Skip to main content Accessibility help
×
Home

Information:

  • Access
  • Cited by 32

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Nutritional psychiatry: the present state of the evidence
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Nutritional psychiatry: the present state of the evidence
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Nutritional psychiatry: the present state of the evidence
        Available formats
        ×
Export citation

Abstract

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

Mental illness is among the leading causes of disability worldwide, accounting for 18·9 % of years lived with a disability( 1 ). Due to the high prevalence of common mental disorders, the social, economic and heath burden associated with these disorders is substantial, with up to $8·5 trillion in lost output attributed to mental, neurological and substance use disorders( 2 ). Pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy, are cornerstones of treatment; however, they avert less than half of the disease burden, suggesting that additional strategies to prevent and treat mental disorders are needed( 3 , 4 ). Indeed, recent evidence suggests that despite a substantial increase in the use of psychotropics and wider availability of psychotherapies, the population burden of depression has not reduced, and may be increasing( 5 ). If indeed this is the case, it suggests the presence of operative environmental risk factors for depression.

The new field of nutritional psychiatry provides evidence for diet quality as a modifiable risk factor for mental illnesses. Recent systematic reviews examining the association between diet and common mental disorders have shown healthy dietary patterns to be inversely associated with the probability of, or risk for, depression( 6 8 ). Such diets are characterised by the high intake of vegetables, fruit, wholegrains, nuts, seeds and fish, with limited processed foods. In contrast, unhealthy diets high in processed, high-fat, high-sugar foods in adolescence and adulthood are shown to be positively associated with the common mental disorders, depression and anxiety( 6 , 9 ). Similar evidence exists in early childhood, where poor maternal nutrition status and early-life diet is associated with childhood emotional and behavioural dysregulation( 9 12 ).

Research investigating the potential biological processes involved in the diet and mental health relationship has primarily implicated inflammation, oxidative stress and neuroplasticity, with the gut microbiome as a key mediating pathway for each of these processes( 13 16 ). An understanding of these pathways has prompted research into the adjunctive use of dietary and nutraceutical (nutritional supplements) interventions that affect these pathways for both common and severe psychiatric disorders; such as n-3 fatty acids in depression and N-acetyl cysteine (NAC) in schizophrenia( 17 19 ). Critically, the first whole diet intervention studies in clinical depression are also now available( 20 ).

This review provides an overview of the field of nutritional psychiatry including discussion of the implicated biological mechanisms that are likely modulated by diet, the results of recent systematic reviews and meta-analyses regarding the use of dietary and nutraceutical interventions in mental disorders, and promising avenues for further research. An executive summary of each section can be found in Table 1.

Table 1. Executive summary of present research areas within Nutrition Psychiatry

For this narrative review, a systematic literature review of five electronic databases (Pubmed, PsychInfo, CiNAHL, Cochrane Database and Embase) was conducted using key search terms related to diet (e.g. ‘diet*’, ‘nutrition’), nutraceuticals (e.g. ‘diet* supplement’) and mental illness (e.g. ‘depression’, ‘mental illness’, ‘mood’). Results from systematic reviews, notable clinical and observational trials, and meta-analyses were prioritised for this review.

Implicated pathways in diet and mental illness

There are several pathways implicated in mental illness and that can be modulated by diet( 13 , 14 , 21 ). This section will provide an overview of the evidence for the primary pathways that have been studied to date. Although described as distinct pathways, it is likely that these pathways overlap synergistically and are mutually interacting.

Inflammation

Chronic low-grade inflammation, characterised by an elevation in pro-inflammatory cytokines and acute phase proteins, is implicated in the development of de novo depression, schizophrenia and bipolar disorder( 13 , 22 , 23 ). The causes of this inflammation are multifaceted and include several lifestyle factors, such as psychological stress, smoking, obesity, lack of sleep and, of particular relevance to the present discussion, poor diet( 13 ). Results from large observational studies suggest that healthy dietary patterns, such as the Mediterranean diet( 24 ), that are higher in PUFA, fibre, fruit and vegetables are associated with lower levels of inflammatory markers( 25 ). Moreover, Mediterranean dietary patterns significantly improve markers of inflammation in intervention studies( 26 ).

Oxidative stress

Oxidative and nitrosative stress are implicated in several chronic diseases and appear to be relevant to mental illness( 14 ). Schizophrenic populations have decreased brain glutathione levels, disordered glutamate metabolism and increased oxidative stress( 27 ). Similar results are reported in depressed populations, with higher levels of oxidative stress markers observed, as well as lower levels of antioxidants, such as vitamin E, vitamin C, coenzyme Q10 and glutathione, when compared with healthy controls( 14 ). Furthermore, a recent meta-analysis of 115 studies reported lower antioxidant capacity in depressed patients during acute episodes( 28 ). Given the abundance of antioxidant compounds present in foods such as fruit and vegetables, this is a pathway that could be modulated through dietary means.

