The goal of this clinical trial is to assess the effect of commercial multi-strains psychobiotics supplementation as an ad-on therapy on depressive symptoms and metabolic syndrome components (HDL-C, FPG, TGs, WC, BP) in adult depressed patients with pre-metabolic syndrome and metabolic syndrome. The second goal is to explore the effect of commercial multi-strains psychobiotics supplementation on the anthropometric measurement (weight, body mass index (BMI)) in adult depressed patients with pre-metabolic syndrome and metabolic syndrome. The main questions they aim to answer are:

• Will commercial multi-strains psychobiotics supplementation help to ease depressive symptoms as an ad-on therapy in patients with pre-metabolic syndrome and metabolic syndrome?
• Will commercial multi-strains psychobiotics supplementation improve anthropometric measurements and metabolic syndrome components (WC, FPG, BP, TGs, HDL-C) in depressed patients? Researchers will compare psychobiotics to a placebo (a look-alike substance that contains no drug) to see if psychobiotics work to improve depression and metabolic syndrome components.

Participants will:

• Be examined for depression, anxiety, and metabolic syndrome components (waist circumference, diabetes, blood pressure, triglycerides, and high-density lipoprotein).
• Be asked to conduct laboratory tests to determine the inclusion and exclusion criteria.
• Be given probiotics/ placebo to consume every day for 3 months (12 weeks).
• Repeat the examination and laboratory tests to determine the results.
• Be followed up weekly for adverse events and to insure their compliance with the study instructions.
• Be followed up after 4 weeks as an end-visit and will conduct the examination and the laboratory blood tests.

Recently, the United Nations (UN) announced depression as the leading cause of disability worldwide. According to the World Health Organization (WHO), depression can increase the risk of suicide and death. Its prevalence increased globally since 2005 from 4.4% and reached 18.4% in 2015 accounting for about 322 million of the population. Based on the study of the Global Burden of Disease (GBD) from 195 countries around the world including Saudi Arabia, depression incidence increased from 172.27 million to 258.16 million from 1990 to 2017 most of whom is from major depressive disorder (MDD).

In addition, according to the Saudi National Mental Health Survey in 2016, 34% of Saudis were having psychiatric disorders and 80% of those with severe situations did not attempt any health care. Moreover, the prevalence of MDD among Saudis was 0.6% and it was one of the top-rated mental health cases in Saudi Arabia. Not only that but also, a cross-sectional study showed that the incidence of depression increased even more among Saudis during the pandemic of coronavirus disease-19 (COVID-19) to be 20.9%.

Depression is characterized by a persistent feeling of sadness, loss of interest, feeling of low self-esteem, loss of energy, decreased or increased appetite, trouble sleeping, and thoughts of suicide. Basically, depression is categorized into two main categories which are MDD and persistent depressive disorder (known as dysthymia). Depression can impair the quality of life and well-being. Unfortunately, it can also affect health negatively by causing comorbid diseases such as cancer, heart disease, inflammation, and neurological and metabolic disorders.

According to Al-Khatib et al (2022), one of the metabolic disorders associated with depression is metabolic syndrome (MetS). The International Diabetes Federation (IDF) defined the MetS as the occurrence of three or more symptoms of the following: central obesity with waist circumference (WC) for men ≥ 94 centimeters while for women ≥ 80 centimeters, increased fasting plasma glucose (FPG) ≥ 100 mg/dl, increased blood pressure (BP) to ≥ 130 /≥ 85 mmHg, increased triglycerides (TGs) to equal or above 150 mg/dl, reduced high-density lipoprotein cholesterol (HDL-C) for men to < 40 mg/dl while for women < 50 mg/dl. Yin et al., 2013 defined the pre-metabolic syndrome (Pre-MetS) as the occurrence of at least two components of MetS that do not reach the diagnostic of MetS. As a matter of fact, depression can lead to MetS and vice versa. About 30% of individuals with depression have MetS; meanwhile, about 41% of individuals with depression and MetS also have high levels of inflammation. Individuals with inflammation tend to have obesity and MetS. Thus, in 2007, it was proposed that the onset of depression with comorbid MetS is called "MetS type II" in which a combination of neuronal, psychological, and metabolic disorder happens. Furthermore, Gawlik-Kotelnicka and Strzelecki mentioned in their recent review the term "metabolic depression" to depict the relationship between depression, obesity, and MetS.

