Diet and Bipolar Disorder: A Review of Its Relationship and Potential Therapeutic Mechanisms of Action

Abstract

Objectives:

It is well accepted that diet quality has an important role in the prevention and treatment of several physical diseases. However, its influence on mental health has received far less attention, although there is increasing evidence to support a relationship with depression. In this narrative review, investigations into the relationship between diet and bipolar disorder are examined and the potential implications in the management and treatment of bipolar disorder are reviewed.

Methods:

The authors provide a narrative review of the relevant information.

Results:

Research is limited, although there are preliminary findings to suggest a relationship between diet and bipolar disorder. Findings from cross-sectional research suggest that people with bipolar disorder consume an unhealthier dietary pattern. This has significant treatment implications as bipolar disorder has a high comorbidity with several physical diseases. In addition, diet also influences several biological processes that are dysregulated in bipolar disorder, namely monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression.

Conclusions:

The role of diet in bipolar disorder requires further attention in research as it presents as a factor that may contribute to the worsening course of this condition and may potentially enhance current treatment outcomes.

Introduction

The role of diet in physical health is well acknowledged. Dietary quality is associated with the risk of several noncommunicable diseases, including type 2 diabetes, cardiovascular disease, obesity, stroke, hypertension, and several forms of cancer.^1,2 Consequently, dietary changes for the prevention and treatment of these conditions are commonly encouraged. However, in mental health, the role of diet has received far less attention and only recently has interest increased in its relationship to depression. It has been confirmed in recent meta-analyses that better diet quality is associated with a reduced probability or risk of depression.^3
–5 Rahe et al.³ concluded from their meta-analysis that the available literature suggested a protective effect of healthy and Mediterranean dietary patterns on depression, whereas a Western dietary pattern was associated with increased odds of depression. In a meta-analysis by Lai et al.,⁴ it was concluded that a high intake of fruit, vegetables, fish, and whole grains was associated with a reduced depression risk. Another meta-analysis confirmed a relationship between higher adherence to Mediterranean-style dietary patterns and reduced risk for depression, as well as stroke and cognitive impairment.⁵ Unhealthy dietary intakes are also associated with poor mental health in children and adolescents⁶ while even in utero nutritional exposures appear to increase the risk for mental health-related behaviors in children.^7
–9 In a systematic review of randomized controlled studies, there was also evidence that dietary interventions can improve depression outcomes, although due to the paucity of high-quality studies, further research is required and underway.^10,11

Bipolar disorder is highly disabling with a lifetime prevalence of 1% and 4%.¹² It is associated with marked occupational, personal, and social impairment and is accompanied by poor physical health and early mortality. In fact, people with this disorder, on average, die 10–20 years earlier than the general population, with suicide accounting for ∼15% of deaths and cardiovascular disease accounting for roughly 35%–40% of deaths.¹³

Bipolar disorder is a heterogeneous disorder with significant symptom variance within diagnostic subtypes that often varies with illness duration.¹⁴ While the pathophysiology of bipolar disorder remains elusive, studies over the past decade suggest that it is associated with disturbances in several areas. These include alterations in several structural brain regions, neuroendocrine and monoaminergic transmission, immune/inflammatory processes, mitochondrial activity, oxidative stress, and neuroprogression.^15,16 Although genetics plays a significant role in the susceptibility to this illness, several psychological, environmental, and lifestyle factors also appear important. For example, life stressors and trauma (prenatal through to adulthood),^17,18 prenatal and early childhood illness,^19,20 drug and alcohol exposure (prenatal through to adulthood),²¹ personality factors,²² and even nutritional deficiencies comprising omega-3 polyunsaturated fatty acids (PUFAs),²³ and iron²⁴ are postulated to be associated with the development and/or exacerbation of this disease.

Investigation into the role of diet in the etiology of bipolar disorder has received surprisingly scant attention. The purpose of this article is to provide a narrative review of research conducted on diet and bipolar disorder, address the potential impact of diet on bipolar disorder and its several medical comorbidities, and discuss the potential of dietary interventions for bipolar disorder.

