Healthy diet, depression and quality of life: A narrative review of biological mechanisms and primary prevention opportunities

Table 1 Summary of aetiological hypotheses and nutritional determinants of depression

Aetiological Hypotheses	Main mechanisms	Biological disturbances in UDD	Relationship with Diet	Ref.
Oxidative stress and inflammation	Higher cytokine levels in patients with UDD induce BBB damage and increased permeability to the brain, mainly through claudin 5 dysfunction. Furthermore, oxidative stress and cytokines stimulate the vagal nerve, further promoting a pro-inflammatory in the CNS.	Increased IL-6, TNF-a, C-reactive protein, INT- γ, and other inflammatory cytokines. BBB damage and translocation of cytokines and immune cells into the brain.	Adequate antioxidant intake and lifestyle habits prevent the development of a pro-inflammatory state.	[16,17,19]
Glucocorticoids and HPA-axis	Chronic stress leads to the constant release of cortisol and eventually a down regulation of cortisol receptors in the hypothalamus. In addition, altered immune responses promote further neuronal damage and other metabolic diseases.	Increased basal cortisol and LPS.	Healthy gut microbiomes prevent the release of LPS and other cytokines into the plasma, limiting the potential damage of stress and theoretically decreasing UDD risk.
		Altered cortisol circadian rhythm.
		Secondarily, T-cell differentiation and release of inflammatory cytokines.
Monoamine activity	Inadequate monoamine production and an increased degradation rate, mediated by the MAO enzyme, are related to depressive symptoms. Although current therapy is based on improving monoamine availability in the synapsis, uncertainties remain regarding this hypothesis.	Reduced monoamine formation and activity.	Vit-B12 and folate are necessary for monoamine production.	[28,29,33,34]
		Homocysteine (also homocysteinic acid or cysteine sulfinic acid) has detrimental effects on neurons.	Homocysteine accumulation is a result of Vit-B12 deficiency.
			MAO-B activity has been associated with Vit-B12 levels and dietary practices.
Neuronal development and activity	Altered BDNF function is caused by oxidative stress and inadequate endothelial function. This neurotrophin is essential for neuronal development, synapse formation and cerebral plasticity, in addition to having anti-depressant effects. However, its antidepressant effects are dependent on brain region and therefore not fully understood	Altered BDNF activity and other markers of endothelial function (IL-6, TNF-a, ICAM-1 and VCAM-1).	Antioxidants, MUFA, and PUFA concentrations regulate endothelial function.	[44–46]
		Decreased post-mortem hippocampal and prefrontal cortex volumes.	Vit-B12 promotes the expression of genes that code for BDNF-receptors (Ntrk-2).
The role of Health Related Quality of Life	Lower HRQoL has been associated with depression relapse and increased risk of suicide.	HRQoL is generally lower in patients with depression. Furthermore, pharmacotherapy improves mental components of HRQoL.	Quality of diet has been direct and cross-sectionally associated with HRQoL scores. The effects of diet on homocysteine level influence HRQoL and thus, potentially improve UDD patient status.	[55,57,62,63]

UDD: Unipolar depressive disorder; IL-6: Interleukin 6; TNF-α: Tumoral necrosis factor-α; INT- γ: Interferon- γ; HPA-axis: Hypothalamus-pituitary-adrenal axis; LPS: Lipopolysaccharides; MAO: Monoamine oxidase; BDNF: Brain derived neurotrophic factor; ICAM: Intercellular adhesion molecule; VCAM: Vascular adhesion molecule; MUFA: Monounsaturated fatty acids; PUFA: Polyunsaturated fatty acids; HRQoL: Health related quality of life.

Table 2 Summary of the effects of various nutrients, food groups, dietary patterns and lifestyle on prevalent or incident depression

