Major depressive disorder (MDD), also referred to as clinical depression, is a common but serious mood disorder that significantly affects an individual’s feelings, thoughts, actions, and daily functioning. (3)(18)(27) According to the World Health Organization, depression affects more than 300 million individuals or approximately 4.4% of the world’s population, (9) making it the leading cause of disability worldwide. (6)(27)

Dr. Holly Lucille discusses the causes, symptoms, diagnosis, and supplemental interventions for depression.

Major depressive disorder symptoms

Depression symptoms may vary between individuals, in order to be diagnosed with MDD, some of the following symptoms must be present almost every day for a minimum of two weeks:

  • Persistent sadness, anxiety, or numbness
  • Feelings of hopelessness, guilt, or worthlessness
  • Mood swings and irritability
  • Loss of interest in activities that used to bring pleasure
  • Appetite and/or changes in weight
  • Restlessness
  • Decreased energy, fatigue, and moving or talking more slowly
  • Difficulty sleeping or oversleeping
  • Difficulty concentrating, remembering, or making decisions
  • Aches or pains, headaches, cramps, or digestive problems without a physical cause and not solved with treatment

Depression can result in serious consequences, including suicidal ideation and attempts. (3)(18) Approximately 800,000 deaths globally each year are attributed to suicide. (26)

Causes of depression

While depression can occur in any individual, the condition is more common in women and typically first presents itself in young adults during their late teens to mid-20s. (3)(27) MDD is believed to be caused by a combination of genetic, biological, environmental, and psychological factors. (18)(27)

Risk factors include:

  • Personal or family history of depression (18)
  • Exposure to trauma or extreme stress (e.g., loss of loved one, unemployment, continuous exposure to abuse, neglect, or poverty) (3)(18)(27)
  • Certain illnesses, such as diabetes, cancer, Parkinson’s, and heart disease (18)
  • Use of certain medications (18)
  • Certain personality traits (e.g., low self-esteem, prone to stress, pessimistic) (3)

Fatigue and difficulty sleeping are among possible symptoms of depression.

Major depressive disorder treatments: evidence-based ingredients and botanicals

Depression is typically addressed using a combination of antidepressant medications and psychotherapy. Despite the availability of numerous antidepressant agents, many individuals with MDD experience adverse effects, fail to respond to treatment, and continue to experience symptoms. (17)(20) In these cases, patients are often treated with brain stimulation therapies, such as electroconvulsive therapy (ECT). (3)(18) However, there are also a number of evidence-based dietary supplements with antidepressant properties that have demonstrated effectiveness.

St. John’s wort (Hypericum perforatum)

Several studies have shown that St. John’s wort (SJW) is effective in the treatment of mild-to-moderate depression. A 2017 meta-analysis examined the use of SJW in patients suffering from depression. Results showed that the effectiveness of SJW was superior to placebo and comparable to selective serotonin reuptake inhibitors (SSRIs), a common class of pharmaceutical antidepressants. (19) Another systematic review noted similar results when comparing the therapeutic potential of SJW to SSRIs, tricyclic antidepressants, and other antidepressant medications. This review also noted that participants receiving SJW experienced fewer adverse effects, results which were comparable to the placebo group. (5) In addition, a randomized, double-blind, placebo-controlled trial conducted over six weeks concluded that 900 mg of SJW (Hypericum extract STW 3-VI) resulted in a longer duration of response and lower relapse and recurrence rates compared to the SSRI citalopram and placebo groups. (23)

Omega-3 fatty acids

Omega-3 polyunsaturated fatty acids (PUFA) may be effective in the prevention and treatment of depression. A 2016 meta-analysis of observational studies associated a higher intake of omega-3 PUFA through fish consumption with a reduced risk of depression. (10) Several meta-analyses of randomized, controlled trials have also noted the benefits of omega-3 PUFA supplementation for individuals suffering with MDD. Supplementation appears to be most effective when formulations contain higher doses of EPA compared to DHA and when used in conjunction with antidepressant medication. (11)(16)(24) Research also demonstrates that adjunctive omega-3 supplementation may improve depressive symptoms related to bipolar disorder without reducing symptoms of mania. (22)

Several mechanisms explaining the antidepressant properties of omega-3 PUFAs have been suggested, including their ability to directly affect membrane properties and decrease inflammation. (6)

Several studies have shown St. John’s wort to be effective in the treatment of mild-to-moderate depression.

