Navigation Menu

Depression – Putting the 5-piece Puzzle Together

Author: Jian Gao, PhD

Editor: Mr. Frederick Malphurs

October 06, 2024

Disclaimer: This article is informational/educational only and should not be used as a substitute for medical advice from your doctors. The sole purpose of this article is to provide science-based information/evidence that you can use to communicate with your doctors to reach the desired outcomes.  

The Big Picture

If you or your loved ones are diagnosed with depression, you are not alone. The prevalence of depression has skyrocketed over the past decades. Unfortunately, the prevailing drug-centered treatment masking the symptoms without addressing the root causes can do more harm than good. History will show focusing on the symptoms rather than the root causes of depression and other mental health disorders is one of the greatest tragedies in modern medicine.

First, what is depression? To date, there are no objective criteria or biomarkers separating low mood (sadness, loneliness, low self-esteem, anxiety, negative rumination etc. due to adverse life events/experiences) from clinical or major depression. Is depression a disorder of the mind (psychological) or the brain (biological)?

To understand depression, it is instructive to see the mind as software and the brain as the hardware of a computer. According to Wikipedia, “the mind is what thinks, feels, perceives, imagines, remembers, and wills, encompassing the totality of mental phenomena.” On the other hand, the brain is a tangible organ. Software runs on hardware.

For the sake of healing depression by addressing the underlying causes, let’s regard low mood as a software problem involving how we think, and depression as a hardware problem involving physical changes such as shrinkage of certain brain regions (e.g., hippocampus, amygdala, and prefrontal cortex) and dysregulation of neurotransmitters (e.g., serotonin, dopamine, and norepinephrine). This computer analogy is by no means scientific, but it can help us conceptualize the problem.

Persistent low mood can cause depression (brain changes), just like malfunctioning software keeping the computer hardware continuously running can overheat and even burn the cooling fans, circuits, or CPU. Conversely, depression (brain changes due to, say, malnutrition or exposure to toxic chemicals) can cause persistent low mood, just like broken hardware can affect the function of the software. In essence, persistent low mood (software) and depression (hardware) are different problems, but their relationship can be reciprocal.

Now, the multi-billion-dollar question is, apart from low mood, what can cause depression?

Despite the poor understanding of depression, one thing is clear: The development of depression is not due to lack of antidepressants in the head. And antidepressants do not fix the root causes of depression either. Worse still, studies have consistently shown antidepressants are not much better than placebos (water pills),1 and the side effects can be unthinkable – “Antidepressants increase the risk of suicide, violence and homicide at all ages.”2

Understanding antidepressants is paramount before starting to take them. There are several scholarly written books that are truly enlightening: Unhinged by Daniel Carlat,3 MD, a well-known practicing psychiatrist, Medical Director of Inpatient Psychiatry/Chairman of Psychiatry at Melrose Wakefield Healthcare. Mad in America by Robert Whitaker,4 an award-winning journalist. And The Emperor’s New Drugs – Exploring the Antidepressant Myth by Dr. Irving Kirsch,5 an internationally recognized psychologist and mental health researcher.

There is no shortcut – “Depression is not caused by a chemical imbalance in the brain, and it is not cured by medication.”5 To heal depression, the first and most important step is to figure out what causes it – no disorders will go away unless the root causes are addressed.

Identifying and managing the underlying causes can be overwhelming. But with the right approach, It is doable. In most if not all cases, depression is a five-piece puzzle: (1) genetics, (2) stress (low mood), (3) toxic chemicals, (4) gut, and (5) nutrition.

The Root Causes

1. Genetics

That depression can run in the family is well known. Statistics show the risk of developing depression is higher if a family member(s) has it. But that does not mean depression is a genetic disease. It is true some are more likely to experience depression than others due to genetic variation (genetic predisposition). However, despite all the advances in DNA sequencing, no depression gene has ever been found,6-8 which clearly tells us no one has to suffer from depression because of his/her genetic makeup.

Of course, genetic variations are not totally irrelevant. For instance, GSTM1 deletion could reduce the enzyme used in the liver for detoxification, and MTHFR 677TT genotype can interfere with folate (vitamin B9) absorption/metabolism, which could contribute to depression. However, the effects of these mutations can be corrected by avoiding toxic chemicals and/or consuming more folate rich food. Bear in mind, vast majority of people with these mutations do not get depression.

Do not blame your genes – in fact, except for rare mutations, most of the genetic variations are normal and essential for the human race to survive. If we all had the same genes, human beings would have been wiped out long ago by one virus or plague – if there were no genetic variations, there would have been no evolution (natural selection) because there would be nothing to select on.

Still, you might wonder why does it run in the family? Well, family members are more likely to have the same life experiences, to learn the same coping skills, to eat the same food, and to live in the same environment. Genes are not your destiny – again, there is no such a gene whereby a carrier would have to suffer from depression.  

2. Stress

What is stress? According to WHO (World Health Organization), “Stress can be defined as a state of worry or mental tension caused by a difficult situation. Stress is a natural human response that prompts us to address challenges and threats in our lives.”  

Stress can energize us to fight off threats, but chronic stress is a health killer – it affects every system in our body and contributes to almost every disease.9-12 In particular, stress disrupts the nerve system (causing anxiety), the digestive system (dysbiosis or pathogenic bacteria overgrowth producing neurotoxin, and leaky gut allowing toxins getting into the blood stream and brain), the endocrinal system (causing hormone imbalance), and gene expression (altering the normal synthesis of hormones, enzymes, neurotransmitters etc.), which directly or indirectly induces low mood and/or depression.13-15

Many things in life, such as adverse life events or experiences (even during childhood), rocky relationships, financial difficulties, uncertainty about the future, needing to be perfect, all of which are called stressors and can create stress. We can take proactive measures to avoid stressors, but nobody can prevent them all or even anticipate them all. When stressors are unavoidable, coping skills can make a huge difference. For instance, some manage financial difficulties well while others do not. If stress plays a role in your depression, consult with a psychologist who can coach you to learn and use effective coping silks.  

Psychotherapy, also called talk therapy, has over 200 years of track record in healing depression and even more severe mental disorders. The earliest psychotherapy, part of the moral treatment, was introduced to asylums in Philadelphia by Quakers from England in 1817. Before the introduction of moral treatment, patients in mental hospitals or asylums were routinely beaten up or chained. Their conditions were typically getting worse rather than better. In contrast, moral treatment (psychotherapy) was reportedly to have resulted in more than half of the patients recovered and discharged.4    

Of course, psychotherapy is not a cure-all – it cannot help those suffering depression triggered by other factors such as toxic chemicals or nutrient deficiency.  

