TABLE 2.

Clinical trials on probiotic supplementation in individuals with depression.

References	Sample size (INT/PL)	Mean age in years ± SD	Gender (males/females)	Study compound and duration	A change in INT group	Limitations/notes
Akkasheh et al., 2016	MDD: 40 INT: 20 PL: 20	INT: 38.30 ± 12.10 PL: 36.20 ± 8.20	INT: (3/17) PL: (3/17)	- The study was performed for 8 weeks. - INT received probiotic capsules daily and consisted of Lactobacillus acidophilus (2 × 109 CFU/g), Lactobacillus casei (2 × 109 CFU/g), and Bifidobacterium bifidum (2 × 109 CFU/g). - PL received capsules containing starch but no bacteria.	- ↓ BDI - ↓Serum insulin levels, homeostasis model assessment of insulin resistance, and serum hs-CRP concentrations - ↑Plasma total glutathione levels - No change in fasting plasma glucose, homeostatic model assessment of beta-cell function, quantitative insulin sensitivity check index, lipid profiles, or total antioxidant capacity levels	- No analysis of other biomarkers of inflammation or oxidative stress - A short intervention - Not knowing which strain in the probiotic supplements caused the treatment effect
Mohammadi et al., 2016	petrochemical workers: 70 INT 1: 25 INT 2: 25 PL: 20	INT 1: 33.20 ± 6.40 INT 2: 31.50 ± 5.80 PL: 33.10 ± 6.10	INT 1: (12/13) INT 2: (12/13) PL: (12/8)	- The study was performed for 6 weeks. - INT 1 received 100 g/day probiotic yogurt (Lactobacillus acidophilus LA5 and Bifidobacterium lactis BB12 with a total of min 1 × 107 CFU) + one placebo capsule. - INT 2 received one probiotic capsule daily (Lactobacillus casei 3 × 103, Lactobacillus acidophilus 3 × 107, Lactobacillus rhamnosus 7 × 109, Lactobacillus bulgaricus 5 × 108, Bifidobacterium breve 2 × 1010, Bifidobacterium longum 1 × 109, Streptococcus thermophilus 3 × 108 CFU/g and 100 mg fructo-oligosaccharide with lactose as carrier substances) + 100 g/day conventional yogurt. - PL received 100 g/day conventional yogurt (Streptococcus thermophilus and Lactobacillus bulgaricus) + one placebo capsule (the same substance without bacteria).	- ↑GHQ in INT 1 and INT 2 - ↓DASS scores in INT 1 and INT 2 - No change of GHQ or DASS scores in PL	- A short intervention -No assessment of the rate that short-chain fatty acids were produced by probiotics in the gut
Slykerman et al., 2017	Pregnant women of 14–16 weeks gestation: 423 INT: 212 PL: 211	INT: 33.50 ± 4.24 PL: 33.70 ± 4.44	Only females	- The study was performed until 6 months postpartum if breastfeeding. -INT received a daily Lacticaseibacillus rhamnosus HN001 at a dose of 6 × 109 CFU. -PL received a daily placebo (corn-derived maltodextrin).	- ↓Depression and anxiety scores in EPDS and STAI6 - ↓Clinically relevant anxiety on screening	- The EPDS and STAI6 are screening tools for postnatal depression and anxiety, but not diagnostic. -The information was collected retrospectively, and neither the EPDS nor the STAI6 has been validated using the questions phrased in the past tense.