A Review of the Relationship Between Diet and Bipolar Disorder

The PubMed, Google Scholar, and PsycInfo databases were searched from all years of record until February 2015, using the terms “diet,” “nutrition,” and “bipolar disorder.” The reference lists of relevant articles were also examined to locate additional studies that were not identified by the database searches. Five studies were identified and are summarized in Table 1. All studies comprised cross-sectional designs and used varying measures to assess diet quality and bipolar severity, thereby making cross-study comparisons difficult.

Table 1.

A Summary of Studies Investigating Diet Quality in Bipolar Disorder

Author	Participants	Study design	Sex; mean age	Dietary measure	Mental health measure	Findings
Elmslie et al.²⁵	89 People with BD and 445 age- and sex-matched comparison group	Cross-sectional	46% Female; 39	24-Hour diet recall and 4-day estimated diet record	Not specified, but reportedly fulfilled DSM-IV diagnostic criteria	BD patients consumed more total carbohydrate, sucrose, nonalcoholic beverages, sweetened drinks, cakes, and sweets; BD women, but not men, consumed a greater total energy intake.
						No control for confounding factors, although age- and sex-matched; 87% of BD group on psychotropic medications.
Noaghiul and Hibbeln²⁶	Epidemiological analysis of adults diagnosed as having BD	Cross-national	NA	Data from National Marine Services and WHO Food and Agriculture Organization	Data from epidemiological studies	Cross-national comparisons revealed greater rates of seafood consumption associated with lower lifetime prevalence of bipolar I disorder, bipolar II disorder, and bipolar spectrum disorder.
						No control for confounding factors or variability in the definition and diagnosis of BD across countries.
Kilbourne et al.²⁷	Veteran's Affairs National Psychosis Registry with a diagnosis of BD (n = 1,945) and those who did not have a serious mental disorder (n = 3,086)	Cross-sectional	10% Female; 55	Dietary-related questions from the Large Health Survey of Veteran Enrollees	Not specified	BD patients more likely to self-report eating only one meal per day, eating alone, and having difficulty obtaining or cooking food; no difference in reported fruit and vegetable intake.
						Several demographic and clinical factors controlled, including gender, age, race/ethnicity, marital status, current employment, smoking, financial strain, substance use disorder, and antipsychotic use.
Jacka et al.²⁹	23 Women with BD and 691 participants with no past or current depressive or anxiety disorders	Cross-sectional	100% Female; 43	Cancer Council Victoria dietary questionnaire (measure of food intake over preceding 12 months)	Structured clinical interview for DSM-IV-TR research version, nonpatient edition	BD patients reported higher energy/kilojoule intake and higher glycemic load; lower traditional food intake (vegetables, fruit, beef, lamb, fish, and wholegrain foods) after adjustment for energy intake; higher modern food intake (fruits and salads, plus fish, tofu, beans, nuts, yoghurt, and red wine), which remained after adjustment for energy intake; higher Western dietary intake (meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), but became nonsignificant after adjustment for energy intake.
						No control for confounding factors, although no difference in groups for BMI, SES, education, physical activity, smoking, or alcohol intake. BD group was younger compared with comparison sample.
Noguchi et al.³¹	75 People with BD treated at a hospital psychiatry clinic in Tokyo	Cross-sectional	33% Female; 37	Brief diet history questionnaire	Himorogi self-rating depression scale; Himorogi self-rating anxiety scale	In BD patients, physical and psychiatric symptoms more pronounced in those reporting an infrequent intake of vegetables, mayonnaise, potatoes, soy products, seaweed, and fish products; physical, psychiatric, and anxiety severity not associated with fish pattern consumption or Western/meat pattern consumption
						Correlations remained significant after adjustment for age, BMI, and sex.

BD, bipolar disorder; BMI, body–mass index; SES, socioeconomic status.