3. Toxic Chemicals

Studies have consistently and clearly shown environmental chemicals contaminating our food, drinking water, air, and personal care products can directly or indirectly induce depression through various mechanisms:16-23

  • Chemicals such as phthalates, BPA (bisphenol A), and certain pesticides such as glyphosate (Roundup) and DDT (banned decades ago but still in the environment) are known endocrine disruptors. They can interfere with the hormone system affecting mood regulation and contributing to depression.
  • Many toxic chemicals such as VOCs (volatile organic compounds) and heavy metals like lead and mercury can interfere with neurotransmitters such as serotonin, dopamine, and norepinephrine by altering their synthesis, release, and reuptake, which play crucial roles in mood regulation.
  • We are often told by the experts that toxic chemicals can trigger inflammatory responses in the brain, which damages brain cells. What really happens is these toxic chemicals trigger the immune system to produce chemicals like antibodies and cytokines to quell the enemies, but they often cause collateral damage in the brain.   
  • Some chemicals (e.g., lead, mercury, cadmium, ethanol, benzene, nitrogen dioxide, DDT, and glyphosate) have direct toxic effects on brain cells. They can impair neuronal function, damage nerve cells, and disrupt neural circuits involved in mood regulation, contributing to the development of depression.
  • Toxic chemicals can also alter gene expression through epigenetic mechanisms. These changes can disrupt the balances of hormones and/or neurotransmitters, affecting stress response, mood regulation, and brain function.

In addition to the manmade chemicals and natural heavy metals such as lead and mercury, toxic chemicals produced by mold in damp homes or offices can also poison the brain and contribute to depression.24,25 Furthermore, food intolerance such as gluten/dairy sensitivity can be a problem too as will be discussed below. Tragically, these invaluable life-saving findings have been largely ignored by the mental health establishment.  

4. Gut

Dysbiosis

Gut dysbiosis is an imbalance of microbiome living in the digestive tract (mainly bacteria, but also include viruses, fungi, and other microbes). Dysbiosis is particularly dangerous when there is an overgrowth of harmful bacteria producing neurotoxins hurting the brain. Dysbiosis can induce depression via different pathways:26-35

  • Dysbiosis can disrupt the production of many neurotransmitters, which plays an important role in depression development. Over 90% of the body’s serotonin and 50% of dopamine are produced in the gut; and substantial amounts of other neurotransmitters such as GABA (Gamma-Aminobutyric Acid), norepinephrine, acetylcholine, histamine are also synthesized in the gut. The synthesis of these neurotransmitters is modulated by SCFAs (short-chain fatty acids) like acetate, propionate, and butyrate, which are produced by gut bacteria fermenting dietary fiber. In fact, bacteria can also directly produce these neurotransmitters.36
  • Overgrowing pathogenic organisms in the gut can produce neurotoxins affecting brain cells directly. An enlightening case in point is auto-brewery syndrome (ABS), also known as gut fermentation syndrome, where overgrowth of yeast (e.g., saccharomyces cerevisiae) in the gut ferments carbohydrates into ethanol. ABS can be so severe that some individuals were arrested for drunk driving without drinking a drop of alcohol.37-39
  • Studies have demonstrated the metabolites (e.g., indole and its derivatives) produced by harmful bacteria can provoke the immune system to produce certain cytokines and antibodies damaging brain cells, which is commonly referred to as chronic inflammation. Some fragments of dead bacteria such as lipopolysaccharides (LPS) have the same harmful effects.26,31
  • Dysbiosis can also induce intestinal permeability, known as leaky gut,40,41 allowing pathogens, toxins, and large molecules pass the lining of the intestines and get into the blood stream, which provoke the immune system to mistakenly attack healthy tissues or organs including the brain.

The observation that dysbiosis can cause depression and other mental disorders is not new. In fact, surgical removal of colon and other body parts to eliminate bad bacteria (dysbiosis) was a common practice in America until early 1940s before the wide use of antibiotics. The leading proponent of this practice was Dr. Henry Cotton, the medical director of the largest mental hospital in America, the New Jersey State Hospital at Trenton.

Cotton and his staff performed surgeries on thousands of patients to remove the infected body parts (e.g., teeth and colon) and claimed great success in curing patients.42 The practice came to an end after Cotton got caught falsifying outcome data – the effectiveness of the surgeries was much lower that he claimed. Cotton fell from grace and unfortunately the concept of dysbiosis was also buried with his fame for nearly 80 years.

The concept and gravity of dysbiosis was rediscovered about two decades ago first by alternative medicine practitioners and then by researchers. For instance, doctors practicing functional medicine would test for candida and other bad germ overgrowth in treating almost every chronic disease. Research on this topic is very active too – a quick search on PubMed with key words “gut microbiota” shows nearly 44,000 published articles.

Worth noting is the relationship between dysbiosis and depression is likely reciprocal or bidirectional – at least, we know depression can cause stress, and stress in turn can induce dysbiosis.43  

In any event, the observation that dysbiosis can induce depression is substantiated by the fact that many patients suffering from depression and other mental disorders are healed by using probiotics, prebiotics, synbiotics, postbiotics, or fecal microbiota transplantation to treat dysbiosis.26,44 Of course, not everyone’s depression is caused by dysbiosis or cured by treating it.

Leaky Gut

Leaky gut, also known as intestinal permeability, happens when the millions of small doors (called tight junctions) of the intestinal lining are jammed open for an extended period of time, allowing bacteria and other toxins to pass through the lining and enter into the blood stream where the immune system is on guard 24/7.

Let alone bacteria and toxins, even protein molecules from food are seen as invaders by the immune system that only recognizes amino acids and certain small peptides as food (our digest system breaks proteins down into amino acids or some amino acid groups called peptides). When the immune system sees enemies coming, it mounts attacks. Unfortunately, our immune system is not perfect – it can be tricked by enemies into attacking healthy tissues including the brain.

One of the most potent invaders that can pass the compromised intestinal lining and spook the immune system is LPS (Lipopolysaccharides). LPS, mainly composed of fat and sugar, is a major structural component of the outer membrane or cell walls of Gram-negative bacteria (a class of bacteria not retaining the crystal violet stain used in the Gram staining method of bacterial differentiation).