Brain plasticity

Neurogenesis, particularly within the hippocampus, is associated with learning, memory and mood regulation, while altered neurogenesis is implicated in mental illness( 21 ). Brain-derived neurotrophic factor (BDNF) as well as other neurotrophins (e.g. bcl-2 and vascular endothelial growth factor) are suggested to mediate hippocampal neurogenesis( 29 , 30 ). There is presently limited clinical investigation of the effect of diet on this pathway; however, preliminary evidence supports the role of diet in improving BDNF levels. For example, a 4-week dietary intervention to increase consumption of carotenoid-rich fruit and vegetables (eight servings daily) in people with schizophrenia resulted in higher serum levels of BDNF than in the control group( 31 ). Moreover, an epidemiological investigation in older adults has demonstrated an association between poor diet and reduced hippocampal volume( 15 ). In addition to possessing antioxidant and anti-inflammatory properties, nutrients, such as n-3 fatty acids( 32 ), polyphenols( 33 ), l-theanine( 34 ) and vitamin E( 35 ), can also stimulate neurogenesis while energy-dense diets high in fat and sugar impair this process( 21 , 36 , 37 ).

Microbiota–gut–brain axis

The role of gastrointestinal microbiota on chronic disease is now a burgeoning area of research. Compelling evidence, predominantly from animal studies, indicates the gut microbiota can affect mental health-related behaviours via multiple pathways( 38 ).

The gastrointestinal microbiota has been implicated in several neurobiological pathways related to mental illness, including the modulation of BDNF( 39 ), serotonin neurotransmission( 40 ), immune function( 41 ) and the hypothalamic–pituitary–adrenal axis-mediated stress response( 39 , 42 ). For example, microbiota-deficient germ-free mice exhibit an exaggerated stress response( 39 ) and lower BDNF and serotonin receptor levels in the cortex and hippocampus of the brain( 39 , 43 ) compared with normal gut colonised mice. At least some of these pathways appear bidirectional, with stress activation of the hypothalamic–pituitary–adrenal axis found to modulate microbial composition in rats( 44 ).

Clinically, differences in patterns of faecal microbiota, reflecting decreased gut microbiota richness and diversity, have been reported in depressed patients compared with healthy controls( 45 ). Transplantation of microbes from depressed patients into rodents results in depression-related behaviours( 45 , 46 ) and altering gut microbiota through probiotic supplementation or food products influences depression-related behaviour in animals( 47 ).

Dietary-induced alterations in intestinal permeability (such as via a high-fat diet( 48 )) may also affect mental health. Integrity of the gut epithelial barrier by tight junctions regulates the movement of substrates from the gut into the blood stream and, when compromised, is associated with depression( 49 , 50 ). Increased permeability may allow bacteria-derived lipopolysaccharides to activate immune cells within the intestinal wall, promoting the production of inflammatory cytokines and activation of nitro-oxidative stress pathways, resulting in elevated systemic inflammation( 50 ).

Mitochondrial dysfunction

Impaired mitochondrial energy production, size and distribution are associated with depression, schizophrenia and may be particularly relevant to bipolar disorder( 51 , 52 ). These changes could be the result of reduced antioxidant capacity and a pro-inflammatory cytokine-mediated increase in mitochondrial-derived oxygen and nitrogen-free radicals, suggesting inflammation and oxidative stress drive mitochondrial dysfunction( 52 ). Dietary and nutraceutical compounds such as coenzyme Q10, α-lipoic acid, carnitine, creatine, resveratrol, NAC and some antidepressants up-regulate mitochondrial respiratory function in animal models( 53 55 ).

Observational literature on diet and mental illness

There is now consistent epidemiological evidence for an association between measures of diet quality and mental health, across multiple populations,( 56 58 ) which do not appear to be explained by other demographic factors or reverse causality( 59 61 ).

Adult data

Several meta-analyses and systematic reviews have established a relationship between diet and depression in adults( 6 , 7 , 62 64 ). Lai et al.( 6 ) conducted a meta-analysis of thirteen observational studies (four cohorts and nine cross-sectional) and reported that consumption of a healthy diet was associated with reduced odds of depression (OR 0·84; 95 % CI 0·76, 0·92). It was, however, unable to establish a statistically significant relationship between western diet and increased odds of depression, likely due to insufficient power from the small number of studies analysed. The second meta-analysis presented similar results, showing moderate and high adherence to a Mediterranean diet to be associated with reduced likelihood of depression( 7 ). A more recent systematic review and meta-analysis including data from twenty-one studies and 117 229 participants has confirmed an inverse relationship between dietary patterns characterised by higher intakes of fruit, vegetables, whole grain, fish, olive oil, low-fat dairy and the probability or risk for depression, and a positive relationship between dietary patterns characterised by a higher consumption of red and/or processed meat, refined grains, sweets, high-fat dairy products and an increased probability or risk of depression( 64 ).