Recently, it has been suggested that gut microbiota modulation by a combination of probiotics and anti-depressant is an effective treatment. Since the bidirectional relationship between brain and gut health was confirmed, the accumulated body of evidence revealed that mental health is impacted by what is called the gut-brain axis (GBA) in which the gut microbiome can affect brain health through special microorganisms known as psychobiotics. Psychobiotics are special types of probiotics; they are specified to positively influence neurotransmitters, endocrinal hormones, and anti-inflammatory cytokines. They are a supporting therapy as an add-on therapy for mood disorders and depression with little or no side effects. To our knowledge, there are no clinical trials conducting in Saudi Arabia to investigate the impact of probiotics efficiency on depressive symptoms, anthropometric measurement, and MetS components in adult patients which is the aim of this experimental study.

Inclusion Criteria:

• Major Depression Disorder (MDD) patients on antidepressants for at least 4 weeks or more.
• MDD patients with pre-metabolic syndrome (at least 2 of the MetS components) and metabolic syndrome (at least 3 of the following components: central obesity with WC for men ≥ 94 centimeters while for women ≥ 80 centimeter, increased FPG ≥ 100 mg/dl, increased BP to ≥ 130 / ≥ 85 mmHg, increased TGs equal or above 150 mg / dl, increased HDL cholesterol for men to < 40 mg / dl while for women < 50 mg / dl) (IDF., 2006).
• MDD patients with other comorbid diseases such as anxiety.

Exclusion Criteria:

• Patients using any other supplements to improve mood.
• Patients using pre/pro/symbiotics supplement or antibiotics during the last 3 weeks before the intervention.
• Patients with chronic diseases (cardiac, renal, or hepatic diseases)
• Patients with gastro intestinal diseases (Crohn's disease, ulcerative colitis).
• Patients with infectious diseases (HIV/AIDS).
• Cancer patients or those undergoing chemotherapy.
• Patients with food allergies such as gluten intolerance or lactose intolerance.
• Pregnant and breastfeeding women.
• Patients with modified antidepressant dose during interventional period or receiving psychotherapy during the intervention.
• Patients with thyroid disorder.
• Patients following a diet to lose weight during the intervention.
• Diabetic patients who are insulin-dependent.
• patients receiving injections or medications to lose weight (Ozempic, Mounjaro …etc) either 3 weeks before or during the intervention.
• Patients using plasma-lipid lowering drug for less than 1 month before the intervention.
• Patients with substance abuse including alcohol addiction.

IPD will be shared with the probiotics company (Winclove's). KSUMC will provide Winclove with "raw data" a complete overview of the final results of the study after analysis and after anonymization to comply with applicable regulations, but not with patient identifying data.

Until January 15th, 2027.

Through electronic files.

The probiotic and the placebo are packed in plain white sachets, with the study acronym and shelf life printed on them. The sachets are packed in plain white boxes that are all equally labelled with the study title, instructions for use and investigator contact details. Each participant will receive 6 boxes of the same randomization number. The study team will be blinded to the contents of each box. The coordinating investigator of the study team will distribute the numbered boxes to the participants. The investigators have access to the randomization data in case it is necessary to unblind for a serious event. Sealed code break envelopes per participant (located at the investigational site in a restricted-access, fireproof, vault, accessible within 24 hours) will be used and in the event of a code break, the name of the code breaker, the signature, date and time will be recorded on the outside of the envelope. Unblinding will automatically lead to exclusion from the trial.