Ghorbani et al., 2018	Individuals with moderate depression: 40 INT: 20 PL: 20	INT: 34.45 ± 3.95 PL: 35.50 ± 5.27	INT: (6/14) PL: (6/14)	- All Patients received fluoxetine (20 mg/d) for 4 weeks before and throughout the whole study. - The study was performed for 6 weeks. - INT received 2 capsules daily containing 500 mg probiotics (Lactobacillus casei 3 × 108 CFU/g, Lactobacillus acidophilus 2 × 108 CFU/g, Lactobacillus bulgaricus 2 × 109 CFU/g, Lactobacillus rhamnosus 3 × 108 CFU/g, Bifidobacterium breve 2 × 108 CFU/g, Bifidobacterium longum, 1 × 109 CFU/g, Streptococcus thermophilus 3 × 108 CFU/g) and 100 mg fructooligosaccharide as prebiotic. - PL received 2 placebo capsules daily containing 1,000 mg magnesium stearate.	- ↓HAM-D score at the endpoint of the intervention	- A short period of follow-up - A small number of participants
Majeed et al., 2018	MDD: 40 INT: 20 PL: 20	INT: 40.36 ± 10.28 PL: 43.88 ± 9.85	INT: (3/17) PL: (3/17)	- The study was performed for 90 days. - INT received a daily dose of 2 × 109 CFU Bacillus coagulans MTCC 5856 (600 mg) that contained also, microcrystalline cellulose, starch, sodium starch glycolate and magnesium stearate. -PL received placebo tablets that had the same ingredients except for Bacillus coagulans MTCC 5856.	- ↓HAM-D, MADRS, CES-D, IBS-QOL in INT - ↓CGI-I, CGI-S, Dementia – TFS, GI-DQ, mESS in INT - ↓ Serum myeloperoxidase in INT but not PL	- A short period of follow-up - A small number of participants
Kazemi et al., 2019	MDD: 110 INT 1: 38 INT 2: 36 PL: 36	INT 1: 36.15 ± 7.85 INT 2: 37.35 ± 7.97 PL: 36.00 ± 8.47	INT 1: (11/27) INT 2: (9/27) PL: (12/24)	- The study was performed for 8 weeks. - INT 1 received probiotic product consisting of freeze-dried Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (CNCM strain I-3470) bacteria (10 × 109 CFU) per 5 g sachet + xylitol, maltodextrin, plum flavor and malic acid - INT 2 received a prebiotic product consisting of galactooligosaccharide and 0.2% Plum flavor - PL received a product consisting of xylitol, maltodextrin, plum flavor and malic acid.	- ↓BDI score in INT 1 compared to PL - ↓Kynurenine/tryptophan ratio compared to PL - ↑Tryptophan/isoleucine ratio compared to PL - No change of BDI score in INT 2 compared to PL - ↓Tryptophan/BCAAs ratio in INT 2 compared to PL	- 10 subjects from INT 1, 9 from INT 2 and 10 from PL dropped out before the trial completion - A lack of fecal microbiome analysis - The intervention was conducted at different times of the year - No control of changes in lifestyle, diet, vitamin D status, etc. - Different used antidepressant drugs
Wallace and Milev, 2021	MDD: 10 INT: 10	INT: 25.20 ± 7.00	INT: (3/7)	- The study was performed for 8 weeks. - INT received a probiotic supplement containing Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 at a dose of 3 × 109 CFU once per day.	- ↓MADRS, QIDS-SR16 and SHAPS scores - ↓GAD-7 and STAI scores - ↑Sleep quality measured by PSQI	-A small number of participants - An open-label design and lack of placebo - A reduced generalizability of the results - The sample was disproportionately skewed toward young adult females.
Östlund-Lagerström et al., 2016	General older adults: 249 INT: 125 PL: 124	INT: 72.60 ± 5.80 PL: 72.00 ± 5.60	INT: (54/71) PL: (43/81)	-The study was performed for 12 weeks. -INT received a product consisting of a stick-pack containing freeze-dried Lactobacillus reuteri DSM 17938 (1 × 108 CFU/stick-pack), rhamnose, galactooligosaccharide and maltodextrin to a total weight of 1 g. -PL received a product consisting of maltodextrin.	- No change in GSRS, depression or anxiety scores - No change in the stress level (PSS scores) - No change in EQ-VAS or EQ-5D-index scores assessing the quality of life - No change in stool frequency	- A possibility that participants suffering from IBS were included in the study - An additional more fine-tuned instrument such as the ROME III symptom criteria, might have increased the sensitivity - The use of a low dose of Lactobacillus reuteri - The study was underpowered.
