Table 1.

A general summary of the main nutraceuticals, dietary sources and their preclinical/clinical evidence.

Nutraceutical	Main Dietary Sources	Probable Antidepressant Effects	Clinical Evidence	Side Effects or Limitations	References
Omega 3	Oily fish, nuts, seeds	Targeting of lipid rafts and G coupled protein receptors; Influencing neurotransmission; Stimulation of myelin proteins; Improved cognitive functioning and neuronal cytoarchitecture; Positive influence in the endocannabinoid system and BDNF activity; Anti-inflammatory effects	Major clinical efficacy appears at combined doses of EPA (>60%) + DHA	Long-term results; More effective in patients with mild to moderate depressive symptoms	[81,82,83,99,100]
Vitamin D	Oily fish, dairy products, eggs, seafood	Immune and microbial homeostasis; Serotonin synthesis; Circadian clock; Increased BDNF activity	Vitamin D3 at a dose of 50,000 IU/week show possible antidepressant effects also improving sleep quality vitamin D deficiency as a possible risk factor for late-life depression	Further clinical evidence is warranted	[114,115,116,118,120]
SAMe	Endogenously synthesized or supplements	Influence monoamine synthesis and activity; Improved methylation status and BDNF activity; Anti-inflammatory effects and targeting microbiota–gut–brain axis.	Combination of SAMe with standard antidepressants but not alone have demonstrated the safety, efficacy and tolerability of this component. One study also shows improved action when combined with probiotics	Possible sex-dependent effects;	[129,130,131,132,133,134,135,136,137,138]
Methylfolate	Endogenously synthesized or supplements	Improved monoamine synthesis and activity; Anti-inflammatory effects; Restoring SAMe levels in the organism	More benefits than supplementation with folate are obtained; 15 mg of methylfolate but not 7.5 exert possible antidepressant effects with standard therapies; High BMI, inflammatory mediators and leptin levels appears to act as predictive; Pregnant women or individuals with reduced MTHFR activity may be potential candidates for this nutraceutical	One case report study described a relapse of psoriasis in a 61 years old woman after 15 mg/day of methylfolate; Further evidence is warranted	[149,150,151,152,153,154]
Prebiotics	Fruits, vegetables, whole grains, legumes	Growing of beneficial bacteria	Some studies have found mild efficacy of prebiotic in MDD, but more prominently with probiotics	Prebiotics alone may not have any positive action for patients with MDD	[195,196,197]
Probiotics	Yogurt, kefir, kombucha, tempeh, miso	Growing of beneficial bacteria in the gut	Certain probiotic species alone or in combination improves clinical parameters in patients <65 years	Elderly people appear to be less sensitive to probiotics	[190,191,192,193,194]
Carnitine	Fish, meats, dairy products	Anti-inflammatory effects; Antioxidant; Improved metabolic profile; Cognitive enhancement; Neuroplastic effects; Increased BDNF activity; Probable effects in neurotransmitter functioning	2 to 6 g per day of creatine supplementation appears to be well-tolerated and effective in patients with MDD	In patients with bipolar depression, it may increase the risk of suffering from hypomania/mania; Most studies are conducted in women (Sex-dependent effect); Further evidence is warranted	[160,161,162,163]
Tyrosine,	Poultry, dairy products, avocado, nuts, pumpkin/sesame seeds	Involved in dopamine and norepinephrine synthesis; Anti-inflammatory effects	Combined use of 100 mg/kg tyrosine plus imipramine show no conclusive antidepressant activity in comparison to placebo; Patients with low levels of dopamine may beneficiate from this nutraceutical	Available data is still controversial	[176,177,178]
Phenylalanine	Red meats, fish, eggs, dairy products, soy, nuts.	Involved in dopamine and norepinephrine synthesis; Anti-inflammatory effects	Some clinical studies described some favorable effects of phenylalanine in MDD	There are no recent studies conducted in the use of this nutraceutical; it may be related to important adverse effects in patients with Parkinson Disease and pregnant women	[171,172,173,174,175]