Rhodiola (Rhodiola rosea)

Rhodiola is an adaptogenic herb with anti-stress and antidepressant effects. The therapeutic actions of rhodiola are thought to be a result of its ability to interact with neuroendocrine-immune and neurotransmitter receptor systems involved in depression. (4) A study examining the effectiveness and safety of a standardized extract of rhodiola (SHR-5) in patients aged 18-70 years with mild-to-moderate depression was conducted over six weeks. Patients were randomized into three groups; each participant was prescribed two tablets twice per day of 340 mg per day SHR-5, 680 mg per day SHR-5, or a placebo. Improvements in symptoms, including depression, insomnia, emotional instability, and somatization, were observed in both SHR-5 groups but not the placebo group. (7)

While research demonstrates that rhodiola produces antidepressant effects, according to a 2015 study, rhodiola was not as effective when compared to the SSRI sertraline. However, the study also demonstrated that rhodiola intake was associated with fewer adverse effects and was better tolerated than sertraline. (14)


The antidepressant effects of curcumin, the primary curcuminoid found in turmeric, have been attributed to a number of mechanisms, specifically its ability to affect the HPA axis, monoaminergic activity, and neuroprogression, as well as immune-inflammatory, oxidative, and nitrosative stress pathways. In a randomized, double-blind, placebo-controlled study, 56 patients with MDD were given curcumin at a dose of 500 mg twice daily for two weeks or a placebo. Four to eight weeks post-treatment, curcumin was shown to be more effective in improving mood symptoms compared to the placebo, with more pronounced results occurring in patients presenting with atypical depression. (13)

A second study compared the use and safety profiles of curcumin to fluoxetine, a commonly prescribed SSRI, in the treatment of MDD. Over six weeks, patients received 20 mg fluoxetine, 1000 mg curcumin, or a combination of both. While all groups responded to treatment, response rates were highest in the combination group (77.8%), followed by the fluoxetine group (64.7%) and the curcumin group (62.5%). However, the researchers noted that these response rates were comparable and differences were not statistically significant, providing evidence that curcumin may be a safe and effective treatment for patients with MDD who are not experiencing suicidal ideation or other psychotic disorders. (21)

Saffron (Crocus sativus)

Crocus sativus, commonly known as saffron, is a perennial herb of the Iridaceae family native to certain countries, such as Iran, India, and Greece. (25) Some studies indicate that the stigma and petal of this herb may produce antidepressive effects. In a six-week double-blind, randomized, placebo-controlled trial, 40 outpatients with major depression were prescribed 30 mg per day of saffron or a placebo. Compared to the placebo, patients receiving saffron had significantly better scores on the Hamilton Depression Rating Scale, a widely used assessment scale for depressive symptoms. (17)

Another study compared the effects of saffron and fluoxetine in the treatment of mild-to-moderate depression. In a randomized, double-blind, pilot study, patients received 15 mg C. sativus or 10 mg fluoxetine twice per day. After eight weeks, C. sativus or fluoxetine demonstrated similar effectiveness. (1)

Saffron is a perennial herb of the Iridaceae family native to Iran, India, and Greece.