Elmslie et al.²⁵ used a 24-h diet recall and 4-day estimated diet record to compare dietary patterns of people with bipolar disorder (n = 89) with an age- and sex-matched comparison group (n = 445). They found that people with bipolar disorder consumed more total carbohydrate, sucrose, nonalcoholic beverages, sweetened drinks, cakes, and sweets. Women, but not men, also had a greater total energy intake. It is important to note that 87% of the bipolar group was on psychotropic medications, thereby presenting a likely important confounding factor influencing dietary intake.

From cross-national comparisons, Noaghiul and Hibblen²⁶ demonstrated that greater rates of seafood consumption were associated with lower lifetime prevalence rates of bipolar I disorder, bipolar II disorder, and bipolar spectrum disorder. These findings are tempered by the lack of control for confounding variables or variability in the definition and diagnosis of bipolar disorder across countries.

Based on the Veterans Affairs National Psychosis Registry, which includes a register of people diagnosed as having bipolar disorder, Kilbourne et al.²⁷ found that people with bipolar disorder (n = 1,945) were more likely than those with no serious mental disorder (n = 3,086) to report eating only one meal a day, eating alone, and having difficulty obtaining or cooking food. However, there was no difference in reported fruit and vegetable intake, which may reflect the generally low level of intake in the general population.²⁸ Several demographic and clinical factors were controlled for in this study, including gender, age, race/ethnicity, marital status, current employment, smoking, financial strain, substance use disorder, and antipsychotic use.²⁷

A cross-sectional analysis comparing 23 women with bipolar disorder with women with no past or current depressive or anxiety disorders was undertaken by Jacka et al.²⁹ Their findings demonstrated that people with bipolar disorder consumed a higher energy/kilojoule intake and a diet with a higher glycemic load. After statistical adjustment for energy intake, respondents with bipolar disorder also had lower scores on a traditional dietary pattern (i.e., vegetables, fruit, beef, lamb, fish, and wholegrain foods). They also reported higher scores on a Western dietary pattern (i.e., meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), although this relationship became nonsignificant after adjustment for energy intake. Interestingly, bipolar patients also reported a higher intake of modern foods (fruits and salads, plus fish, tofu, beans, nuts, yogurt, and red wine). The authors postulated that this may reflect attempts by people with bipolar disorder to improve symptoms through healthy dietary changes. This behavior has been confirmed by a recent study where previously depressed individuals who had sought professional treatment reported consuming a healthier diet, suggesting that some may attempt to improve their depressive symptoms through dietary modification.³⁰

Finally, Noguchi et al.³¹ found that in people with bipolar disorder attending a psychiatric clinic (n = 75), physical and psychiatric symptoms were more pronounced in those reporting an infrequent intake of vegetables, soy products, seaweed, and fish products. This correlation remained significant after adjustment for age, body–mass index (BMI), and sex. However, they found that physical, psychiatric, and anxiety severities were not associated with fish pattern consumption or a Western/meat dietary pattern.

Findings from this initial research suggest a relationship between diet and bipolar disorder, wherein people with bipolar disorder consume an unhealthier diet and diet quality may influence symptom severity. Unfortunately, studies are scant, comprise only cross-sectional analyses, and most do not adequately control for potential confounding variables. These include medication use, BMI, socioeconomic status (SES), comorbid diseases, and other drug use. At this time, it is therefore unknown whether diet quality has a causative role in bipolar disorder or is simply a lifestyle-based factor associated with this disease. It is possible that sweet and fatty foods are consumed as a food of self-medication; sugar reduces stress-induced cortisol³² as well as being somewhat addictive.³³ Highly powered prospective studies controlling for confounding variables are required to help elucidate the role of diet in bipolar disorder. The use of validated dietary measures on clinically diagnosed bipolar patients using validated diagnostic instruments is also important to help increase the robustness of findings. Analyses examining the most important dietary components (i.e., macro- and micronutrients), dietary patterns (i.e., Western, traditional, Mediterranean), and eating habits (i.e., meal frequency, meal skipping) are also important.

What Is the Potential Significance of Diet in Bipolar Disorder?

