An Anti-Inflammatory Diet Reduces Vulnerability to Depression

Ageing may be an inevitable part of life but depression should not be. Despite its high prevalence within the elderly population and the significant implications it can have on physical, cognitive and social functioning, depression is an often under-recognised and under-treated psychiatric condition. Adjibade et al. has recently concluded that an anti-inflammatory diet is associated with incidence of depression within men but not within the general population [1]. However, examination of the wider literature has found that consuming high quantities of fruits and vegetables and oily fish can reduce inflammation and may lower vulnerability to onset of depression.

22% of men and 28% of women aged 65 or over in England suffer from depression [2], a serious medical illness characterised by a persistent feeling of sadness or emptiness in addition to other symptoms including fatigue, apathy, appetite changes, insomnia and difficulty concentrating [3]. Depression in old age is linked to increased morbidity and mortality [4] due to risk of suicide [5], neurological impairment predisposing to dementia [5] and health neglect elevating incidence of chronic illnesses such as coronary heart disease [6].

Common causes of depression in older individuals include chronic pain or living in isolation due to physical illness [7], side effects of medication, upset due to suffering long term disease [8], confusion or memory problems [6], traumatic life events or loneliness due to death of a spouse [3]. Although not a sole cause, inflammation is also involved in the aetiology of depression, being considered as a precipitating factor and potential obstacle to recovery.   

Inflammation and a peripheral immune response signals production of pro-inflammatory cytokines by microglial cells due to the activation of primary afferent neurons such as the vagal and trigeminal nerves by locally produced cytokines [9] or by the induction of prostaglandin E2 release by cytokine interaction with IL-1 receptors on cerebral endothelial cells [9]. Elevated cytokine levels in the brain are also a consequence of their diffusion from systemic circulation through circumventricular organs or active transport across the blood-brain barrier [10]. This inflammatory response impacts neurotransmission pathways. The cytokines interferon-ʏ (IFNʏ), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) activate the p38 mitogen-activated protein kinase, which increases expression and functioning of serotonin pre-synapse reuptake transporters, as well as activating indolamine 2, 3-diozygenase (IDO). The latter effect results in degradation of tryptophan, a serotonin precursor, and its conversion to kynurenine. Kynurenine is subsequently metabolised to quinolinic acid, an agonist of glutamergic N-methyl-D-aspartate (NMDA) receptors, stimulating glutamate release, and blocking reuptake by astrocytes [11]. Finally, reactive oxygen species (ROS) and reactive nitrogen species (RNS) decrease availability of tetrahydrobiopterin (BH4), an enzyme cofactor in serotonin synthesis [12]. Ultimately inflammation decreases serotonin synthesis and neurotransmission, and increases glutamateric activity; this is typically associated with depression [11].

In addition to contributing factors for chronic inflammation such as physical inactivity and smoking, it is widely believed that diet plays a modulating role due to the antioxidant activity of many vitamins and bioactive compounds and the pro- and anti-inflammatory nature of dietary fats. A recent study by Abjibade et al. investigated the association between incidence of depression and the inflammatory potential of the diet within the general population and specific subgroups [1] to determine whether promoting a healthy diet could reduce incidence of symptom onset. This review will discuss their conclusions then evaluate the wider literature to establish whether recommendations should be made regarding specific foods to consume or optimum dietary patterns that may make depression not an ‘inevitable part of ageing’.

Method

Study population

Subjects from the Supplémentation en Vitamines et Minéraux Antioxydants study were selected who exhibited no depressive symptoms at baseline, nor were being treated with antidepressants, and that had sufficient data for calculating a dietary inflammatory index (DII) value. Demographic information was collected and anthropometric measurements taken.

Depressive symptoms

Depressive symptoms were assessed using the French version of the Center for Epidemiological Studies Depression Scale (CES-D). Responses were summed to a score between 0 and 60 with a higher score reflecting greater depressive symptoms. The cut off values for depressive symptoms were ≥17 for men and ≥23 for women.

Dietary data

Average daily food intake was determined from 24 hour dietary records at 2 monthly intervals. The DII score was calculated using data on 36 of 45 variables including nutrients, specific foods and bioactive compounds. Pro-inflammatory factors included energy, fat, saturated fat (SFA) and cholesterol, vitamin B12 and iron, and anti-inflammatory factors included omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), vitamin A, vitamin C, vitamin D, vitamin E, folic acid, anthocyanins, flavan-3-ols, isoflavones, ẞ-carotene.