Romijn et al., 2017	Individuals with low mood: 79 INT: 40 PL: 39	INT: 35.80 ± 14.00 PL: 35.10 ± 14.50	INT: (8/32) PL: (9/30)	- The study was performed for 8 weeks. -INT received a product consisting of freeze-dried Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 bacteria at a dosage of 3 × 109 CFU per 1.5 g sachet + xylitol, maltodextrin, plum flavor and malic acid. -PL received a product consisting of xylitol, maltodextrin, plum flavor and malic acid.	- No change in MADRS, CGI-S, CGI-I, QIDS-SR16, GAF, DASS - No difference in biomarker levels	- No measurement of BMI, body fat, dietary intake and physical activity -A lack of intestinal microbiome analysis -A small sample size - A short length of the intervention period
Rudzki et al., 2019	MDD: 60 INT: 30 PL: 30	INT: 39.13 ± 9.96 PL: 38.90 ± 12.00	INT: (7/23) PL: (10/20)	- The study was performed for 8 weeks. -Both INT and PL received SSRI treatment during the whole study. - INT received 2 capsules daily with each containing 10 × 109 CFU of probiotic bacteria Lactobacillus Plantarum 299v. - PL received 2 capsules daily containing crystalline cellulose powder.	- No change in HAM-D 17, SCL-90 or PSS - Improvement of work speed in APT - Improvement of CVLT total recall -↓Kynurenine concentration -↑3HKYN:KYN ratio	-A small sample size - No measurements of intestinal permeability - No measurement of QUIN or vitamin B levels
Reininghaus et al., 2020	Inpatient MDD: 61 INT: 28 PL: 33	INT: 43.00 ± 14.31 PL: 40.11 ± 11.45	INT: (8/20) PL: (6/27)	- The study was performed for 4 weeks. -INT and PL received 125 mg D-Biotin. -INT received probiotics containing Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Bifidobacterium lactis W52, Lactobacillus acidophilus W22, Lacticaseibacillus casei W56, Lacticaseibacillus paracasei W20, Lactiplantibacillus plantarum W62, Lactobacillus salivarius W24 and Lactococcus lactis W19 + 30 mg of common horsetail, 30 mg of fish collagen and 30 mg of keratin plus matrix -PL received a product containing 30 mg of common horsetail, 30 mg of fish collagen and 30 mg of keratin plus matrix.	- No difference between INT and PL in any of the psychiatric scales - No difference in intestinal barrier function -↑Ruminococcus gauvreauii in INT -↑Taxonomically related Coprococcus	- A short length of the intervention Period -The strong decrease in depression in both groups may have masked the difference between them - Changes in nutritional habits might have influenced the results. -A difference at baseline for smoking status between both groups - The high number of females may have skewed the results.

The clinical studies of Östlund-Lagerström et al. (2016), Romijn et al. (2017), Rudzki et al. (2019), Reininghaus et al. (2020) did not reveal a significant improvement in the depression phenotype. INT, Intervention; PL, Placebo; CFU, Colony-forming units, SSRI, Selective serotonin reuptake inhibitor; BDI, Beck Depression Inventory; GHQ, General health questionnaire; DASS, Depression anxiety and stress scale; EPDS, Edinburgh Postnatal Depression Scale; STAI6, State Trait Anxiety Inventory 6 item version; HAM-D, Hamilton rating scale for depression; MADRS, Montgomery–Asberg Depression Rating Scale; CES-D, Center for Epidemiological Studies Depression Scale; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; CGI-I, Clinical Global Impression-Improvement rating Scale; CGI-S, Clinical Global Impression Severity Rating Scale; Dementia – TFS, Dementia – Total frequency scoring; GI-DQ, Gastrointestinal Discomfort Questionnaire; mESS, Modified Epworth Sleepiness Scale; QIDS-SR16, Quick Inventory of Depressive Symptomatology; SHAPS, Snaith-Hamilton Pleasure Scale; GAD-7, Generalized Anxiety Disorder 7-item scale; STAI, State Trait Anxiety Inventory; PSQI, Pittsburgh Sleep Quality Index; GSRS, Gastrointestinal symptoms rating scale; PSS, Perceived stress scale; GAF, Global Assessment of Functioning; SCL-90, Symptom Checklist; APT, Attention and Perceptivity Test; CVLT, California Verbal Learning Test.