When Gram-negative bacteria die and their cell walls break down, LPS is released into the digestive system. Upon getting into the blood stream through the compromised intestinal lining, LPS induces violent immune responses. In animal models, it has been demonstrated LPS provokes neuroinflammation, causes cognitive impairment, raises the level of beta-amyloid (a hallmark of Alzheimer’s disease), and decreases the production of BDNF (brain derived neurotrophic factor) that in turn affects neuroplasticity (ability to adapt and form new neural connections), neuronal survival, neurogenesis (generating new neurons), and mood regulation (low levels of BDNF is associated with mood disorders like depression and anxiety).45-48

Given that up to 75% of the microbiota in human gut are Gram-negative and constantly dividing and dying, a leaky gut for an extended period spells nothing but trouble. And LSP is not the only troublemaker out there – countless other substances (even protein molecules from food), once getting into the blood stream, can confuse the immune system which in turn mistakenly starts to attack the brain. Indeed, studies have clearly demonstrated leaky gut can lead to depression.49-54

The concept of leaky gut is relatively new. Although alternative medicine practitioners started to address leaky gut for variety of diseases for over two decades, the medical establishment has so far refused to recognize the problem. The good news is the medical establishment’s attitude towards leaky gut has been changing from angrily denouncing it as pseudoscience to pretending to not see it.

For starters, the lining of the small intestine is composed of two layers: the intestinal epithelium and the mucus layer which is on top of but not attached to the epithelium. The epithelium is a single cell layer which, of course, is very thin. Amazingly, these cells are not the same – there are at least seven types of cells (together called epithelial cells), and each type of cells performs different functions.55 For example, enterocytes, the most abundant epithelial cells in both the small and large intestines, not only absorb nutrition but also secrete a variety of antimicrobial proteins that directly attack and kill harmful bacteria. Even more amazingly, all the epithelial cells have a very short lifespan – they are renewed every 3-5 days.

All the epithelial cells are linked together by the molecules called tight junctions (consisting of at least 35 different proteins), which forms a membrane only allowing tiny particles to pass through when it works properly.56 The breakthrough in understanding leaky gut came just a little over two decades ago when the now renowned pediatric gastroenterologist Dr. Alessio Fasano and his team discovered that these tight junctions, like billions of tiny doors, can open and close in minutes.

Not only did Dr. Fasano find the tiny doors can be opened and closed, but also spotted the doorman with a master key to the doors, a protein called zonulin in our body regulating the movement of these doors. When our body releases zonulin, all the mini doors are opened. Probably this is a nature-given defense mechanism; for instance, when sensing E coli have invaded the digestive system, our body releases zonulin to open the mini-doors so that fluid from inside our body can rush into the intestines and wash away the bacteria. That’s why and how diarrhea happens.

However, this defensive mechanism has glitches – Dr. Fasano and his team have demonstrated gluten can stimulate the release of zonulin opening the mini-doors,57 and these mini-doors are not one-way streets – the bad guys taking advantage of the open-door policy can get into the blood stream and confuse the immune system. So, for the genetically predisposed individuals, the mini doors can be jammed open for too long and a chain reaction ensues: gluten → zonulin → leaky gut → confused immune system → maladies of all kinds including depression.58-61

Unfortunately, gluten and bacteria are not the only triggers out there. Some medications, especially NSAIDs (Nonsteroidal anti-inflammatory drugs) such as ibuprofen and aspirin can induce leaky gut within 12–24 hours.62,63 In addition, although the evidence on humans is not definitive, lab and animal models have clearly demonstrated psychological stress can cause leaky gut too.64

5. Nutrition 

Despite the fact that nutrition plays a significant role in depression development, severity, and treatment, it has been largely overlooked. Our nutrition status is not as good as we think, especially when it comes to micronutrients (minerals, vitamins, and polyphenols).

In a 2017 press release, the CDC reported “Only 1 in 10 Adults Get Enough Fruits or Vegetables.”65 The problem is compounded by the decline of micronutrients in vegetables, fruits, and grains. Soil has been depleted of micronutrients due to intensive farming with chemical fertilizers.66-68 For instance, a recent study shows a 49.1% decrease of copper, 50.2% of iron, 51.7% of sodium, and 9.7% of magnesium in fruit and vegetables in the UK from 1940 to 2019.66

Consequently, the micronutrition status is troubling. NHANES (National Health and Nutrition Examination Survey) revealed a high prevalence of inadequacies for multiple micronutrients.69 For instance, 94.3% of the population do not meet the daily requirement for vitamin D, 88.5% for vitamin E, 52.2% for magnesium, 44.1% for calcium, 43.0% for vitamin A, and 38.9% for vitamin C.

Yet, these micronutrients are essential for our brain to function properly. They are indispensable for the production and regulation of neurotransmitters like serotonin, dopamine, and norepinephrine, which play a key role in mood regulation.70,71 And studies have consistently shown micronutrient deficiency or insufficiency is associated with the development, severity, and recovery of depression.72-80 Although all the vitamins and essential minerals are needed for good mental health, vitamin D and the various vitamin B’s merit special attention.  

Studies including randomized controlled trials and prospective analyses have convincingly demonstrated the serum vitamin D level in the individuals suffering from depression is lower, and more importantly, vitamin D supplementation significantly improves depressive symptoms.81-89 Unfortunately, vitamin D deficiency and insufficiency, which are easy to fix, are still wide spread.

The link between folate (vitamin B9) deficiency and depression was discovered 62 years ago in 1962 by Dr. Victor Herbert (1927-2002) who heroically placed himself on a folate deficiency diet for four months, which resulted in depressive symptoms. After folate replenishment, all the depressive symptoms were resolved.90 The self-sacrificing experiment clearly demonstrated a causal relationship between folate deficiency and depression development. Be aware that, in real life, folate deficiency is not necessarily due to poor diet. Many other factors can contribute to the deficiency. For instance, some medications (e.g., anticonvulsants, contraceptives, certain chemotherapies), chronic diseases such as autoimmune disorders (e.g., rheumatoid arthritis), malabsorption syndrome, and genetic variability (e.g., MTHFR 677TT genotype) can either interfere with folate absorption/metabolism or increase its excretion.91

Other vitamin B’s essential for neuronal function are vitamin B1 (thiamine), vitamin B3 (niacin), vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Numerous studies have shown a diet rich in vitamin B’s or supplementation of vitamin B’s improves depressive symptoms.92-98  

In addition to vitamins, several minerals also play a crucial role in depression onset, severity, and recovery. Among them, zinc deserves more attention – studies have consistently shown zinc deficiency increases the risk of depression, and zinc supplementation reduces depressive symptoms.99 Apart from zinc, deficiency in magnesium, selenium, iron, copper, and calcium has also been found to increase the risk of depression.72,79,100-103 Anyone suffering from depression should have the vitamin and mineral levels checked. And also keep in mind that overdosing minerals can be toxic.

In contrast to micronutrition, deficiency in macronutrition (carbohydrates, fat, and protein) is uncommon. However, insufficient intake of dietary fiber and excessive consumption of sugary food can fuel overgrowth of bad bacteria (dysbiosis) which in turn can induce depression as  noted earlier.104 Remember, bad bacteria thrive on sugar, and good bacteria grow on dietary fiber.  