Childhood and maternal perinatal data

The association between diet and mental health has also been studied in children, adolescents and women in the perinatal period( 9 , 65 67 ). A systematic review of nine cross-sectional and three prospective studies reported an inverse relationship between high-quality diet and mental health disturbances and a positive relationship between unhealthy diets and poorer mental health outcomes in children and adolescents( 9 ). Since this systematic review, three prospective cohort studies have reported maternal nutrition and early-life nutrition to be independently associated with mental symptomatology, such as internalising and externalising problems in children aged 5–7 years, when controlling for prenatal and postnatal confounders( 10 12 ).

During pregnancy, women are more susceptible to nutrient deficiencies due to increased physiological stress on the body and increased nutrient demand from a growing fetus. These deficiencies are likely exacerbated by poor quality diets. Given the potential role of dietary nutrients in the biochemical pathways of mental illnesses, generalised maternal nutrient deficiency may explain rates of perinatal depression. Baskin et al.( 67 ) found associations between poor diet quality and antenatal depression; however, evidence was inconsistent for an association between diet quality and postnatal depression and anxiety. Together this literature indicates diet is likely relevant to mental health at all stages of life.

Specific dietary patterns and individual nutrients

A healthy diet is generally characterised as a higher intake of fruit, vegetables, fish and wholegrains, while a western diet, in contrast, is characterised by higher consumption of processed foods, processed meats, refined grains, salty and sugary snacks and beverages( 63 ). However, there is still substantial heterogeneity in defining a healthy diet, as many unique cultures have diverse but still healthy dietary patterns( 68 ). At the core of these diets are nutrient-dense plant foods and high-quality sources of protein, which are likely to be a significant contributor to the observed results( 69 ). Rahe et al.( 63 ) differentiated between a healthy/traditional diet and a Mediterranean diet, with a Mediterranean diet having a greater emphasis on high intake of legumes, moderate intake of meat and dairy, and olive oil as the main fat source. They reported both diets were protective against depression. Observational studies have examined the association with other diets, including the traditional Japanese diet( 70 ) and the Norwegian diet( 71 ); however, evidence is limited and conflicting( 62 ).

It is important to note that the favourable association of healthy foods and mental health outcomes is consistently independent of the association between unhealthy foods and poorer mental health outcomes( 72 ), which suggests that different physiological pathways may be mediating the potential effects of these contrasting dietary patterns. These associations are also independent of body weight, suggesting dietary patterns can affect mental illness via pathways that are independent of weight status.

A 2010 review of thirty-four publications investigating a number of dietary variables, including long chain n-3 PUFA, fish, folate and B vitamins as markers of dietary intake, did not establish a definitive association between the intake of specific dietary components and depressive symptoms( 73 ). However, more recent meta-analyses of observational studies have identified fish consumption, and dietary magnesium, iron and zinc as associated with lower rates of depression( 74 76 ).

While most observational studies have made appropriate adjustments for potential confounding variables, such as socioeconomic status, physical activity and smoking( 59 ), residual confounding by these variables is likely. Moreover, while reverse causality has been examined as an explanatory factor (e.g. ( 60 )), observational studies, particularly when cross-sectional, are unable to establish causality. Therefore, observational studies using prospective and case–control cohorts and intervention randomised controlled trials (RCT) should be prioritised in future studies. Most studies to date have examined the association between diet and depression, with only a limited exploration of anxiety and more severe mental illnesses, such as schizophrenia and bipolar disorder. There is now a need to extend observational nutritional psychiatry research into these areas.

Dietary interventions for mental illness

While observational studies have reported consistent evidence for an association between diet quality and common mental disorders, there are relatively few interventions that have investigated this relationship. Our 2013 systematic review of seventeen previous intervention studies provides an overview of existing dietary intervention studies with depression, anxiety and mood disturbance endpoints( 8 ). The results were mixed, with approximately half the studies reporting improvements in outcomes, with successful trials generally including at least one of the following: single delivery mode (e.g. single or group face-to-face meetings only), employment of a dietitian, explicit recommendation of a diet high in fibre and/or fruit and vegetables. These trials were also less likely to recommend weight loss, reduce red meat intake or follow a low-cholesterol diet.

The review also identified multiple limitations within the literature. Primarily, only one study recruited participants with a depressive/anxiety diagnosis, while others included other participant populations, such as breast cancer and obese/overweight participants, and/or excluded participants with pre-existing mental health symptoms or disorders. Some studies included only one gender or had a sample comprising primarily Caucasian adults with a high education level. Hence, the findings may not be generalisable to other clinical and general populations.

Since the publication of this review, the potential impact of a Mediterranean diet on the incidence of de novo depression has been assessed in a post hoc analysis of the PREDIMED study( 77 ); this was a large RCT that investigated the effect of Mediterranean diet on CVD endpoints. While underpowered for the depression endpoint, the analysis suggested a non-significant reduction in the incidence of de novo depression for those randomised to a Mediterranean diet with nuts, and significant reduction in a subset of those with type 2 diabetes.

