Biologically Active Compounds from Nature for the Treatment of Depression

Depression is a general term for a group of disorders characterized by feelings of sadness, lack of motivation, and dissatisfaction. Severe symptoms lasting more than two weeks and interfering with a patient’s ability to carry out daily activities are classified as major depressive disorder, with individual depressive episodes ranging from mild to moderate or severe. Patients often also experience mixed anxiety–depressive disorder, characterized by the simultaneous presence of mild or moderate depressive and anxiety symptoms; although it is not classified as a depressive disorder in the strict sense, it usually requires depression treatment (because depressive symptoms are typically more pronounced than anxiety symptoms).

The global prevalence of depression is about 4.4%, occurring more frequently in women (5.1%) than men (3.6%). In Croatia, between 100,000 and 200,000 people suffer from some form of depressive disorder, and one in five citizens will experience at least one depressive episode in their lifetime. The prevalence of depressive disorders is steadily increasing, and together with chronic non-communicable diseases, they are becoming one of the biggest public health problems, especially in developed countries. A notable increase in the prevalence of mild and moderate depressive disorders was observed during the COVID-19 pandemic, when depression was found to be seven times more prevalent than before the pandemic.

Treatment of depression usually involves a combination of psychotherapy and antidepressant medication. Side effects of antidepressants include, among others, the occurrence of serotonin syndrome and hypertensive crises, reduced sexual function, and weight gain, and many antidepressants have clinically significant interactions with other drugs. Achieving significant antidepressant effects requires therapy to be carried out for at least several weeks. However, in 20–30% of patients, antidepressants do not lead to the desired symptom relief. This is largely due to non-adherence, as recent studies show that about 30% of patients with diagnosed depression voluntarily stop taking medication within the first month of therapy, and about 44% within the first three months.

On the other hand, patients with depression often turn to alternative therapies, including dietary supplements. The types of dietary supplements most commonly recommended for alleviating depressive symptoms, their mechanisms of action, and methods and safety of use are listed in Table 1.

Table 1. Dietary supplements most commonly recommended for alleviating mild to moderate depressive symptoms

St. John’s Wort preparations have long been used as natural remedies for depression. Their effectiveness and safety have been demonstrated in numerous high-quality clinical studies, with properly dosed dry extracts standardized to hyperforin (and hypericin) content showing effects comparable to conventional antidepressants, but with significantly fewer side effects. However, their use in clinical practice is limited. One reason is that doctors rarely recommend them to patients, often opting for conventional antidepressants instead—likely due to variable product quality on the market and the fact that St. John’s Wort extracts have clinically significant interactions with many drugs.

Other dietary supplements with potential antidepressant effects (SAMe, 5-HTP, EPA, B-complex) are either less researched or have not shown significant clinical effects. Recently, there has been growing scientific interest in saffron preparations, which exhibit a combination of antidepressant and mild anxiolytic effects.

Saffron (Crocus sativus L., Iridaceae) is a plant species cultivated in Central Asia, China, India, Turkey, Iran, Algeria, and Europe. The dried stigmas of saffron flowers are among the most expensive spices in the world and have a history of use in traditional medicine as relaxants, antidepressants, expectorants, antispasmodics, abortifacients, and emmenagogues. The main active compounds in saffron with antidepressant effects are (apo)carotenoids: crocins, crocetin, picrocrocin, and safranal (Figure 1).

Figure 1. Active Compounds of Saffron

Saffron extract has antioxidant and anti-apoptotic effects, balances neurotransmitter levels (dopamine, serotonin, gamma-aminobutyric acid, and noradrenaline) in brain synapses, and reduces stress by acting on cortisol secretion. For this reason, its use in depression and anxiety therapy is being intensively researched.

The efficacy of saffron extract as an antidepressant has been studied for some time and has been demonstrated in numerous high-quality clinical studies (Table 2).

Table 2. Overview of clinical studies on the antidepressant and anxiolytic effects of saffron extract

Table 2 shows that saffron is effective in doses of 30–100 mg of dry extract per day, can be successfully combined with conventional antidepressants to enhance their efficacy, and can be used alone with effectiveness comparable to standard antidepressants. The recommended duration of therapy necessary to achieve clinically significant effects is 4–6 weeks. Saffron preparations are safe for use, but due to potential abortive effects of very high doses demonstrated in animal studies, they are not recommended for pregnant women.

Currently, there are various saffron products on the market that differ in pharmaceutical form (powdered dried stigmas, tinctures, dry extracts), composition, and quality (differences in dosage; standardized vs. non-standardized extracts). The best form is standardized encapsulated extracts (usually standardized to 0.3% safranal), which ensure the stability of active compounds that are otherwise prone to oxidation and degradation, allowing precise dosing. An example on our market is the high-dose saffron extract Safr’Inside®, standardized to 0.3% safranal.

In addition to antidepressant effects, saffron extract also has anxiolytic properties, making it particularly suitable for alleviating symptoms of restlessness and insomnia in mixed anxiety-depressive disorder. A similar effect is seen in a relatively new category of products available on the market—bioactive peptides, most commonly isolated from (mother’s) milk. These are obtained through controlled hydrolysis of the protein fraction of the food, are resistant to digestive processes, are successfully absorbed, cross the blood-brain barrier, and act on the central nervous system.

To date, the clinical efficacy of a relatively small number of peptides has been studied. On our market, Lactium®, a hydrolysate of alpha-s1 casein, is available, which at a daily dose of 300 mg is effective for alleviating symptoms of mild to moderate insomnia. Its effectiveness has been demonstrated in randomized clinical studies, either as monotherapy or in combination with other plant extracts, pyridoxine, and magnesium. A particular advantage of using Lactium (and other bioactive peptides) as an anxiolytic is its excellent safety profile, making it suitable even for use in pregnant women.

Apocarotenoids from saffron extract and bioactive milk peptides represent new categories of bioactive compounds being intensively investigated in depression and anxiety therapy. Their use in the form of high-quality preparations and at appropriate doses can significantly contribute to improving therapeutic outcomes in the treatment of mild to moderate depression and anxiety, which are among the fastest-growing public health problems in developed countries.

References

1. DSM-5: https://www.psychiatry.org/psychiatrists/practice/dsm

2. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet, 2018, 392(10159):1789–1858.

3. HZJZ 2021: https://www.hzjz.hr/sluzba-promicanje-zdravlja/depresija/

4. Bueno-Notivol J. et al., Int J Clin Health Psychol, 2021, 21(1).

5. WHO: https://www.who.int/news-room/fact-sheets/detail/depression

6. Ng Q.X. et al., J Affect Disord, 2017, 210:211–221.

7. Sharma B. et al., Saffron, the Age-Old Panacea in a New Light, 2020, 117–130.

8. Kim H.J. et al., Nutrients, 2019, 11(7):1466.

9. Scholey A. et al., Nutrients, 2017, 9(2):154.