Proteins are needed for good mental as well as physical health for that matter. In the digestive system, proteins are broken down into amino acids and peptides (a small number of amino acids bonded together). Amino acids are the building blocks of many neurotransmitters. For instance, dopamine is made of tyrosine (an amino acid), and serotonin is made from tryptophan (another amino acid). Protein deficiency is rare, even among vegetarians; but adequate protein intake is a must for the brain to work properly.

As to dietary fats, we all know saturated and trans fats are detrimental. However, many might have overlooked the benefits of omega-3 fatty acids for mental health, especially EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). Omega-3 fatty acids are believed to inhibit neuroinflammation, promote neurogenesis, improve neuroplasticity, and help nervous system repair.105-108 Studies have shown eating more fish is associated with low risk of depression.109,110 However, the findings from randomized controlled trials assessing the effect omega 3 fatty acid supplementation on depression are inconclusive.111 This is no surprise – the percentage of individuals suffering from depression solely due to omega-3 deficiency is unlikely to be high – omega-3 supplementation without addressing other root causes is unlikely to be effective for most depressive patients.

Regardless, studies have consistently shown high quality diets such as the Mediterranean diet are associated with low risk of depression.112-118 We are what we eat, which is true for both mental and physical health.

The Cure

No disorders, mental or physical, will go away unless the root causes are addressed – the only cure is to fix the underlining causes. Identifying and managing the root causes are not always easy because, in most cases, depression is not set off by one trigger, but by any combination of the five risk factors – it is a 5-piece puzzle. Fortunately, there is no depression gene – nobody has to suffer from depression because of his or her genetic makeup. So, you only need to manage four pieces of the puzzle.

When you are not sure which piece(s) causes the problem, take a shotgun approach – address all four pieces. Psychotherapies provided by psychologists or psychiatrists are very effective in managing stress or persistent negative thoughts. Alternative medicine (e.g., functional medicine) practitioners can guide you for detoxification, fixing dysbiosis as well as leaky gut, and addressing deficiencies in micronutrients.

Bear in mind, your brain does not malfunction for no reason. And no triggers or root causes are beyond the 5-piece puzzle. However, you need to guard against the “last straw” fallacy. It is true that the last straw breaks the camel’s back, but do not expect a camel to get up and run after the last straw is lifted off. Diseases, once onset, have momentum and can be kept going by a minor trigger. Just like a standstill 18-wheeler, it is hard to get it moving; once in motion, it is hard to stop.

The bottom line is you need to fix all the root causes at the same time. It can be challenging, but it is doable and well worth the effort. If you do not see progress or feel lost, do not give up – you must have missed something – go back to the four pieces: stress (including low mood and chronic rumination), toxic chemicals (including mold infection and food sensitivity), gut (dysbiosis and leaky gut), and nutrition (mainly micronutrients). Once again: the only cure is to fix the root causes.

About the Author and Editor: Jian Gao, PhD, is a healthcare analyst/researcher for the last 27 years who devoted his analytical skills to understanding health sciences and clinical evidence. Mr. Frederick Malphurs is a retired senior healthcare executive in charge of multiple hospitals for decades who dedicated his entire 37 year career to improving patient care. Neither of us takes pleasure in criticizing any individuals, groups, or organizations for the failed state of healthcare, but we share a common passion — to reduce unnecessary sufferings inflicted by the so-called chronic or incurable diseases on patients and their loved ones by analyzing and sharing information on root causes, effective treatments, and prevention.

Disclaimer: This article and any contents on this website are informational or educational only and should by no means be considered as a substitute for the advice of a qualified medical professional. It is the patients and caregivers’ solemn responsibility to work with qualified professionals to develop the best treatment plan. The author and editor assume no liability of any outcomes from any treatments or interventions.