Statistical analysis

Quartiles of DII scores were used with the highest quartile referring to the most pro-inflammatory diet. The association between DII and incidence of depressive symptoms was estimated, adjusting for lifestyle factors and incidence of cancer and cardiovascular disease (CVD) during follow up.

Results

Subject characteristics

3523 participants were included in the analysis, with mean ages of 52.1 years for men and 47.6 years for women. Total population mean DII score was 0.5, and was 0.1 for men and 0.8 for women. 172 subjects had incident depressive symptoms at follow-up.

Characteristics within DII score quartiles

Subjects in the highest DII quartile were less educated and physically active, had lower energy, PUFAs, fibre, vitamins and mineral intake, but higher saturated fat (SFA).

Results of statistical analysis

In the whole population there was no association between DII score and incidence of depressive symptoms. A marginal positive association was observed in men between the highest DII quartile and risk of incident depressive symptoms but not in women. Adjustment for cancer and CVD events attenuated the association. There were no significant associations in the age group sub-analysis.

Discussion

The study by Adjibade et al. found no significant association between DII and incidence of depression in the general population but a borderline positive association within men [1]. This contrasts wider research as healthier diets have been frequently associated with lower odds of depression [13] where those in the highest tertile of adherence to a ‘whole food’ dietary pattern have been shown to be less likely to be depressed than those in the lowest quartile [14]. Moreover, in much of the literature an elevation of inflammatory markers has been linked to depressive symptoms [15], particularly cytokines TNF-α, IL-1, IL-6 and C-reactive protein (CRP) [11,16], with dietary pattern being subsequently linked to such a state [17]. Lopez-Garcia et al. observed that adherence to a prudent diet was inversely related to levels of CRP, and conversely a western dietary pattern was positively associated with CRP and IL-6 [18], and similarly  Chrysohoou et al.  reported that those in the highest tertile of Mediterranean diet consumption had lower CRP and IL-6 concentrations [19]. The potential for negative causality is high within psychiatric disorders as those suffering depressive symptoms may often have poorer diets due to apathy and appetite changes. This may explain some of the contradiction between conclusions as it cannot be confidently determined whether adherence to an unhealthy diet is a cause or effect of depression.

One significant commonality between those diets related to reduced incidence of depression is the inclusion of high quantities of fruits and vegetables [14, 18, 20]. It has been found that daily intake of less than 5 servings of fruit and vegetables is linked to higher odds of experiencing depressive symptoms or increased distress level [21]. The effect of such foods could be attributed to their antioxidant capacity due to them providing vitamin C, vitamin E and polyphenols [4]. Vitamin C supplementation has been shown to reduce mood disturbance and psychological distress in deficient patients [22], although this does not necessarily indicate the benefits of vitamin C in excess of recommended nutrient intake (RNI) within the general population. However, the potential for polyphenols to suppress ROS formation, scavenge free radicals and upregulate other antioxidant defenses [23] suggests that fruit and vegetables may have a key role in reducing oxidative stress and inflammation. As well as the antioxidant activity, a higher intake of magnesium may be likely [24], which has been linked to lower CRP concentration [4], and folate is commonly associated with depressive symptoms due to its effects on the conversion of homocysteine to methionine . Low folate reduces methylation capacity and impairs synthesis of neurotransmitters [20]. Moreover, disturbance of one-carbon metabolism reduces BH4 availability, which acts as an endogenous antioxidant but is also involved in serotonin synthesis [20].

The healthier diets studied also frequently feature high fish consumption which would be likely to correlate with intake of n-3 PUFAs. A reduction in inflammation is biologically plausible as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compete with arachidonic acid (ARA) in the cycloxygenase eicosanoid synthesis pathway, impeding the production of pro-inflammatory eicosanoids. In addition, EPA and DHA combine with ARA to lower its cellular and plasma concentrations by amalgamation into phospholipid membranes [25]. EPA also acts to modulate gene expression by binding to peroxisome proliferator response elements on DNA, inhibiting activation of nuclear factor-kB which initiates genes encoding for TNF-α and IL-6 [26]. These mechanisms result in n-3 PUFAs suppressing production of IL-1β, IL-2, IL-6 and TNF-α [27], which are linked to incidence of depressive symptoms. Despite this, there are inconsistent findings amongst research regarding n-3 PUFA monotherapy [27], with the general conclusion being that n-3 PUFAs have no significant effect on depression treatment [28], although results from supplemented food and fish oil have been more positive [25]. It may be that the number of other causes of depression means n-3 PUFA monotherapy may only benefit those suffering due to deficiency. When considering diet it may therefore be more appropriate to consider the n-3/n-6 PUFA ratio not absolute quantities of n-3 PUFAs [29] as this would affect relative rates of pro- and anti-inflammatory eicosanoid, and hence neurotransmitter, synthesis [25]. Li et al. observed that CRP, IL-6 and TNF-α were reduced following n-3 PUFA supplementation compared to linoleic acid (n-6) supplementation, but not oleic acid [26]. The effect of ARA on nuclear factor-kB, initiating its activity, opposes that of EPA. Ensuring a favourable ratio of n-3 and n-6 PUFAs may therefore be advisable for reducing inflammation and subsequently incidence of depression.