Forsyth et al.( 78 ) conducted a 12-week RCT in 119 individuals treated for depression and/or anxiety in primary care. The intervention group received motivational interviewing, activity scheduling and an individualised lifestyle programme focusing on changes in physical activity and diet (e.g. reducing fat intake, increasing vegetable intake and variety). The control group received regular phone contact with research staff that did not include dietary advice but asked participants about changes to their diet or physical activity patterns. Both groups reported improved symptoms of depression and/or anxiety as well as dietary intake over time. However, no significant differences in symptoms were observed between the two groups.

We have recently published the results of the SMILES trial, an RCT that investigated a 12-week modified Mediterranean diet intervention in sixty-seven participants with major depression( 20 ). Participants in the intervention group received personalised dietary and nutritional counselling based on a traditional Mediterranean diet and the Australian Dietary Guidelines. Participants in the control group received the same number of scheduled visits but received a ‘befriending’ protocol (social support) whereby research staff met with participants and discussed neutral topics of interest (e.g. sport, hobbies). At 12 weeks, there was a significantly greater improvement in depression scores in the dietary support group compared with the social support control group. Furthermore, there was a significantly greater level of remission in the dietary support group (defined as a Montgomery–Åsberg Depression Rating Scale score <10) with 32·3 % (n 10/31) of the dietary support group reporting remission compared with 8·0 % (n 2/25) in the social support control group and a number needed to treat of 4·1. Participants did not significantly change their energy intake or body weight during the trial, which suggests that these improvements were not primarily related to weight status. The results of the SMILES trial provide preliminary evidence that dietary interventions in clinically diagnosed populations are feasible and can provide clinical benefit. Further studies in larger samples are now required to confirm these results.

Nutraceutical interventions for mental illness

There is a broad array of nutraceutical interventions that target pathways implicated in mental illness, including inflammation, oxidative stress, modulation of the methylation cycle and prevention of hippocampal-associated cognitive decline, as well as mitochondrial dysfunction and neurotransmitter pathways( 79 81 ). Due to their action on these pathways, clinical trials have investigated specific nutrients and herbal preparations for their effect on mental illness. As this area of research is expansive, this section will only provide an overview of recent systematic reviews and meta-analyses that have evaluated intervention studies in this area.

St John's Wort, a widely researched herbal nutraceutical, has been reported in a recent meta-analysis to achieve similar improvements in depression to selective serotonin reuptake inhibitor medication controls( 82 ). The n-3 PUFA are another supplement that have a long history of investigation, with several meta-analyses reporting mixed findings( 17 , 83 , 84 ). However, interventions that use n-3 formulations with a high EPA : DHA ratio as an adjunctive to antidepressants might be beneficial to patients with depression( 17 , 84 ). S-adenosylmethionine, methylfolate and vitamin D may also have a positive effect on depression as adjunctive interventions, although there are also large negative studies( 17 , 85 ). Furthermore, some nutraceuticals, including creatine, folinic acid and an amino acid combination, have yielded positive preliminary data from single trials, while zinc, folic acid, vitamin C, inositol and tryptophan have mixed or non-significant effects for depression( 86 ). The results of additional meta-analyses also report no benefit from folate, vitamin B12 ( 87 ) and vitamin D supplementation for depression( 88 ).

While not as extensively studied, clinical trials have also investigated some nutraceuticals for other mental illnesses. Three meta-analyses concluded that adjunctive n-3 supplementation can be beneficial for both unipolar and bipolar depressions( 86 , 89 , 90 ). The results of a recent meta-analysis suggest that NAC may be efficacious for depression and depressive symptoms regardless of the main clinical diagnosis, although again there are negative studies( 91 ). Furthermore, l-tryptophan, magnesium, folic acid and branched-chain amino acids may be effective for bipolar disorder-related mania and chelated mineral and vitamin formulas may be effective in improving both bipolar disorder-related depression and mania( 86 ).

The use of micronutrient combinations for mental illness has also been investigated. A systematic review by Rucklidge and Kaplan( 92 ) reported limited evidence for micronutrient combinations for stress, antisocial behaviours and depressed mood in healthy people, as well as potentially for attention-deficit hyperactive disorder and autism. However, the review identified few studies in this area and most studies were conducted in healthy rather than clinically diagnosed populations.

A 2010 systematic review concluded that passionflower, kava and combinations of l-lysine and l-arginine were promising interventions for anxiety and that more research is required to make recommendations regarding magnesium supplementation due to limited published studies on this intervention. The results of a meta-analysis reported that folate and other vitamin B supplementation (including B6 and B12) may be beneficial for certain populations diagnosed with schizophrenia( 93 ).

Nutraceuticals including n-3 fatty acids, calcium, multivitamin and B vitamins have been investigated for perinatal depression; however, a recent review concluded that there is presently limited support for nutraceutical interventions in this population with few intervention studies reporting significant improvements and several trials rated as having a medium or high risk of bias( 66 ).