S-adenosylmethionine (SAMe)

S-adenosylmethionine, often referred to by its acronym SAMe, is a naturally-occurring compound in the body. As a methyl donor, SAMe plays an important role in cellular metabolism. Research suggests that this compound may be used to address MDD in patients who do not respond to antidepressant therapy. A six-week, randomized, double-blind trial examined the effects of SAMe administered as an adjunct to SSRIs in 73 nonresponders. Results from the Hamilton Depression Rating Scale demonstrated significantly better response and remission rates compared to a placebo. (20)

Another uncontrolled pilot study provided preliminary evidence supporting the use of SAMe as an adjunctive treatment for Parkinson’s disease-related depression. In this study, 800 to 3600 mg of SAMe per day were administered for a period of ten weeks in conjunction with antidepressant medication. Participants who completed the trial demonstrated improvements in depressive symptoms, indicated by the Hamilton Depression Scale. (8)


Imbalances in the intestinal microbiota, known as dysbiosis, have been associated with the development of several health conditions, including depression. Research has, therefore, examined whether modulation of the gut microbiome with probiotic supplementation would improve symptoms in individuals with MDD. Several studies have shown that concomitant use of certain probiotic strains and antidepressant medications may improve clinical outcomes.

In one eight-week study, 110 depressed patients received a placebo, a probiotic supplement consisting of Lactobacillus helveticus and Bifidobacterium longum strains, or a prebiotic galactooligosaccharide supplement. While no changes were observed in the prebiotic group, individuals supplementing with probiotics demonstrated improvements in Beck Depression Inventory (BDI) scores, a rating scale widely used for the detection of depression. (12) Similarly, another randomized, double-blind, placebo-controlled trial found that a probiotic supplement consisting of Lactobacillus acidophilus (2 × 10(9) CFU/g), Lactobacillus casei (2 × 10(9) CFU/g), and Bifidobacterium bifidum (2 × 10(9) CFU/g) also improved BDI scores compared to a placebo. Improvements were also seen in certain metabolic markers, including insulin levels, hs-CRP concentrations, and glutathione concentrations. (2) Furthermore, in an eight-week open-label trial, patients with treatment-resistant MDD were randomized to receive 60 mg per day of Clostridium butyricum MIYAIRI 588 (CBM588) or a placebo concomitantly with various antidepressant medication (e.g., sertraline, fluvoxamine, paroxetine, escitalopram, and duloxetine). Compared to the placebo, CBM588 resulted in significant improvements in depressive symptoms. (15)

Learn more about the clinical applications of probiotics in neurological conditions.

The bottom line

Depression is a serious mental condition affecting a significant portion of the global population. Fortunately, treatment options are available to individuals with MDD, including a number of evidence-based ingredients. Supplementation with omega-3 PUFAs, SAMe, and certain strains of probiotics, as well as the botanicals St. John’s wort, rhodiola, curcumin, and saffron has demonstrated effectiveness on their own and/or concomitantly with pharmaceutical medication.