References

  1. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008 Feb;5(2):e45. doi: 10.1371/journal.pmed.0050045. PMID: 18303940; PMCID: PMC2253608.
  2. Gøtzsche PC. Antidepressants and murder: case not closed. BMJ 2017; 358:j3697 doi: https://doi.org/10.1136/bmj.j3697.
  3. Carlat DJ. Unhinged. The Trouble with Psychiatry – A Doctor’s Revelations about a Profession in Crisis. Free Press. 2010. 1230 Ave of the Americans. New York, NY 10020.
  4. Whitaker R. Mad in America. Bad Science, Bad Medicine, and the Enduring Mistreatment of the Mentally Ill. Basic Books. Hachette Book Group. 1290 Avenue of the Americas, New York, NY 10114.
  5. Kirsch I. The emperor’s New Drugs – Exploding the Antidepressant Myth. Basic Books. 2010. New York, NY 10016.
  6. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry. 2000;157:1552–1562. doi: 10.1176/appi.ajp.157.10.1552. [PubMed] [CrossRef] [Google Scholar]
  7. Howard DM, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 2019;22:343. doi: 10.1038/s41593-018-0326-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  8. Radjabzadeh D, Bosch JA, Uitterlinden AG, et al. Gut microbiome-wide association study of depressive symptoms. Nat Commun. 2022 Dec 6;13(1):7128. doi: 10.1038/s41467-022-34502-3. PMID: 36473852; PMCID: PMC9726982.
  9. Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017 Jul 21;16:1057-1072. doi: 10.17179/excli2017-480. PMID: 28900385; PMCID: PMC5579396.
  10. Zafar MS, Nauman M, Nauman H, Nauman S, Kabir A, Shahid Z, et al. Impact of Stress on Human Body: A Review. European Journal of Medical and Health Sciences, 2021;3(3):1–7. https://doi.org/10.24018/ejmed.2021.3.3.821.
  11. O’Connor DB, Thayer JF, Vedhara K. Stress and Health: A Review of Psychobiological Processes. Annu Rev Psychol. 2021 Jan 4;72:663-688.
  12. Stress effects on the body. American Psychological Association. March 8, 2023. https://www.apa.org/topics/stress/body#:~:text=The%20autonomic%20nervous%20system%20has,%E2%80%9Cfight%20or%20flight%E2%80%9D%20response.
  13. Liu RT, Alloy LB. Stress generation in depression: A systematic review of the empirical literature and recommendations for future study. Clin Psychol Rev. 2010 Jul;30(5):582-93. doi: 10.1016/j.cpr.2010.04.010. Epub 2010 May 15. PMID: 20478648; PMCID: PMC3049314.
  14. LeMoult J. From Stress to Depression: Bringing Together Cognitive and Biological Science. Curr Dir Psychol Sci. 2020 Dec;29(6):592-598. doi: 10.1177/0963721420964039. Epub 2020 Nov 9. PMID: 33343103; PMCID: PMC7727022.
  15. Hussenoeder FS, Conrad I, Pabst A, et al. Different Areas of Chronic Stress and Their Associations with Depression. Int J Environ Res Public Health. 2022 Jul 19;19(14):8773. doi: 10.3390/ijerph19148773. PMID: 35886625; PMCID: PMC9315834.
  16. Guo J, Garshick E, Si F, Tang Z, Lian X, Wang Y, Li J, Koutrakis P. Environmental Toxicant Exposure and Depressive Symptoms. JAMA Netw Open. 2024 Jul 1;7(7):e2420259. doi: 10.1001/jamanetworkopen.2024.20259. PMID: 38958973; PMCID: PMC11222999.
  17. Yang T, Wang J, Huang J, Kelly FJ, Li G. Long-term Exposure to Multiple Ambient Air Pollutants and Association With Incident Depression and Anxiety. JAMA Psychiatry. 2023 Apr 1;80(4):305-313. doi: 10.1001/jamapsychiatry.2022.4812. PMID: 36723924; PMCID: PMC10077109.
  18. Dickerson AS, Wu AC, Liew Z, Weisskopf M. A Scoping Review of Non-Occupational Exposures to Environmental Pollutants and Adult Depression, Anxiety, and Suicide. Curr Environ Health Rep. 2020 Sep;7(3):256-271. doi: 10.1007/s40572-020-00280-7. PMID: 32533365; PMCID: PMC7483936.
  19. Tang L, Liu M, Tian J. Volatile organic compounds exposure associated with depression among U.S. adults: Results from NHANES 2011-2020. Chemosphere. 2024 Feb;349:140690. doi: 10.1016/j.chemosphere.2023.140690. Epub 2023 Nov 21. PMID: 37995973.
  20. van den Bosch M, Meyer-Lindenberg A. Environmental Exposures and Depression: Biological Mechanisms and Epidemiological Evidence. Annu Rev Public Health. 2019 Apr 1;40:239-259. doi: 10.1146/annurev-publhealth-040218-044106. Epub 2019 Jan 11. PMID: 30633709.
  21. James AA, OShaughnessy KL. Environmental chemical exposures and mental health outcomes in children: a narrative review of recent literature. Front Toxicol. 2023 Nov 30;5:1290119. doi: 10.3389/ftox.2023.1290119. PMID: 38098750; PMCID: PMC10720725.
  22. Richardson JR, Fitsanakis V, Westerink RHS, Kanthasamy AG. Neurotoxicity of pesticides. Acta Neuropathol. 2019 Sep;138(3):343-362. doi: 10.1007/s00401-019-02033-9. Epub 2019 Jun 13. PMID: 31197504; PMCID: PMC6826260.
  23. Genuis SJ, Kelln KL. Toxicant exposure and bioaccumulation: a common and potentially reversible cause of cognitive dysfunction and dementia. Behav Neurol. 2015;2015:620143. doi: 10.1155/2015/620143. Epub 2015 Feb 4. PMID: 25722540; PMCID: PMC4334623.
  24. Potera C. Molding a link to depression. Environ Health Perspect. 2007 Nov;115(11):A536. doi: 10.1289/ehp.115-a536a. PMID: 18007972; PMCID: PMC2072855.
  25. Shenassa ED, Daskalakis C, Liebhaber A, Braubach M, Brown M. Dampness and mold in the home and depression: an examination of mold-related illness and perceived control of one’s home as possible depression pathways. Am J Public Health. 2007 Oct;97(10):1893-9. doi: 10.2105/AJPH.2006.093773. Epub 2007 Aug 29. PMID: 17761567; PMCID: PMC1994167.
  26. Liu L, Wang H, Chen X, Zhang Y, Zhang H, Xie P. Gut microbiota and its metabolites in depression: from pathogenesis to treatment. EBioMedicine. 2023 Apr;90:104527. doi: 10.1016/j.ebiom.2023.104527. Epub 2023 Mar 22. PMID: 36963238; PMCID: PMC10051028.
  27. Irum N, Afzal T, Faraz MH, Aslam Z, Rasheed F. The role of gut microbiota in depression: an analysis of the gut-brain axis. Front Behav Neurosci. 2023 Jun 2;17:1185522. doi: 10.3389/fnbeh.2023.1185522. PMID: 37333479; PMCID: PMC10272349.
  28. Eltokhi A, Sommer IE. A Reciprocal Link Between Gut Microbiota, Inflammation and Depression: A Place for Probiotics? Front Neurosci. 2022 Apr 25;16:852506. doi: 10.3389/fnins.2022.852506. PMID: 35546876; PMCID: PMC9081810.
