score from baseline to week 8. Fecal samples were collected before 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 (ROC) curves were used to analyze the response to SSRIs and related bacteria.

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

Table. Increases in Genera in the Control Group, SSRI Responders, and SSRI Nonresponders

Table. Increases in Genera in the Control Group, SSRI Responders, and SSRI Nonresponders

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

Study Conclusions

The authors concluded that gut microbiota—specifically the genera Blautia, Bifidobacterium, and Coprococcus—was associated with increased response to SSRIs in MDD. These 3 bacterial groups are related to the production of short-chain fatty acids.9

Study strengths include that participants were experiencing their first episode of depression and were antidepressant-naïve. Study limitations include modest sample size, absence of a placebo group, and the failure to control for dietary habits, which could influence 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 MDD.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the editorial board of Psychiatric Times® and serves as 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 an add-on therapy to SSRIs for depression: a randomized controlled trialJ Psychiatr Res. 2019;114:24-33.

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

3. Jiang H, Ling Z, Zhang Y, et al. Altered fecal microbiota composition in patients with major depressive disorderBrain Behav Immun. 2015;48:186-194.

4. Kelly JR, Borre Y, O’Brien C, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109-118.

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

6. Ramsteijn AS, Jašarević 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 depressionGut Microbes. 2020;11(4):735-753.

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

8. Gao M, Tu H, Liu P, et al. Association analysis of gut microbiota and efficacy of SSRIs antidepressants in patients with major depressive disorder. J Affect Disord. 2023;330:40-47.

9. Sorbara MT, Littmann ER, Fontana E, et al. Functional and genomic variation between human-derived isolates of Lachnospiraceae reveals inter- and intra-species diversityCell Host Microbe. 2020;28(1):134-146.e4.

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