The difference in the observed association between DII and depression incidence in men and women in the study by Adjibade et al. [1] limits the generalisability of their findings. However, it may be a consequence of the higher rate of reporting of depressive symptoms by women due to the effect of hormonal imbalances within the menstrual cycle on mood. This may have resulted in a greater spread of women experiencing depression throughout each quartile of DII. A number of further weaknesses may have also limited the results, including the high number of subjects excluded, assessment of only 36 of 45 dietary inflammatory variables and the lack of adjustment for other risk factors for depression. This suggests that the conclusions from the wider research should be deemed significant when drawing conclusions.

Although no effect was observed based upon age, the subjects in the study were only aged up to 60 years [1]. Within elderly women the effect of hormonal levels, which has been previously discussed, would be less significant, therefore it may not be possible to assume the same results would be observed within the older age group and a positive association between DII and incidence of depression may in fact exist.

Impacts

Overall the findings from the study by Adjibade et al. are not consistent with the conclusions from the wider literature. Conducting further research has ascertained that the association between inflammation and depression is biologically plausible and that a diet that is correlated with lower inflammatory markers may have a positive effect on incidence of depressive symptoms. More specifically, regularly consuming fruits, vegetables and oily fish should provide high levels of antioxidants, folate and result in a favourable n-3/n-6 PUFA ratio. It cannot be stated that such dietary modifications would prevent onset of depressive symptoms. However a higher DII and deficiencies in key anti-inflammatory nutrients, both of which are generally more prevalent within the elderly due to poor dietary quality as a consequence of age-related anorexia, financial insecurity, living alone and physical disability [30], may increase susceptibility to psychological conditions within older individuals [20], whom already have an elevated risk.

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[1] Adjibade, M., Andreeva, V.A., Lemogne, C., Touvier, M., Shivappa, N., Hébert, J.R., Wirth, M.D., Hercberg, S., Galan, P., Julia, C., Assmann, K.E., Kesse-Guyot, E. (2017) The inflammatory potential of the diet is associated with depressive symptoms in different subgroups of the general population. The Journal of Nutrition, jn245167.

[2] Age UK (2017) Later life in the United Kingdom. [pdf] Age UK. Available at: https://www.ageuk.org.uk/Documents/EN-GB/Factsheets/Later_Life_UK_factsheet.pdf?dtrk=true [8^th May 2017]

[3] NIH (2017?) Older adults and depression.[pdf] NIH. Available at: https://www.nimh.nih.gov/health/publications/older-adults-and-depression/qf-16-7697_153371.pdf [8th May 2017]

[4] Nguyen, B., Ding, D., Mihrshahi, S. (2017) Fruit and vegetable consumption and psychological distress: Cross-sectional and longitudinal analyses based on a large Australian sample. BMJ Open, 7(3), e014201.

[5] Rodda, J., Walker, Z., Carter, J. (2011) Depression in older adults. BMJ, 343, d5219. 

[6] National Mental Health Development Unit (2011) Management of depression in older people: Why this is important in primary care. [pdf] NMH. Available at: http://www.psige.org/public/files/NMH_10095_OPMH%20%26%20depression_5.pdf [8th May 2017]

[7] Singh, A., Misra, N. (2009) Loneliness, depression and sociability in old age. Industrial Psychiatry Journal, 18(1), 51-55.

[8] Royal College of Psychiatrists (2014) Depression in older adults. URL: http://www.rcpsych.ac.uk/healthadvice/problemsdisorders/depressioninolderadults.aspx [8th May 2017]

[9] Dantzer, R., O’Connor, J.C., Freund, G.G., Johnson, R.W., Kelley, K.W. (2010) From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46-56.