  29. Radjabzadeh D, Bosch JA, Uitterlinden AG, et al. Gut microbiome-wide association study of depressive symptoms. Nat Commun. 2022 Dec 6;13(1):7128. doi: 10.1038/s41467-022-34502-3. PMID: 36473852; PMCID: PMC9726982.
  30. Capuco A, Urits I, Hasoon J, et al. Current Perspectives on Gut Microbiome Dysbiosis and Depression. Adv Ther. 2020 Apr;37(4):1328-1346. doi: 10.1007/s12325-020-01272-7. Epub 2020 Mar 4. PMID: 32130662; PMCID: PMC7140737.
  31. Sonali S, Ray B, Ahmed Tousif H, et al. Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review. Cells. 2022 Apr 16;11(8):1362. doi: 10.3390/cells11081362. PMID: 35456041; PMCID: PMC9030021.
  32. Capuco A, Urits I, Hasoon J, et al. Gut Microbiome Dysbiosis and Depression: a Comprehensive Review. Curr Pain Headache Rep. 2020 Jun 6;24(7):36. doi: 10.1007/s11916-020-00871-x. Retraction in: Curr Pain Headache Rep. 2023 May;27(5):129. doi: 10.1007/s11916-023-01106-5. PMID: 32506238.
  33. Xiong RG, Li J, Cheng J, et al. The Role of Gut Microbiota in Anxiety, Depression, and Other Mental Disorders as Well as the Protective Effects of Dietary Components. Nutrients. 2023 Jul 23;15(14):3258. doi: 10.3390/nu15143258. PMID: 37513676; PMCID: PMC10384867.
  34. Suda K, Matsuda K. How Microbes Affect Depression: Underlying Mechanisms via the Gut-Brain Axis and the Modulating Role of Probiotics. Int J Mol Sci. 2022 Jan 21;23(3):1172. doi: 10.3390/ijms23031172. PMID: 35163104; PMCID: PMC8835211.
  35. Schrodt C, Mahavni A, McNamara GPJ, et al. The gut microbiome and depression: a review. Nutr Neurosci. 2023 Oct;26(10):953-959. doi: 10.1080/1028415X.2022.2111745. Epub 2022 Aug 30. PMID: 36039916.
  36. Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018 Aug 15;1693(Pt B):128-133. doi: 10.1016/j.brainres.2018.03.015. PMID: 29903615; PMCID: PMC6005194.
  37. Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol. 2019 Aug 5;6(1):e000325. doi: 10.1136/bmjgast-2019-000325.
  38. Malik F, Wickremesinghe P, Saleem A. Auto-Brewery Syndrome: A Schematic for Diagnosis and Appropriate Treatment. https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2021/07/July-2021-Auto-Brewery-Syndrome.pdf
  39. LaMotte S. Her gut was producing alcohol. Doctors didn’t believe her. CNN. https://www.cnn.com/2024/06/03/health/auto-brewery-syndrome-wellness/index.html
  40. Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021 Apr 22;12:673708. doi: 10.3389/fimmu.2021.673708. PMID: 33968085; PMCID: PMC8100306.
  41. Safadi JM, Quinton AMG, Lennox BR, Burnet PWJ, Minichino A. Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis. Mol Psychiatry. 2022 Jan;27(1):141-153. doi: 10.1038/s41380-021-01032-1. Epub 2021 Feb 8. PMID: 33558650; PMCID: PMC8960409.
  42. Andrew Scull A. Madhouse: A Tragic Tale of Megalomania and Modern Medicine. Yale University Press. 2005.
  43. Gao F, Guo R, Ma Q, et al. Stressful events induce long-term gut microbiota dysbiosis and associated post-traumatic stress symptoms in healthcare workers fighting against COVID-19. J Affect Disord. 2022 Apr 15;303:187-195. doi: 10.1016/j.jad.2022.02.024. Epub 2022 Feb 12. PMID: 35157946; PMCID: PMC8837476.
  44. Perlmutter D. Brain Maker. 2015. Little, Brown and Company. 1290 Avenue of the Americas, New York, NY 10104.
  45. Zhao J, Bi W, Xiao S, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 9, 5790 (2019). https://doi.org/10.1038/s41598-019-42286-8.
  46. Skrzypczak-Wiercioch A, Sałat K. Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use. Molecules. 2022 Aug 26;27(17):5481. doi: 10.3390/molecules27175481. PMID: 36080253; PMCID: PMC9457753.
  47. Batista CRA, Gomes GF, Candelario-Jalil E, Fiebich BL, de Oliveira ACP. Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration. Int J Mol Sci. 2019 May 9;20(9):2293. doi: 10.3390/ijms20092293. PMID: 31075861; PMCID: PMC6539529.
  48. Li W, Ali T, He K, et al. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression. Brain Behav Immun. 2021 Feb;92:10-24. doi: 10.1016/j.bbi.2020.11.008. Epub 2020 Nov 10. PMID: 33181270.
  49. Rudzki L, Maes M. From “Leaky Gut” to Impaired Glia-Neuron Communication in Depression. Adv Exp Med Biol. 2021;1305:129-155. doi: 10.1007/978-981-33-6044-0_9. PMID: 33834399.
  50. Ohlsson L, Gustafsson A, Lavant E, et al. Leaky gut biomarkers in depression and suicidal behavior. Acta Psychiatr Scand. 2019 Feb;139(2):185-193. doi: 10.1111/acps.12978. Epub 2018 Nov 1. Erratum in: Acta Psychiatr Scand. 2020 Nov;142(5):423. doi: 10.1111/acps.13223. PMID: 30347427; PMCID: PMC6587489.
  51. Obrenovich MEM. Leaky Gut, Leaky Brain? Microorganisms. 2018 Oct 18;6(4):107. doi: 10.3390/microorganisms6040107. PMID: 30340384; PMCID: PMC6313445.
  52. Kiecolt-Glaser JK, Wilson SJ, Bailey ML, et al. Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation. Psychoneuroendocrinology. 2018 Dec;98:52-60. doi: 10.1016/j.psyneuen.2018.08.007. Epub 2018 Aug 4. PMID: 30098513; PMCID: PMC6260591.
  53. Maes M., Kubera M., Leunis J., Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: Further evidence for increased bacterial translocation or leaky gut. J. Affect. Disord. 2012;141:55–62. doi: 10.1016/j.jad.2012.02.023.
  54. Maes M., Kubera M., Leunis J. The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol. Lett. 2008;29:117–124.
  55. Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut as a Danger Signal for Autoimmune Diseases. Front Immunol. 2017 May 23;8:598. doi: 10.3389/fimmu.2017.00598. eCollection 2017.
  56. Khan N, Asif AR. Transcriptional regulators of claudins in epithelial tight junctions. Mediators Inflamm. 2015;2015:219843. doi: 10.1155/2015/219843.
  57. Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000;113(Pt 24):4435–4440.
  58. Pizzorno, J. Zonulin! The Wheat Conundrum Solved (Well, Mostly). Integrative Medicine. 2013. Vol 12 (4) 8-14.
  59. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75.
  60. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012 Jul;1258:25-33.
  61. Busby E, Bold J, Fellows L, Rostami K. Mood Disorders and Gluten: It’s Not All in Your Mind! A Systematic Review with Meta-Analysis. Nutrients. 2018 Nov 8;10(11):1708. doi: 10.3390/nu10111708. PMID: 30413036; PMCID: PMC6266949.