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  1. Akhondzadeh Basti, A., Moshiri, E., Noorbala, A.A., Jamshidi, A.H., Abbasi, S.H., & Akhondzadeh, S. (2007). Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 31(2), 439-42.
  2. Akkasheh, G., Kashani-Poor, Z., Tajabadi-Ebrahimi, M., Jafari, P., Akbari, H., Taghizadeh, M., … Esmaillzadeh, A. (2016). Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition, 32(3), 315-20.
  3. American Psychiatry Association. (2017). What is depression? Retrieved from
  4. Amsterdam, J.D., & Panossian, A.G. (2016). Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine, 23(7), 770-83.
  5. Apaydin, E. A., Maher, A. R., Shanman, R., Booth, M. S., Miles, J. N., Sorbero, M. E., & Hempel, S. (2016). A systematic review of St. John’s wort for major depressive disorder. Systematic Reviews, 5(1), 148.
  6. Burhani, M. D., & Rasenick, M. M. (2017). Fish oil and depression: The skinny on fats. Journal of Integrative Neuroscience, 16(s1), S115–S124.
  7. Darbinyan, V., Aslanyan, G., Amroyan, E., Gabrielyan, E., Malmström, C., & Panossian, A. (2007). Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nordic Journal of Psychiatry, 61(5), 343-8.
  8. Di Rocco, A., Rogers, J.D., Brown, R., Werner, P., & Bottiglieri, T. (2000). S-Adenosyl-Methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial. Movement Disorders, 15(6), 1225-9.
  9. Friedrich, M.J. (2017). Depression is the leading cause of disability around the world. JAMA, 317(15), 1517.
  10. Grosso, G., Micek, A., Marventano, S., Castellano, S., Mistretta, A., Pajak, A., & Galvano, F. (2016). Dietary n-3 PUFA, fish consumption and depression: A systematic review and meta-analysis of observational studies. Journal of Affective Disorders, 205, 269-281.
  11. Grosso, G., Pajak, A., Marventano, S., Castellano, S., Galvano, F., Bucolo, C., … Caraci, F. (2014). Role of omega-3 fatty acids in the treatment of depressive disorders: A comprehensive meta-analysis of randomized clinical trials. PLoS One, 9(5), e96905.
  12. Kazemi, A., Noorbala, A.A., Azam, K., Eskandari, M.H., & Djafarian K. (2019). Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clinical Nutrition, 38(2), 522-528.
  13. Lopresti, A.L., Maes, M., Maker, G.L., Hood, S.D., & Drummond, P.D. (2014). Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study. Journal of Affective Disorders, 167, 368-75.
  14. Mao, J.J., Xie, S.X., Zee, J., Soeller, I., Li, Q.S., Rockwell, K., & Amsterdam, J.D. (2015). Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine, 22(3), 394-9.
  15. Miyaoka, T., Kanayama, M., Wake, R., Hashioka, S., Hayashida, M., Nagahama, M., … Horiguchi. J. (2018). Clostridium butyricum MIYAIRI 588 as adjunctive therapy for treatment-resistant major depressive disorder: A prospective open-label trial. Clinical Neuropharmacology, 41(5), 151-155.
  16. Mocking, R. J., Harmsen, I., Assies, J., Koeter, M. W., Ruhé, H. G., & Schene, A. H. (2016). Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Translational Psychiatry, 6(3), e756.
  17. Moshiri, E., Basti, A.A., Noorbala, A.A., Jamshidi, A.H., Hesameddin Abbasi, S., & Akhondzadeh, S. (2006). Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine, 13(9-10), 607-11.
  18. National Institute of Mental Health. (2018). Depression. Retrieved from
  19. Ng, Q.X., Venkatanarayanan, N., & Ho, C.Y. (2017). Clinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysis. Journal of Affective Disorders, 210, 211-221.
  20. Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E., & Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. The American Journal of Psychiatry, 167(8), 942-8.
  21. Sanmukhani, J., Satodia, V., Trivedi, J., Patel, T., Tiwari, D., Panchal, B., … Tripathi, C.B. (2014). Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytotherapy Research, 28(4), 579-85.
  22. Sarris, J., Mischoulon, D., & Schweitzer, I. (2012). Omega-3 for bipolar disorder: Meta-analyses of use in mania and bipolar depression. Journal of Clinical Psychiatry, 73(1), 81-6.
  23. Singer, A., Schmidt, M., Hauke, W., & Stade, K. (2011). Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine, 18(8-9), 739-42.
  24. Sublette, M. E., Ellis, S. P., Geant, A. L., & Mann, J. J. (2011). Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. The Journal of Clinical Psychiatry, 72(12), 1577–1584.
  25. Srivastava, R., Ahmed, H., Dixit, R. K., Dharamveer, & Saraf, S. A. (2010). Crocus sativus L.: A comprehensive review. Pharmacognosy Reviews, 4(8), 200–208.
  26. UN News. (2017). UN health agency reports depression now ‘leading cause of disability worldwide’. Retrieved from
    World Health Organization. (2018). Depression. Retrieved from