[10] Slavich, G.M., Irwin, M.R. (2014) From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychological Bulletin, 140(3), 774-815.

[11] Almond, M. (2013) Depression and inflammation: Examining the link. Current Psychiatry, 12(6), 24-32.

[12] Miller, A.H., Raison, C.L. (2015) The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16, 22-34.

[13] Lai, J.S., Hiles, S., Bisquera, A., Hure, A.J., McEvoy, M., Attia, J. (2013) A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults. The American Journal of Clinical Nutrition, 99(1), 181-197.

[14] Akbaraly, T., Brunner, E., Ferrie, J., Marmot, M., Kivimaki, M., Singh-Manoux, A. (2009) Dietary pattern and depressive symptoms in middle age. The British Journal of Psychiatry, 195(5), 408-413.

[15] Krishnadas, R., Cavanagh, J. (2012) Depression: An inflammatory illness? Journal of Neurology, Neurosurgery and Psychiatry, 83, 495-502.

[16] Jokela, M., Virtanen, M., Batty, G.D. (2016) Inflammation and specific symptoms of depression. JAMA Psychiatry, 73(1), 87-88.

[17] Berk, M., Williams, L.J., Jacka, F.N., O’Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart, A.L., Hayley, A.C., Byrne, M.L., Maes, M. (2013) So depression is an inflammatory disease, but where does the inflammation come from? BMC Medicine, 11(200).

[18] Lopez-Garcia, E., Schulze, M.B., Fung, T.T., Meigs, J.B., Rifai, N., Manson, J.E., Hu, F.B. (2004) Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. The American Journal of Clinical Nutrition, 80(4), 1029-1035.

[19] Chrysohoou, C., Panagiotakos, D.B., Pitsavos, C., Das, U.N., Stefanadis, C. (2004) Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. Journal of The American College of Cardiology, 44(1), 152-158.

[20] Samieri, C, Jutand, M, Féart, C., Capuron, L., Letenneur, L., Barberger-Gateau, P. (2008) Dietary patterns derived by hybrid clustering method in older people: Association with cognition, mood and self-related health. Journal of the American Dietetic Association, 108(9), 1461-1471. 

[21] Bishwajit, G., O’Leary, D.P., Ghosh, S., Sanni, Y., Shanfeng, T., Zhanchun, F. (2016) Association between depression and fruit and vegetable consumption among adults in South Asia. BMC Psychiatry, 17(15).

[22] Wang, Y., Liu, X.J., Robitaille, L., Eintracht, S., MacNamara, E., Hoffer, L.J. (2013) Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients. The American Journal of Clinical Nutrition, 98(3), 705-711.

[23] Hussain, T., Tan, B., Yin, Y., Blachier, F., Tossou, M.B.B., Rahu, N. (2016) Oxidative stress and inflammation: What polyphenols can do for us? Oxidative Medicine and Cellular Longevity, 2016, 7432797.

[24] Kaner, G., Soylu, M., Yüksel, Inanç, N., Ongan, D., Başmisirh, E. (2015) Evaluation of nutritional status of patients with depression. Biomedical Research International, 2015, 521481.

[25] Wani, A.L., Bhat, S.A., Ara, A. (2015) Omega-3 fatty acids and the treatment of depression: A review of scientific evidence. Integrative Medicine Research, 4(3), 132-141.

[26] Li, K., Huang, T., Zheng, J., Wu, K., Li, D. (2014) Effect of marine-derived n-3 polyunsaturated fatty acids on C- reactive protein, interleukin 6 and tumor necrosis factor ɑ: A meta-analysis. PLOS One, 9(2), e88103.

[27] Das, U. (2007) Is depression a low-grade systemic inflammatory condition? The American Journal of Clinical Nutrition, 85(6), 1665-1666.

[28] Bloch, M.H., Hannestad, J. (2011) Omega-3 fatty acids for the treatment of depression: A systematic review and meta-analysis. Molecular Pyschiatry, 17(12), 1272-1282.

[29] Parekh, A., Smeeth, D., Milner, Y., Thuret, S. (2017) The role of lipid biomarkers in major depression. Healthcare, 5(1), 5.

[30] Raats, M.M., de Groot, L., van Staveren, W.A. (2009) Food for the ageing population. Cambridge: Woodhead Publishing.