  62. Bjarnason, I., Scarpignato, C., Holmgren, E., et al. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. 2018. Gastroenterology 154, 500–514. doi: 10.1053/j.gastro.2017.10.049
  63. Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol. 2020 Aug 7;11:1153. doi: 10.3389/fphar.2020.01153. PMID: 32848762; PMCID: PMC7426480.
  64. La Torre D, Van Oudenhove L, Vanuytsel T, Verbeke K. Psychosocial stress-induced intestinal permeability in healthy humans: What is the evidence? Neurobiol Stress. 2023 Oct 6;27:100579. doi: 10.1016/j.ynstr.2023.100579. PMID: 37842017; PMCID: PMC10569989.
  65. Only 1 in 10 Adults Get Enough Fruits or Vegetables. February 16, 2021. https://www.cdc.gov/nccdphp/dnpao/division-information/media-tools/adults-fruits-vegetables.html .
  66. Mayer AB, Trenchard L, Rayns F. Historical changes in the mineral content of fruit and vegetables in the UK from 1940 to 2019: a concern for human nutrition and agriculture. Int J Food Sci Nutr. 2021 Oct 15:1-12.
  67. Davis DR, Epp MD, Riordan HD. Changes in USDA food composition data for 43 garden crops, 1950 to 1999. J Am Coll Nutr. 2004 Dec;23(6):669-82.
  68. Marles RJ. Mineral Nutrient Composition of Vegetables, Fruits and Grains: The Context of Reports of Apparent Historical Declines. Journal of Food Composition and Analysis. 2017;56:93-103.
  69. Wallace TC, McBurney M, Fulgoni VL, 3rd. Multivitamin/mineral supplement contribution to micronutrient intakes in the United States, 2007-2010. J Am Coll Nutr. 2014;33(2):94-102
  70. Marx W, Lane M, Hockey M, et al. Diet and depression: exploring the biological mechanisms of action. Mol Psychiatry. 2021 Jan;26(1):134-150. doi: 10.1038/s41380-020-00925-x. Epub 2020 Nov 3. PMID: 33144709.
  71. Upton N. Developing our understanding of nutrition in depression. Br J Nutr. 2022 Apr 14;127(7):1010-1017. doi: 10.1017/S0007114521001744. Epub 2021 May 27. PMID: 34039462.
  72. Ekinci GN, Sanlier N. The relationship between nutrition and depression in the life process: A mini-review. Exp Gerontol. 2023 Feb;172:112072. doi: 10.1016/j.exger.2022.112072. Epub 2022 Dec 21. PMID: 36565729.
  73. Kris-Etherton PM, Petersen KS, Hibbeln JR, et al. Nutrition and behavioral health disorders: depression and anxiety. Nutr Rev. 2021 Feb 11;79(3):247-260. doi: 10.1093/nutrit/nuaa025. PMID: 32447382; PMCID: PMC8453603.
  74. Adan RAH, van der Beek EM, Buitelaar JK, et al. Nutritional psychiatry: Towards improving mental health by what you eat. Eur Neuropsychopharmacol. 2019 Dec;29(12):1321-1332. doi: 10.1016/j.euroneuro.2019.10.011. Epub 2019 Nov 14. PMID: 31735529.
  75. Molendijk M, Molero P, Ortuño Sánchez-Pedreño F, et al. Diet quality and depression risk: A systematic review and dose-response meta-analysis of prospective studies. J Affect Disord. 2018 Jan 15;226:346-354. doi: 10.1016/j.jad.2017.09.022. Epub 2017 Sep 23. PMID: 29031185.
  76. Kris-Etherton PM, Petersen KS, Hibbeln JR, et al. Nutrition and behavioral health disorders: depression and anxiety. Nutr Rev. 2021 Feb 11;79(3):247-260. doi: 10.1093/nutrit/nuaa025. PMID: 32447382; PMCID: PMC8453603.
  77. Popa TA, Ladea M. Nutrition and depression at the forefront of progress. J Med Life. 2012 Dec 15;5(4):414-9. Epub 2012 Dec 25. PMID: 23346242; PMCID: PMC3539842.
  78. Firth J, Gangwisch JE, Borisini A, Wootton RE, Mayer EA. Food and mood: how do diet and nutrition affect mental wellbeing? BMJ. 2020 Jun 29;369:m2382. doi: 10.1136/bmj.m2382. Erratum in: BMJ. 2020 Nov 9;371:m4269. doi: 10.1136/bmj.m4269. PMID: 32601102; PMCID: PMC7322666.
  79. Zielińska M, Łuszczki E, Dereń K. Dietary Nutrient Deficiencies and Risk of Depression (Review Article 2018-2023). Nutrients. 2023 May 23;15(11):2433. doi: 10.3390/nu15112433. PMID: 37299394; PMCID: PMC10255717.
  80. Quan Z, Li H, Quan Z, Qing H. Appropriate Macronutrients or Mineral Elements Are Beneficial to Improve Depression and Reduce the Risk of Depression. Int J Mol Sci. 2023 Apr 12;24(8):7098. doi: 10.3390/ijms24087098. PMID: 37108261; PMCID: PMC10138658.
  81. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7. doi: 10.1192/bjp.bp.111.106666. PMID: 23377209.
  82. Akpınar Ş, Karadağ MG. Is Vitamin D Important in Anxiety or Depression? What Is the Truth? Curr Nutr Rep. 2022 Dec;11(4):675-681. doi: 10.1007/s13668-022-00441-0. Epub 2022 Sep 13. PMID: 36097104; PMCID: PMC9468237.
  83. Musazadeh V, Keramati M, Ghalichi F, et al. Vitamin D protects against depression: Evidence from an umbrella meta-analysis on interventional and observational meta-analyses. Pharmacol Res. 2023 Jan;187:106605. doi: 10.1016/j.phrs.2022.106605. Epub 2022 Dec 9. PMID: 36509315.
  84. Casseb GAS, Kaster MP, Rodrigues ALS. Potential Role of Vitamin D for the Management of Depression and Anxiety. CNS Drugs. 2019 Jul;33(7):619-637. doi: 10.1007/s40263-019-00640-4. PMID: 31093951.
  85. Xie F, Huang T, Lou D, et al. Effect of vitamin D supplementation on the incidence and prognosis of depression: An updated meta-analysis based on randomized controlled trials. Front Public Health. 2022 Aug 1;10:903547. doi: 10.3389/fpubh.2022.903547. PMID: 35979473; PMCID: PMC9376678.
  86. Kaviani M, Nikooyeh B, Zand H, Yaghmaei P, Neyestani TR. Effects of vitamin D supplementation on depression and some involved neurotransmitters. J Affect Disord. 2020 May 15;269:28-35. doi: 10.1016/j.jad.2020.03.029. Epub 2020 Mar 13. PMID: 32217340.
  87. Guzek D, Kołota A, Lachowicz K, Skolmowska D, Stachoń M, Głąbska D. Effect of Vitamin D Supplementation on Depression in Adults: A Systematic Review of Randomized Controlled Trials (RCTs). Nutrients. 2023 Feb 14;15(4):951. doi: 10.3390/nu15040951. PMID: 36839310; PMCID: PMC9963956.
  88. Kaviani M, Nikooyeh B, Etesam F, et al. Effects of vitamin D supplementation on depression and some selected pro-inflammatory biomarkers: a double-blind randomized clinical trial. BMC Psychiatry. 2022 Nov 11;22(1):694. doi: 10.1186/s12888-022-04305-3. PMID: 36368945; PMCID: PMC9651884.
  89. Di Gessa G, Biddulph JP, Zaninotto P, de Oliveira C. Changes in vitamin D levels and depressive symptoms in later life in England. Sci Rep. 2021 Apr 8;11(1):7724. doi: 10.1038/s41598-021-87432-3. PMID: 33833363; PMCID: PMC8032652.