Dietary components	Total/number of cases	mean follow-up t (yr)	Main Results1 [comparisons between quantiles (q) or the designated categories]
Cohort studies
Nutrients
Omega-3 fatty acids[6]	7903/512	2.4	q4 vs q1: OR (95%CI) 0.65 (0.47–0.90). P for trend = 0.376
Trans fatty acids[37]	12059/657	6.1	q5 vs q1: 1.42 (1.09-1.84); P for trend = 0.003
MUFA[37]	12059/657	6.1	q5 vs q1: 0.80 (0.62-1.03); P for trend = 0.05
PUFA[37]	12059/657	6.1	q5 vs q1; 0.76 (0.59-0.99; P for trend = 0.03
Magnesium[123]	12939/737	6.3	q5 vs q1: 1.11 (0.77-1.59) No association.
Nutritional adequacy[124]	13983/953	8.5	≥ 4 nutritional deficiencies vs ≤ 1: 1.37 (1.01-1.85)
Total Fiber[40]	548/198	Cross-sectional	q4 vs q1: OR = 0.54 (95%CI: 0.11–2.63); Non significant association
Foods and food groups
Fast food[125]	8964/493	6.2	q5 vs q1: 1.36 (1.02-1.81); P for trend = 0.03
Ultra-processed foods[126]	14907/774	10.3	q4 vs q1: 1.33 (1.07, 1.64); P for trend = 0.004
Baked goods[125]	8964/493	6.2	q2-5 vs q1: 1.38 (1.06-1.80);
Olive oil[37]	12059/657	6.1	q5 vs q1: 0.80 (0.62-1.04); P for trend = 0.06
Seafoods[127]	6587/1367	Cross-sectional	q3 vs q1 of fatty fish consumption: OR 0.72 (0.59–0.88). Higher intakes were non-significant
Coffee[128]	14413/199	10	≥ 4 cups/d vs < 1 cup/d: 0.37 (0.15–0.95); P for trend = 0.220
Yoghurt[36]	14542/727	9.3	Low fat: max vs min: 1.32 (1.06–1.65); P for trend = 0.001
			Whole fat: max vs min: 0.78 (0.63–0.98); P for trend = 0.02
Dietary patterns
MD score[8]	10094/480	4.4	3pts vs 0-2pts: 0.74 (0.57-0.98)
			4pts vs 0-2pts: 0.66 (0.50-0.86)
			5pts vs 0-2pts: 0.49 (0.36-0.67)
			6-9pts vs 0-2pts: 0.58 (0.44-0.77); P for trend <0.001
MD score (updated)[103]	15093/1051	8.5	q5 vs q1: 0.84 (0.69-1.02); P for trend = 0.001
Pro-vegetarian[103]	15093/1051	8.5	q5 vs q1: 0.74 (0.61-0.89); P for trend < 0.001
AHEI 2010[103]	15093/1051	8.5	q5 vs q1: 0.60 (0.49-0.72); P for trend < 0.001
DASH-Fung diet[102]	14051/410	8	< 2pts vs 3-9pts: 0.76 (0.61-0.94):
Pro-inflammatory pattern[129]	15093/1051	8.5	q5 vs q1: 1.47 (1.17, 1.85); P for trend = 0.010
Lifestyle
Mediterranean lifestyle[130]	11800/806	8.5	High vs low : 0.50 (0.32-0.81)
Healthy lifestyle score[131]	14908/774	10.4	Max vs min: 0.68 (0.49-0.95); P for trend 0.010
Alcohol[132]	13619/459	8	Moderate vs no consumption: 0.62 (0.43-0.89) in female subjects
CV risk equation[133]	16739/927	6	q5 vs q1: 3.45 (2.40-4.95) starting at 40 yr
Physical activity[7]	10381/923	6	q5 vs q1: OR (95% CI) 0.81 (0.65-1.00) P for trend < 0.01
Leisure time physical activity[134]	6343/311	10.5	> 20 METs-h/wk vs < 10 METs-h/wk; 0.84 (0.72–0.99); P for trend 0.046
Tobacco[135]	8556/190	4	Smokers vs non-smokers: 1.30 (0.97-1.73)
Childhood obesity (5 yr)[136]	11825/651	6.1	Obese vs low weight: 1.50 (1.06-2.12); P for trend = 0.012
Youth obesity (20 yr)[136]	11825/651	6.1	Obese vs low weight: 2.22 (1.20-4.08); P for trend = 0.005
Clinical trials
The PREDIMED study[119]	3923/224	5.4	MD + EVOO2 or nut supplements vs Low fat diet: multivariable adjusted 0.85 (0.64 to 1.13); Non significant associations
The MoodFOOD Study[117]	512/54	1	Multi-nutrient supplement vs placebo groups: OR = 1.06 (0.87-1.29); Non significant associations.

¹Estimates are presented as HR (95%CI) for incident depression unless stated otherwise.

²Extra virgin olive oil. MUFA: Monounsaturated fatty acids; PUFA: Polyunsaturated fatty acids; MD: Mediterranean diet.