Dietary modification to combat medical comorbidity

There is a greater comorbidity of bipolar disorder with several noncommunicable diseases. These include type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity.^34
–36 These diseases are significantly influenced by lifestyle factors, diet quality being of particular importance. Diet quality therefore has relevance in bipolar disorder by contributing to the increased prevalence of these conditions. This increased disease burden is associated with greater medical costs, polypharmacy use, increased hospitalizations, reduced quality of life, and increased risk of early mortality.³⁵ Given the common problem of weight gain associated with psychotropic interventions, diet also has a role in preventing or minimizing this adverse effect. This is especially important as weight gain is a common reason cited for medication noncompliance.³⁷

There is also evidence to suggest that medical comorbidity in bipolar disorder is associated with greater treatment resistance and illness severity. For example, patients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder compared with euglycemic patients.³⁸ A history of weight cycling was also associated with a greater frequency of manic and depressive episodes.³⁹ Medical comorbidity is also concerning as bipolar patients have markedly higher rates of mortality after myocardial infarction⁴⁰ and there is inferior global cognitive ability in bipolar patients with obesity and treated hypertension.⁴¹ Obesity in bipolar disorder is also associated with greater suicidality.⁴²

Dietary modification to normalize dysregulated biological pathways

Bipolar disorder is confirmed to be associated with several biological dysregulations. These include disturbances in monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression.^15,16 As outlined by a selection of studies below, all these biological pathways can be influenced by diet composition and quality.

Monoaminergic activity

In animal studies, the intake of a combination of dietary fat and sugar reduced D₂ receptor signaling,⁴³ and the consumption of a low-protein–high-carbohydrate diet decreased D₂ receptor density.⁴⁴ Fasting and high-sucrose diets also influenced catechol-O-methyltransferase activity.^45,46 Dietary fat intake and a ketogenic diet (very low-carbohydrate, high-fat diet) influenced the expression of glutamic acid decarboxylase and brain gamma-aminobutyric acid (GABA) concentrations.^47,48 Finally, in a human study, hypercaloric high-fat–high-sugar snacking decreased serotonin transporters in the human hypothalamic region.⁴⁹ Interestingly, in an animal study using an unpredicted chronic mild stress (UCMS) model, a high-fat diet regimen prevented the antidepressant, fluoxetine, from abolishing UCMS-induced behavioral changes.⁵⁰

Immune/inflammatory processes

A Mediterranean diet and a greater consumption of fruit and vegetables have regularly been associated with reduced inflammation.^51
–53 In contrast, consuming a Western dietary pattern is commonly associated with increased inflammation as demonstrated by elevated C-reactive protein and interleukin-6.^54,55

Oxidative stress

Markers of oxidative stress such as malondialdehyde (lipid peroxidation) and 8-hydroxy-2′-deoxyguanosine (DNA oxidation) were lowered after the consumption of a Mediterranean diet or increased fish intake.^56,57 Calorie restriction also positively influenced the oxidant/antioxidant balance, particularly through its effects on glutathione concentration.^58,59

Neuroprogression

In a human study, consuming a Mediterranean diet was associated with increased levels of brain-derived neurotrophic factor (BDNF), a neurotrophin that supports the survival, growth, and differentiation of neurons.⁶⁰ There are also extensive data from preclinical studies implicating diet in hippocampal neurogenesis.⁶¹ In an animal study, caloric restriction increased BDNF concentrations,⁶² whereas a high-fat diet lowered BDNF expression.^63,64 Consuming a high-fat diet also decreased the quantity of newly generated cells in the dentate gyrus of the hippocampus.⁶³ Zainuddin and Thuret⁶¹ have reviewed findings demonstrating that adult hippocampal neurogenesis is influenced by caloric intake, meal frequency, food texture, and meal composition (e.g., sugar, fat, omega-3 PUFAs, zinc, and polyphenols such as curcumin and resveratrol).