Overall, clinical trials have evaluated numerous nutraceutical interventions; however, there is a lack of trials that have evaluated their clinical efficacy and safety in populations with clinical mental disorders. Future studies are required to investigate these interventions using sufficiently powered RCT study designs. Importantly, likely effect modifiers, including baseline diet, inflammatory status and gut microbiome composition, are essential variables to include in future interventions.

Promising new avenues for investigation

The field of nutritional psychiatry has provided a significant body of evidence to suggest that dietary patterns are relevant to common mental illnesses. However, continued research is required to translate the evidence base into clinical and public health recommendations.

Dietary patterns may modulate numerous biological pathways involved in mental illness including inflammation, oxidative stress, the gut–brain axis and neurogenesis. Continued research is required to elucidate the impact of these as well as additional pathways, including the role of homocysteine( 94 ), telomerase( 95 ) and epigenetics( 96 ), on mental health and to develop optimal strategies for interventions.

Most observational data to date have focused on common mental disorders and there is now a need to examine dietary patterns in those with severe mental illnesses. Numerous systematic reviews and meta-analyses have considered the effects of dietary patterns on weight loss and metabolic diseases in individuals with severe mental illnesses, namely schizophrenia and bipolar disorder, yet few have specifically considered diet and its possible effect on psychiatric symptoms in these populations. Limited evidence suggests a positive association between obesity/weight gain and impaired functioning in individuals with bipolar disorder; however, the directionality of this relationship has not been firmly established, indicating the need for further research in this area( 97 ). Schizophrenia is associated with gastrointestinal and microbial dysfunction, immune and inflammatory mechanisms( 98 , 99 ). Further investigation into the possible role of dietary factors and gut microbiota dysbiosis in psychosis and associated neurodegeneration is warranted.

The microbiota–gut–brain diet axis is a promising target that could be modified via dietary and nutraceutical intervention, such as prebiotics (e.g. high-fibre foods and supplements) and probiotics (e.g. fermented foods or supplements) directly targeting microbial populations. A 2015 systematic review of ten RCT investigated probiotic supplements for stress, mood, anxiety, schizophrenic symptoms and externalising behaviours in autism spectrum disorder. It concluded that few studies reported significant improvements from probiotic supplementation. Alternatively, a more recent meta-analysis of five RCT reported that probiotic supplementation decreased measures of depression (−0·30, 95 % CI −0·51, −0·09; P = 0·005)( 100 ), and an additional systematic review of ten RCT also concluded that probiotics may be beneficial to cognition, mood and anxiety( 101 ). However, few studies included in these reviews were conducted within populations with diagnosed mental illness and the clinical relevance to psychiatry is thus far unclear. Furthermore, all studies noted additional limitations in the literature including uncertainty regarding the optimal duration of intervention, dose and strains of the probiotics( 100 102 ). Future quality intervention studies are required to improve the existing evidence base for probiotic supplementation and to explore the role of dietary manipulation (e.g. pro and prebiotic foods) on mental health. Characterisation of changes in microbial signature and composition and gut permeability in response to diet, and associated changes in mental health and related behaviours are also needed.

NAC is an amino acid-derived glutathione precursor that may modulate glutamatergic and neurotrophic transmission, glutathione production for antioxidant capacity, mitochondrial function and inflammation( 19 ). Recent reviews conclude that, while the present evidence is preliminary, NAC is a promising therapeutic intervention for addiction (e.g. substance dependence, gambling) and bipolar, schizophrenic and depressed populations( 91 , 103 , 104 ). However, while NAC has been investigated in a range of these clinical populations, further RCT are required to confirm these results( 55 ).

Conclusion

Nutritional psychiatry is a rapidly growing field of research that has the potential to provide clinically meaningful interventions to both prevent and manage mental illness. Observational research has demonstrated a consistent relationship between diet quality and common mental illnesses, while biological pathways including inflammation, oxidative stress, gastrointestinal microbiota and neurotrophic factors provide viable mechanisms of action for this observed effect. Preliminary clinical evidence provides support for the feasibility and efficacy of dietary and some nutraceutical interventions. It is likely that changes to public policy are needed to translate these findings into population-wide changes in eating behaviour to achieve associated benefits( 105 ). More research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders, in order to build on the existing evidence base and to inform clinical practice.

Acknowledgements

M. B. is supported by an NHMRC Senior Principal Research Fellowship (1059660). F. J. is supported by an NHMRC Career Development Fellowship (2) (1108125).

Financial Support

None.

Conflicts of Interest

None.

Authorship

W. M. and G. M. contributed equally, with primary responsibility for writing this work. M. B. and F. J. contributed to planning and editing this work.