Tryptophan	Soy, fish, poultry, eggs, dairy products, cocoa	Involved in serotonin synthesis	0.14–3 g of tryptophan per day in a context of a healthy diet may favorably influence patient’s mood	Tryptophan may be converted to quinolinic acid in patients with MDD (Neurotoxicity)	[179,180,181,182,183]
Vitamin B	Whole grains, meats, eggs, dairy products, seeds, nuts, dark leafy vegetables, fruits	Anti-inflammatory and antioxidant properties	Most trials are negative. However, dual supplementation of probiotics plus vitamin B8 obtained some clinical improvements	Including a varied diet with high vitamin content is much more effective than supplementation according to available scientific data	[198,199,200,201,204]
Vitamin A	Fruits and vegetables, meats, fish and dairy products		Serum levels of this component are reduced in patients with MDD.		[205,206,207]
Vitamin E	Dark leafy vegetables, nuts, seeds, vegetable oils		Serum levels of this component are reduced in patients with MDD		[205,206,207]
Calcium	Dairy products, fish, dark leafy vegetables	Neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission and cognitive functions	One study obtained favorable results from calcium plus vitamin D supplementation, but not alone	This nutraceutical has not provided too much interest	[212,213]
Magnesium	Dairy products, fish, dark leafy vegetables, legumes, nuts, seeds	Involved in complex cognitive processes	Daily consumption of 500 mg magnesium oxide per day improved depression status and hypomagnesemia; A 6-weeks intervention trial with magnesium in comparison to 6 weeks without any supplement in patients with mild and moderate MDD, regardless of age, gender, baseline severity of depression, baseline magnesium level, or use of antidepressant treatments; Magnesium exerts rapid actions (1–2 weeks)	Little evidence available	[216,217,218]
Zinc	Dairy products, fish, dark leafy vegetables, legumes, nuts, seeds, fish, red meat, poultry.	Pleiotropic effects	Zinc combined with antidepressants maximize clinical outcomes even in non-responsive patients		[220,221]
Trace elements (Iron, selenium, manganese)	Meat, fish, cereals, milk and dairy foods, vegetables and nuts	Targeting oxidative stress, monoaminergic system, systemic and local inflammation, GABAergic system, sleep regulation and neuroprotective effects mediated by BDNF	Iron supplementation might provide prophylactic effects in patients with anemia	Further evidence is warranted	[222,223,224,225,226]
Ultra-trace elements (Lithium)	Potato, vegetables, fish and seafood	Involved in complex cognitive processes	Some studies reported positive outcomes from long-term prophylaxis for non-responder patients, as well as in the prevention of suicidal thoughts	Most studies are conducted in patients with bipolar disorder	[227,228,229]
Alkaloids (Caffeine and theobromine)	Coffee, cocoa	Pleiotropic effects (Non selective antagonist of adenosine receptors)	Different studies have demonstrated the antidepressant effects of caffeine and probably of theobromine	High doses of both components are associated with increased anxiety, depressive and negative symptoms	[238,239,240,241,242,243,244,245]
Flavonoids polyphenols	Vegetables and fruits	Improved functioning of the monoaminergic system, GABAergic transmission, BDNF activity and amelioration of the neuroinflammatory response in the brain		No clinical studies have been conducted	[248,249]
Nonflavonoids polyphenols	Curcumin (Curcuma), resveratrol (grapes) Hydroxytyrosol (Olive oil)	Improving BDNF activity, serotoninergic and dopamine transmission, antioxidant and anti-inflammatory properties	Some studies have proven antidepressant benefits from curcumin in Asian patients with MDD	Further evidence is warranted	[250,251,252,253,254,255,256]
CBD	Only supplements	Influences serotoninergic, glutamatergic and GABAergic transmission, as well as the endocannabinoid system; Targeting of multiple cellular and molecular components, increasing the levels of BDNF, neurogenesis and neuroplasticity	-	There are no clinical studies conducted probably by its social perception	[257,258,259,260,261]