Mitochondrial activity

Compared with rats on a calorie-restricted diet, mitochondrial efficiency and oxidative damage in skeletal muscle were significantly increased, while antioxidant defense was significantly lowered in food-restricted rats fed a high-fat diet.⁶⁵ A ketogenic diet upregulated mitochondrial antioxidant status and protected mitochondrial DNA from oxidant-induced damage.⁶⁶

Despite evidence through animal and a selection of human studies that diet can influence the above-mentioned biological processes, its effects in patients with bipolar disorder are currently unknown. Whether dietary changes can normalize such dysregulations in a clinical sample requires investigation. Furthermore, its relevance to symptomatic change also needs to be investigated as it is currently unknown whether normalization in these pathways is necessary for clinical improvement. To the authors' knowledge, there is only one study, currently underway, investigating dietary improvement as a treatment strategy for mood disorders.¹¹ This study may throw light on this question.

Conclusion and Directions for Future Research

Investigations into the role of diet in bipolar disorder are still in their infancy. Although the impact of diet on physical health is well acknowledged, its role in mental disorders has received far less attention. As demonstrated from this review, diet has potentially significant implications for the treatment of bipolar disorder. At the very least, it has a role in the management and prevention of several highly comorbid physical diseases, including type 2 diabetes, metabolic syndrome, obesity, and cardiovascular disease. Moreover, it theoretically has a role in the prevention and treatment of bipolar disorder, although further research is required. Because diet can influence several biological pathways that are regularly dysregulated in bipolar disorder, it presents as a natural intervention that can help normalize these disturbances. However, as discussed above, it remains to be determined whether normalization in these pathways is necessary for symptomatic improvement in bipolar disorder.

Highly powered prospective studies adequately controlling for important confounding variables such as BMI, SES, medication use, and medical comorbidity are necessary to enhance the understanding of the role of diet in bipolar disorder. Currently, studies have only comprised cross-sectional designs, thereby preventing conclusions about the causative influence of diet on the development and exacerbation of bipolar symptoms. In addition, an examination of dietary interventions on bipolar disorder is also needed. As an adjunct to pharmacological and psychological interventions, it has the potential to enhance treatment efficacy.

Although research on single nutrient therapies has not been covered in this review, its influence on disturbed biological pathways in bipolar disorder and the enhancement of treatment efficacy in conjunction with whole-of-diet interventions also merits consideration. Promising findings have been demonstrated for the use of omega-3 PUFAs, n-acetyl cysteine, magnesium, and folic acid in bipolar disorder.^67,68 There have also been positive results for a proprietary multinutrient formula in several open-label studies.⁶⁹ However, most studies are poorly designed and contain small sample sizes. Deficiencies in such nutrients and in insufficiency resulting from genetic polymorphisms can influence several of the previously mentioned biological pathways^70,71 and require further investigation.

Ongoing research into the relationship between diet and bipolar disorder is urgently needed. To date, no study has yet been conducted examining the potential of whole-of-diet interventions for this disorder. This is concerning as diet has proven to be an important component for the enhancement of physical health, but its role in mental health, along with other lifestyle factors such as exercise, requires greater attention in research.

Authors' Contributions

A.L.L. conducted a literature search and wrote the first draft of this manuscript. F.N.J. reviewed the manuscript and provided feedback, corrections, and recommendations on further drafts of this manuscript. All authors contributed to and have approved the final manuscript.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Willett

, Koplan

, Nugent

, et al. Prevention of chronic disease by means of diet and lifestyle changes. In: Jamison

, Breman

, Measham

, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: The World Bank Group, 2006.

Rees

, Dyakova

, Wilson

, et al. Dietary advice for reducing cardiovascular risk. Cochrane Database Syst Rev, 2013; 12:CD002128.

Rahe

, Unrath

, Berger

. Dietary patterns and the risk of depression in adults: A systematic review of observational studies. Eur J Nutri, 2014; 53:997–1013.

Lai

, Hiles

, Bisquera

, et al. A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults. Am J Clin Nutr, 2014; 99:181–197.