References

1. Whiteford, HA, Ferrari, AJ, Degenhardt, L et al. (2015) The global burden of mental, neurological and substance use disorders: an analysis from the global burden of disease study 2010. PLoS ONE 10, e0116820.
2. Chisholm, D, Sweeny, K, Sheehan, P et al. (2016) Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry 3, 415424.
3. Olfson, M, Druss, BG & Marcus, SC (2015) Trends in mental health care among children and adolescents. N Engl J Med 372, 20292038.
4. Casacalenda, N, Perry, JC & Looper, K (2002) Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 159, 13541360.
5. Jorm, AF, Patten, SB, Brugha, TS et al. (2017) Has increased provision of treatment reduced the prevalence of common mental disorders? Review of the evidence from four countries. World Psychiatry 16, 9099.
6. Lai, JS, Hiles, S, Bisquera, A et al. (2014) A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults. Am J Clin Nutr 99, 181197.
7. Psaltopoulou, T, Sergentanis, TN, Panagiotakos, DB et al. (2013) Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol 74, 580591.
8. Opie, RS, O'Neil, A, Itsiopoulos, C et al. (2015) The impact of whole-of-diet interventions on depression and anxiety: a systematic review of randomised controlled trials. Public Health Nutr 18, 20472093.
9. O'Neil, A, Quirk, SE, Housden, S et al. (2014) Relationship between diet and mental health in children and adolescents: a systematic review. Am J Public Health 104, e31e42.
10. Jacka, FN, Ystrom, E, Brantsaeter, AL et al. (2013) Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. J Am Acad Child Adolesc Psychiatry 52, 10381047.
11. Pina-Camacho, L, Jensen, SK, Gaysina, D et al. (2015) Maternal depression symptoms, unhealthy diet and child emotional-behavioural dysregulation. Psychol Med 45, 18511860.
12. Steenweg-de Graaff, J, Tiemeier, H, Steegers-Theunissen, RP et al. (2014) Maternal dietary patterns during pregnancy and child internalising and externalising problems. Gener R Study Clin Nutr 33, 115121.
13. Berk, M, Williams, LJ, Jacka, FN et al. (2013) So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 11, 200.
14. Moylan, S, Berk, M, Dean, OM et al. (2014) Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev 45, 4662.
15. Jacka, FN, Cherbuin, N, Anstey, KJ et al. (2015) Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med 13, 215.
16. Slyepchenko, A, Maes, M, Jacka, FN et al. (2017) Gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. Psychother Psychosom 86, 3146.
17. Sarris, J, Murphy, J, Mischoulon, D et al. (2016) Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry 173, 575587.
18. Sarris, J, Schoendorfer, N & Kavanagh, DJ (2009) Major depressive disorder and nutritional medicine: a review of monotherapies and adjuvant treatments. Nutr Rev 67, 125131.
19. Berk, M, Malhi, GS, Gray, LJ et al. (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 34, 167177.
20. Jacka, FN, O'Neil, A, Opie, R et al. (2017) A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Med 15, 23.
21. Zainuddin, MS & Thuret, S (2012) Nutrition, adult hippocampal neurogenesis and mental health. Br Med Bull 103, 89114.
22. Fernandes, BS, Steiner, J, Molendijk, ML et al. (2016) C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry 3, 11471156.
23. Fernandes, BS, Steiner, J, Bernstein, HG et al. (2016) C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry 21, 554564.
24. Estruch, R (2010) Anti-inflammatory effects of the Mediterranean diet: the experience of the PREDIMED study. Proc Nutr Soc 69, 333340.
25. Watzl, B, Kulling, SE, Moseneder, J et al. (2005) A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. Am J Clin Nutr 82, 10521058.
26. Schwingshackl, L & Hoffmann, G (2014) Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis 24, 929939.
27. Dean, OM, van den Buuse, M, Bush, AI et al. (2009) A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Curr Med Chem 16, 29652976.
28. Liu, T, Zhong, S, Liao, X et al. (2015) A meta-analysis of oxidative stress markers in depression. PLoS ONE 10, e0138904.
29. Fernandes, BS, Berk, M, Turck, CW et al. (2014) Decreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative meta-analysis. Mol Psychiatry 19, 750751.
30. Fernandes, BS, Molendijk, ML, Kohler, CA et al. (2015) Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 13, 289.
31. Guimaraes, LR, Jacka, FN, Gama, CS et al. (2008) Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet. Prog Neuropsychopharmacol Biol Psychiatry 32, 15951598.
32. Kawakita, E, Hashimoto, M & Shido, O (2006) Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 139, 991997.
33. Williams, CM, El Mohsen, MA, Vauzour, D et al. (2008) Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med 45, 295305.
34. Wakabayashi, C, Numakawa, T, Ninomiya, M et al. (2012) Behavioral and molecular evidence for psychotropic effects in L-theanine. Psychopharmacology (Berl) 219, 10991109.
35. Cecchini, T, Ciaroni, S, Ferri, P et al. (2003) Alpha-tocopherol, an exogenous factor of adult hippocampal neurogenesis regulation. J Neurosci Res 73, 447455.