  90. Herbert V. Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians. 1962;75:307-20. PMID: 13953904.
  91. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997 May;55(5):145-9. doi: 10.1111/j.1753-4887.1997.tb06468.x. PMID: 9212690.
  92. Young LM, Pipingas A, White DJ, Gauci S, Scholey A. A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and ‘At-Risk’ Individuals. Nutrients. 2019 Sep 16;11(9):2232. doi: 10.3390/nu11092232. PMID: 31527485; PMCID: PMC6770181.
  93. Liwinski T, Lang UE. Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review. Nutrients. 2023 Sep 4;15(17):3859. doi: 10.3390/nu15173859. PMID: 37686891; PMCID: PMC10490031.
  94. Mikkelsen K, Stojanovska L, Apostolopoulos V. The Effects of Vitamin B in Depression. Curr Med Chem. 2016;23(38):4317-4337. doi: 10.2174/0929867323666160920110810. PMID: 27655070.
  95. Hanna M, Jaqua E, Nguyen V, Clay J. B Vitamins: Functions and Uses in Medicine. Perm J. 2022 Jun 29;26(2):89-97. doi: 10.7812/TPP/21.204. Epub 2022 Jun 17. PMID: 35933667; PMCID: PMC9662251.
  96. Mikkelsen K, Stojanovska L, Prakash M, Apostolopoulos V. The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas. 2017 Feb;96:58-71. doi: 10.1016/j.maturitas.2016.11.012. Epub 2016 Nov 19. PMID: 28041597.
  97. Borges-Vieira JG, Cardoso CKS. Efficacy of B-vitamins and vitamin D therapy in improving depressive and anxiety disorders: a systematic review of randomized controlled trials. Nutr Neurosci. 2023 Mar;26(3):187-207. doi: 10.1080/1028415X.2022.2031494. Epub 2022 Feb 14. PMID: 35156551.
  98. Khosravi M, Sotoudeh G, Amini M, Raisi F, Mansoori A, Hosseinzadeh M. The relationship between dietary patterns and depression mediated by serum levels of Folate and vitamin B12. BMC Psychiatry. 2020 Feb 13;20(1):63. doi: 10.1186/s12888-020-2455-2. PMID: 32054533; PMCID: PMC7020545.
  99. Wang J, Um P, Dickerman BA, Liu J. Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications. Nutrients. 2018 May 9;10(5):584. doi: 10.3390/nu10050584. PMID: 29747386; PMCID: PMC5986464.
  100. Baj J, Bargieł J, Cabaj J, et al. Trace Elements Levels in Major Depressive Disorder-Evaluation of Potential Threats and Possible Therapeutic Approaches. Int J Mol Sci. 2023 Oct 11;24(20):15071. doi: 10.3390/ijms242015071. PMID: 37894749; PMCID: PMC10606638.
  101. Li Z, Li B, Song X, Zhang D. Dietary zinc and iron intake and risk of depression: A meta-analysis. Psychiatry Res. 2017 May;251:41-47. doi: 10.1016/j.psychres.2017.02.006. Epub 2017 Feb 3. PMID: 28189077.
  102. Młyniec K, Davies CL, de Agüero Sánchez IG, Pytka K, Budziszewska B, Nowak G. Essential elements in depression and anxiety. Part I. Pharmacol Rep. 2014 Aug;66(4):534-44. doi: 10.1016/j.pharep.2014.03.001. Epub 2014 Apr 2. PMID: 24948052.
  103. Młyniec K, Gaweł M, Doboszewska U, et al. Essential elements in depression and anxiety. Part II. Pharmacol Rep. 2015 Apr;67(2):187-94. doi: 10.1016/j.pharep.2014.09.009. Epub 2014 Sep 27. PMID: 25712638.
  104. Satokari R. High Intake of Sugar and the Balance between Pro- and Anti-Inflammatory Gut Bacteria. Nutrients. 2020 May 8;12(5):1348. doi: 10.3390/nu12051348. PMID: 32397233; PMCID: PMC7284805.
  105. Zhou L, Xiong JY, Chai YQ, et al. Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system. Front Psychiatry. 2022 Aug 31;13:933704. doi: 10.3389/fpsyt.2022.933704. PMID: 36117650; PMCID: PMC9473681.
  106. Cutuli D. Functional and structural benefits induced by omega-3 polyunsaturated fatty acids during aging. Curr Neuropharmacol. (2017) 15:534–42. doi: 10.2174/1570159X14666160614091311. Dyall SC.
  107. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of Epa, Dpa and Dha. Front Aging Neurosci. (2015) 7:52. doi: 10.3389/fnagi.2015.00052
  108. Tomaszewski N, He X, Solomon V, Lee M, Mack WJ, Quinn JF, et al. Effect of Apoe genotype on plasma docosahexaenoic acid (Dha), eicosapentaenoic acid, arachidonic acid, and hippocampal volume in the Alzheimer’s Disease cooperative study-sponsored Dha clinical trial. J Alzheimers Dis. (2020) 74:975–90. doi: 10.3233/JAD-191017.
  109. Li F, Liu X, Zhang D. Fish consumption and risk of depression: a meta-analysis. J Epidemiol Community Health. 2016;70:299–304.
  110. Grosso G, Micek A, Marventano S, et al.. Dietary n-3 PUFA, fish consumption and depression: a systematic review and meta-analysis of observational studies. J Affect Disord. 2016;205:269–281.
  111. Appleton KM, Voyias PD, Sallis HM, et al. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2021 Nov 24;11(11):CD004692. doi: 10.1002/14651858.CD004692.pub5. PMID: 34817851; PMCID: PMC8612309.
  112. Molendijk M, Molero P, Ortuno Sanchez-Pedreno F, et al. Diet quality and depression risk: a systematic review and dose-response meta-analysis of prospective studies. J Affect Disord. 2018;226:346–354.
  113. Lai JS, Hiles S, Bisquera A, 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.
  114. Gómez-Donoso C, Sánchez-Villegas A, Martínez-González MA, et al. Ultra-processed food consumption and the incidence of depression in a Mediterranean cohort: the SUN Project. Eur J Nutr. 2020 Apr;59(3):1093-1103. doi: 10.1007/s00394-019-01970-1. Epub 2019 May 4. PMID: 31055621.
  115. Gibson-Smith D, Bot M, Brouwer IA, Visser M, Giltay EJ, Penninx BWJH. Association of food groups with depression and anxiety disorders. Eur J Nutr. 2020 Mar;59(2):767-778. doi: 10.1007/s00394-019-01943-4. Epub 2019 Apr 3. PMID: 30945032; PMCID: PMC7058560.
  116. Martinez-Gonzalez MA, Sanchez-Villegas A. Food patterns and the prevention of depression. Proc Nutr Soc. 2016;75:139–146.
  117. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, et al. Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol. 2013;74:580–591.
  118. Chrzastek Z, Guligowska A, Sobczuk P, Kostka T. Dietary factors, risk of developing depression, and severity of its symptoms in older adults-A narrative review of current knowledge. Nutrition. 2023 Feb;106:111892. doi: 10.1016/j.nut.2022.111892. Epub 2022 Oct 29. PMID: 36436336.
Scroll to Top