Psaltopoulou

, Sergentanis

, Panagiotakos

, et al. Mediterranean diet, stroke, cognitive impairment, and depression: A meta-analysis. Ann Neurol, 2013; 74:580–591.

O'Neil

, Quirk

, Housden

, et al. Relationship between diet and mental health in children and adolescents: A systematic review. Am J Public Health, 2014; 104:e31–e42.

Jacka

, Ystrom

, Brantsaeter

, et al. Maternal and early postnatal nutrition and mental health of offspring by age 5 years: A prospective cohort study. J Am Acad Child Adolesc Psychiatry, 2013; 52:1038–1047.

Steenweg-de Graaff

, Tiemeier

, Steegers-Theunissen

, et al. Maternal dietary patterns during pregnancy and child internalising and externalising problems. The Generation R Study. Clin Nutr, 2014; 33:115–121.

Pina-Camacho

, Jensen

, Gaysina

, Barker

. Maternal depression symptoms, unhealthy diet and child emotional-behavioural dysregulation. Psychol Med, 2015; 45:1851–1860.

10.

Opie

, O'Neil

, Itsiopoulos

, Jacka

. The impact of whole-of-diet interventions on depression and anxiety: A systematic review of randomised controlled trials. Public Health Nutr, 2015; 18:2074–2093.

11.

O'Neil

, Berk

, Itsiopoulos

, et al. A randomised, controlled trial of a dietary intervention for adults with major depression (the “SMILES” trial): Study protocol. BMC Psychiatry, 2013; 13:114.

12.

Miller

, Dell'Osso

, Ketter

. The prevalence and burden of bipolar depression. J Affect Disord, 2014; 169 (Suppl 1):S3–S11.

13.

Miller

, Bauer

. Excess mortality in bipolar disorders. Curr Psychiatry Rep, 2014; 16:499.

14.

Berk

, Berk

, Dodd

, et al. Stage managing bipolar disorder. Bipolar Disord, 2014; 16:471–477.

15.

Maletic

, Raison

. Integrated neurobiology of bipolar disorder. Front Psychiatry, 2014; 5:98.

16.

Berk

, Kapczinski

, Andreazza

, et al. Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev, 2011; 35:804–817.

17.

Daruy-Filho

, Brietzke

, Lafer

, Grassi-Oliveira

. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand, 2011; 124:427–434.

18.

O'Hare

, Sherrer

. Lifetime trauma, subjective distress, substance use, and PTSD symptoms in people with severe mental illness: Comparisons among four diagnostic groups. Community Ment Health J, 2013; 49:728–732.

19.

Canetta

, Bao

, Co

, et al. Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. Am J Psychiatry, 2014; 171:557–563.

20.

Parboosing

, Bao

, Shen

, et al. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry, 2013; 70:677–685.

21.

Talati

, Bao

, Kaufman

, et al. Maternal smoking during pregnancy and bipolar disorder in offspring. Am J Psychiatry, 2013; 170:1178–1185.

22.

Stange

, Adams

, O'Garro-Moore

, et al. Extreme cognitions in bipolar spectrum disorders: Associations with personality disorder characteristics and risk for episode recurrence. Behav Ther, 2015; 46:242–256.

23.

Balanza-Martinez

, Fries

, Colpo

, et al. Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Rev Neurother, 2011; 11:1029–1047.

24.

Chen

, Su

, Chen

, et al. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: A nationwide population-based study. BMC Psychiatry, 2013; 13:161.

25.

Elmslie

, Mann

, Silverstone

, et al. Determinants of overweight and obesity in patients with bipolar disorder. J Clin Psychiatry, 2001; 62:486–491; quiz 492–483.

26.

Noaghiul

, Hibbeln

. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry, 2003; 160:2222–2227.

27.

Kilbourne

, Rofey

, McCarthy

, et al. Nutrition and exercise behavior among patients with bipolar disorder. Bipolar Disord, 2007; 9:443–452.

28.