36. Molteni, R, Barnard, RJ, Ying, Z et al. (2002) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112, 803814.
37. Martire, SI, Maniam, J, South, T et al. (2014) Extended exposure to a palatable cafeteria diet alters gene expression in brain regions implicated in reward, and withdrawal from this diet alters gene expression in brain regions associated with stress. Behav Brain Res 265, 132141.
38. Fung, TC, Olson, CA & Hsiao, EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20, 145155.
39. Sudo, N, Chida, Y, Aiba, Y et al. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1), 263275.
40. O'Mahony, SM, Clarke, G, Borre, YE et al. (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277, 3248.
41. Hooper, LV, Littman, DR & Macpherson, AJ (2012) Interactions between the microbiota and the immune system. Science (New York, NY) 336, 12681273.
42. Dinan, TG & Cryan, JF (2012) Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37, 13691378.
43. Clarke, G, Grenham, S, Scully, P et al. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18, 666673.
44. O'Mahony, SM, Marchesi, JR, Scully, P et al. (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65, 263267.
45. Kelly, JR, Borre, Y, O'Brien, C et al. (2016) Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 82, 109118.
46. Zheng, P, Zeng, B, Zhou, C et al. (2016) Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol Psychiatry 21, 786796.
47. Bravo, JA, Forsythe, P, Chew, MV et al. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 108, 1605016055.
48. Amar, J, Chabo, C, Waget, A et al. (2011) Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 3, 559572.
49. Dantzer, R, O'Connor, JC, Freund, GG et al. (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9, 4656.
50. Maes, M, Kubera, M, Leunis, JC et al. (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127, 344354.
51. Morris, G, Walder, K, McGee, SL et al. (2017) A model of the mitochondrial basis of bipolar disorder. Neurosci Biobehav Rev 74(Pt A), 120.
52. Morris, G & Berk, M (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13, 68.
53. Wright, DJ, Renoir, T, Smith, ZM et al. (2015) N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease. Transl Psychiatry 5, e492.
54. Maes, M, Fisar, Z, Medina, M et al. (2012) New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates – Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20, 127150.
55. Dean, OM, Turner, A, Malhi, GS et al. (2015) Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Rev Bras Psiquiatr 37, 312.
56. Jacka, FN, Kremer, PJ, Berk, M et al. (2011) A prospective study of diet quality and mental health in adolescents. PLoS ONE 6, e24805.
57. Munoz, MA, Fito, M, Marrugat, J et al. (2009) Adherence to the Mediterranean diet is associated with better mental and physical health. Br J Nutr 101, 18211827.
58. Oellingrath, IM, Svendsen, MV & Hestetun, I (2014) Eating patterns and mental health problems in early adolescence – a cross-sectional study of 12–13-year-old Norwegian schoolchildren. Public Health Nutr 17, 25542562.
59. Jacka, FN, Cherbuin, N, Anstey, KJ et al. (2014) Dietary patterns and depressive symptoms over time: examining the relationships with socioeconomic position, health behaviours and cardiovascular risk. PLoS ONE 9, e87657.
60. Jacka, FN, Cherbuin, N, Anstey, KJ et al. (2015) Does reverse causality explain the relationship between diet and depression? J Affect Disord 175, 248250.
61. Sanchez-Villegas, A, Delgado-Rodriguez, M, Alonso, A et al. (2009) Association of the Mediterranean dietary pattern with the incidence of depression: the Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch Gen Psychiatry 66, 10901098.
62. Quirk, SE, Williams, LJ, O'Neil, A et al. (2013) The association between diet quality, dietary patterns and depression in adults: a systematic review. BMC Psychiatry 13, 175.
63. Rahe, C, Unrath, M & Berger, K (2014) Dietary patterns and the risk of depression in adults: a systematic review of observational studies. Eur J Nutr 53, 9971013.
64. Li, Y, Lv, MR, Wei, YJ et al. (2017) Dietary patterns and depression risk: a meta-analysis. Psychiatry Res 253, 373382.
65. Muhlig, Y, Antel, J, Focker, M et al. (2016) Are bidirectional associations of obesity and depression already apparent in childhood and adolescence as based on high-quality studies? A systematic review. Obes Rev 17, 235249.
66. Sparling, TM, Henschke, N, Nesbitt, RC et al. (2017) The role of diet and nutritional supplementation in perinatal depression: a systematic review. Matern Child Nutr 13, e12235.
67. Baskin, R, Hill, B, Jacka, FN et al. (2015) The association between diet quality and mental health during the perinatal period. A systematic review. Appetite 91, 4147.
68. Martinez-Gonzalez, MA & Sanchez-Villegas, A (2016) Food patterns and the prevention of depression. Proc Nutr Soc 75, 139146.
69. Jacka, FN, Pasco, JA, Mykletun, A et al. (2010) Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry 167, 305311.