Bowman

, Friday

, Thoerig

, et al. Americans consume less added sugars and solid fats and consume more whole grains and oils: Changes from 2003–2004. FASEB J, 2014; 28:369.

29.

Jacka

, Pasco

, Mykletun

, et al. Diet quality in bipolar disorder in a population-based sample of women. J Affect Disord, 2011; 129:332–337.

30.

Jacka

, Cherbuin

, Anstey

, Butterworth

. Does reverse causality explain the relationship between diet and depression?. J Affect Disord, 2015; 175C:248–250.

31.

Noguchi

, Hiraoka

, Watanabe

, Kagawa

. Relationship between dietary patterns and depressive symptoms: Difference by gender, and unipolar and bipolar depression. J Nutr Sci Vitaminol (Tokyo), 2013; 59:115–122.

32.

Tryon

, Stanhope

, Epel

, et al. Excessive sugar consumption may be a difficult habit to break: A view from the brain and body. J Clin Endocrinol Metab, 2015:jc20144353.

33.

Avena

, Rada

, Hoebel

. Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev, 2008; 32:20–39.

34.

Perugi

, Quaranta

, Belletti

, et al. General medical conditions in 347 bipolar disorder patients: Clinical correlates of metabolic and autoimmune-allergic diseases. J Affect Disord, 2015; 170:95–103.

35.

Sylvia

, Shelton

, Kemp

, et al. Medical burden in bipolar disorder: Findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE). Bipolar Disord, 2015; 17:212–223.

36.

Gomes

, Almeida

, Magalhaes

, et al. Cardiovascular risk factors in outpatients with bipolar disorder: A report from the Brazilian Research Network in Bipolar Disorder. Rev Bras Psiquiatr, 2013; 35:126–130.

37.

Velligan

, Weiden

, Sajatovic

, et al. The expert consensus guideline series: Adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry, 2009; 70 (Suppl 4):1–46; quiz 47–48.

38.

Calkin

, Ruzickova

, Uher

, et al. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry, 2015; 206:52–57.

39.

Reininghaus

, Lackner

, Fellendorf

, et al. Weight cycling in bipolar disorder. J Affect Disord, 2015; 171:33–38.

40.

Boden

, Molin

, Jernberg

, et al. Higher mortality after myocardial infarction in patients with severe mental illness: A nationwide cohort study. J Intern Med, 2015; 277:727–736.

41.

Depp

, Strassnig

, Mausbach

, et al. Association of obesity and treated hypertension and diabetes with cognitive ability in bipolar disorder and schizophrenia. Bipolar Disord, 2014; 16:422–431.

42.

Gomes

, Kauer-Sant'Anna

, Magalhaes

, et al. Obesity is associated with previous suicide attempts in bipolar disorder. Acta Neuropsychiatrica, 2010; 22:63–67.

43.

Pritchett

, Hajnal

. Obesogenic diets may differentially alter dopamine control of sucrose and fructose intake in rats. Physiol Behav, 2011; 104:111–116.

44.

Hamdi

, Onaivi

, Prasad

. A low protein-high carbohydrate diet decreases D2 dopamine receptor density in rat brain. Life Sci, 1992; 50:1529–1534.

45.

Busserolles

, Zimowska

, Rock

, et al. Rats fed a high sucrose diet have altered heart antioxidant enzyme activity and gene expression. Life Sci, 2002; 71:1303–1312.

46.

Vujovic

, Stamenkovic

, Jasnic

, et al. Fasting induced cytoplasmic Fto expression in some neurons of rat hypothalamus. PLoS One, 2013; 8:e63694.

47.

Fisler

, Shimizu

, Bray

. Brain 3-hydroxybutyrate, glutamate, and GABA in a rat model of dietary obesity. Physiol Behav, 1989; 45:571–577.

48.

Cheng

, Hicks

, Wang

, et al. Caloric restriction augments brain glutamic acid decarboxylase-65 and −67 expression. J Neurosci Res, 2004; 77:270–276.

49.

Koopman

, Booij

, Fliers

, et al. Diet-induced changes in the Lean Brain: Hypercaloric high-fat-high-sugar snacking decreases serotonin transporters in the human hypothalamic region. Mol Metab, 2013; 2:417–422.

50.

Isingrini

, Camus

, Le Guisquet

, et al. Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: A model of fluoxetine resistance in mice. PLoS One, 2010; 5:e10404.

51.

Chrysohoou

, Panagiotakos

, Pitsavos

, et al. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol, 2004; 44:152–158.

52.

Holt

, Steffen

, Moran

, et al. Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J Am Diet Assoc, 2009; 109:414–421.

53.

Barbaresko

, Koch

, Schulze

, Nothlings

. Dietary pattern analysis and biomarkers of low-grade inflammation: A systematic literature review. Nutr Rev, 2013; 71:511–527.

54.

Esmaillzadeh

, Kimiagar

, Mehrabi

, et al. Dietary patterns and markers of systemic inflammation among Iranian women. J Nutr, 2007; 137:992–998.

55.

Nettleton

, Steffen

, Mayer-Davis

, et al. Dietary patterns are associated with biochemical markers of inflammation and endothelial activation in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr, 2006; 83:1369–1379.

56.

Fito

, Guxens

, Corella

, et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: A randomized controlled trial. Arch Intern Med, 2007; 167:1195–1203.

57.

Mitjavila

, Fandos

, Salas-Salvado

, et al. The Mediterranean diet improves the systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled, trial. Clin Nutr, 2013; 32:172–178.

58.

Kawahara

, Maues

, dos Santos

, et al. Energy restriction and impact on indirect calorimetry and oxidative stress in cardiac tissue in rat. Indian J Biochem Biophys, 2014; 51:365–371.

59.

Walsh

, Shi

, Van Remmen

. The effects of dietary restriction on oxidative stress in rodents. Free Radic Biol Med, 2014; 66:88–99.

60.

Sanchez-Villegas

, Galbete

, Martinez-Gonzalez

, et al. The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: The PREDIMED-NAVARRA randomized trial. Nutr Neurosci, 2011; 14:195–201.

61.

Zainuddin

, Thuret

. Nutrition, adult hippocampal neurogenesis and mental health. Br Med Bull, 2012; 103:89–114.

62.

Kishi

, Hirooka

, Nagayama

, et al. Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor. Int Heart J, 2015; 56:110–115.

63.

Park

, Park

, Choi

, et al. A high-fat diet impairs neurogenesis: Involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett, 2010; 482:235–239.

64.

Liu

, Zhu

, Kalyani

, et al. Effects of energy status and diet on Bdnf expression in the ventromedial hypothalamus of male and female rats. Physiol Behav, 2014; 130:99–107.

65.

Crescenzo

, Bianco

, Coppola

, et al. Caloric restriction followed by high fat feeding predisposes to oxidative stress in skeletal muscle mitochondria. Horm Metab Res, 2013; 45:874–879.

66.

Jarrett

, Milder

, Liang

, Patel

. The ketogenic diet increases mitochondrial glutathione levels. J Neurochem, 2008; 106:1044–1051.

67.

Sarris

, Mischoulon

, Schweitzer

. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: A systematic review of clinical trials. Bipolar Disord, 2011; 13:454–465.

68.

Rakofsky

, Dunlop

. Review of nutritional supplements for the treatment of bipolar depression. Depress Anxiety, 2014; 31:379–390.

69.

Rucklidge

, Kaplan

. Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: A systematic review. Expert Rev Neurother, 2013; 13:49–73.

70.

Ames

, Elson-Schwab

, Silver

. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): Relevance to genetic disease and polymorphisms. Am J Clin Nutr, 2002; 75:616–658.

71.

, Zhu

, Bao

, et al. The role of nutrients in protecting mitochondrial function and neurotransmitter signaling: implications for the treatment of depression, PTSD, and suicidal behaviors. Crit Rev Food Sci Nutr, 2014. [Epub ahead of print]