70. Nanri, A, Kimura, Y, Matsushita, Y et al. (2010) Dietary patterns and depressive symptoms among Japanese men and women. Eur J Clin Nutr 64, 832839.
71. Jacka, FN, Mykletun, A, Berk, M et al. (2011) The association between habitual diet quality and the common mental disorders in community-dwelling adults: the Hordaland Health Study. Psychosom Med 73, 483490.
72. Jacka, FN (2017) Nutritional psychiatry: where to next? EBio Med 17, 2429.
73. Murakami, K & Sasaki, S (2010) Dietary intake and depressive symptoms: a systematic review of observational studies. Mol Nutr Food Res 54, 471488.
74. Delgado-Lista, J, Perez-Martinez, P, Garcia-Rios, A et al. (2016) CORonary diet intervention with olive oil and cardiovascular PREVention study (the CORDIOPREV study): rationale, methods, and baseline characteristics. Am Heart J 177, 4250.
75. Li, Z, Li, B, Song, X et al. (2017) Dietary zinc and iron intake and risk of depression: a meta-analysis. Psychiatry Res 251, 4147.
76. Li, F, Liu, X & Zhang, D (2016) Fish consumption and risk of depression: a meta-analysis. J Epidemiol Commun Health 70, 299304.
77. Sanchez-Villegas, A, Martinez-Gonzalez, MA, Estruch, R et al. (2013) Mediterranean dietary pattern and depression: the PREDIMED randomized trial. BMC Med 11, 208.
78. Forsyth, A, Deane, FP & Williams, P (2015) A lifestyle intervention for primary care patients with depression and anxiety: a randomised controlled trial. Psychiatry Res 230, 537544.
79. Wu, A, Ying, Z & Gomez-Pinilla, F (2004) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 21, 14571467.
80. Wu, A, Ying, Z & Gomez-Pinilla, F (2004) The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci 19, 16991707.
81. Lim, SY, Kim, EJ, Kim, A et al. (2016) Nutritional factors affecting mental health. Clin Nutr Res 5, 143152.
82. Cui, Y-h & Zheng, Y (2016) A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis Treat 12, 17151723.
83. Appleton, KM, Sallis, HM, Perry, R et al. (2016) ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review. BMJ Open 6, e010172.
84. Sublette, ME, Ellis, SP, Geant, AL et al. (2011) Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 72, 15771584.
85. Sanders, KM, Stuart, AL, Williamson, EJ et al. (2011) Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry 198, 357364.
86. Sarris, J, Mischoulon, D & Schweitzer, I (2011) Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord 13, 454465.
87. Almeida, OP, Ford, AH & Flicker, L (2015) Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr 27, 727737.
88. Gowda, U, Mutowo, MP, Smith, BJ et al. (2015) Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition 31, 421429.
89. Sarris, J, Mischoulon, D & Schweitzer, I (2012) Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry 73, 8186.
90. Grosso, G, Pajak, A, Marventano, S et al. (2014) Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS ONE 9, e96905.
91. Fernandes, BS, Dean, OM, Dodd, S et al. (2016) N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry 77, e457e466.
92. Rucklidge, JJ & Kaplan, BJ (2013) Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review. Expert Rev Neurother 13, 4973.
93. Firth, J, Stubbs, B, Sarris, J et al. (2017) The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychol Med 47, 15151527.
94. Salagre, E, Vizuete, AF, Leite, M et al. (2017) Homocysteine as a peripheral biomarker in bipolar disorder: a meta-analysis. Eur Psychiatry 43, 8191.
95. Deng, W, Cheung, ST, Tsao, SW et al. (2016) Telomerase activity and its association with psychological stress, mental disorders, lifestyle factors and interventions: a systematic review. Psychoneuroendocrinology 64, 150163.
96. Januar, V, Saffery, R & Ryan, J (2015) Epigenetics and depressive disorders: a review of current progress and future directions. Int J Epidemiol 44, 13641387.
97. Cerimele, JM & Katon, WJ (2013) Associations between health risk behaviors and symptoms of schizophrenia and bipolar disorder: a systematic review. Gen Hosp Psychiatry 35, 1622.
98. Anderson, G, Berk, M, Dodd, S et al. (2013) Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42, 14.
99. Nemani, K, Hosseini Ghomi, R, McCormick, B et al. (2015) Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry 56, 155160.
100. Huang, R, Wang, K & Hu, J (2016) Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials. Nutrients 8, e483.
101. Wallace, CJK & Milev, R (2017) The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry 16, 14.
102. Romijn, AR & Rucklidge, JJ (2015) Systematic review of evidence to support the theory of psychobiotics. Nutr Rev 73, 675693.
103. Asevedo, E, Mendes, AC, Berk, M et al. (2014) Systematic review of N-acetylcysteine in the treatment of addictions. Rev Bras Psiquiatr 36, 168175.
104. Deepmala, D, Slattery, J, Kumar, N et al. (2015) Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev 55, 294321.
105. Dash, SR, O'Neil, A & Jacka, FN (2016) Diet and common mental disorders: the imperative to translate evidence into action. Frontiers in Public Health 4, 81.
106. Lakhan, SE & Vieira, KF (2010) Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. Nutr J 9, 42.