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Depression: signs and causative factors

Updated: Aug 21, 2021


Sadness and mood fluctuations are normal human feelings. We all experience these emotions from time to time, but they usually go away in a short period of time. Depression, however, is something more. It may become a serious health condition especially when long-lasting and with moderate or severe intensity. This common worldwide disorder, with more than 265 million people being affected (GBD, 2017), causes suffering and poor functioning in private and professional life. At its worst, depression can lead to suicide. It is predicted that in few years depression will be a leading cause of disease burden (Ferrari et al., 2014). Besides effective treatments for moderate and severe depression, 76-85% of people in low- and middle-income countries receive no treatment (Wang et al., 2007).

Depression takes a heavy toll on physical health. For most of the day or nearly every day, person with depression may experience a variety of different symptoms including:

· persistent sadness, anxiety, or “empty” mood

· feelings of hopelessness, pessimism, guilt, worthlessness, or helplessness

· irritability

· disinterest in hobbies or activities

· decreased energy or fatigue

· moving or talking more slowly

· feeling restless or having trouble sitting still

· difficulty concentrating, remembering, or making decisions

· changes in sleep and appetite pattern

· body aches or pains, headaches

· abdominal cramps and digestive problems without a clear physical cause and/or that do not ease even with treatment

· low sex drive

· thoughts of death or suicide

· suicide attempts.


We often hear that depression results from a chemical imbalance, but this statement does not tell us about complexity of this illness. Research suggests that depression does not result from simply having too much or too little of certain brain chemical messengers (neurotransmitters). Rather, it results from the interaction between several factors including genetic vulnerability, environmental factors, personal circumstances and decisions, and physical health. All of these and more affect body’s dynamic chemical system that is responsible for the mood and perception. Here an overview of the current understanding of the major factors believed to play a causative role in the development of depression.

1. Chronic stress and trauma

Chronic stress has an inflammatory effect on the body. In response to a stresror, complex and cooperative networks within our body are activated, one of them called the “hypothalamus-pituitary-adrenal” (HPA) axis. The relationship between stress levels and HPA axis is complex. Simplifying, an acute stressful event activates sympathetic nervous system, triggering the HPA to release stress hormones to help respond to the stressor. After that event, the parasympathetic nervous takes over and decreases the HPA axis activity, reducing therefore stress hormone production (Lowrance et al., 2016). However, in state of prolonged stress, the sympathetic nervous system and HPA axis can remain chronically activated, causing health problems including depression. Researchers have found that accumulation of multiple chronic mild stressors, such as financial problems, work-related stress, or family responsibilities predispose much more to depression than the major life events such as loss of a job or divorce (Billings and Moos, 1984; Monroe and Depue, 1991; Mazure, 1998). Traumatic experiences in childhood may serve as a factor for adult depression, possibly by altering the function of the HPA axis long-term and contributing to chronic, systemic inflammation during (Copeland et al., 2014; Menke et al., 2018). Depression can also be triggered by trauma experiences during adulthood including things like involvement in a serious accident or natural disasters, caring for a sick person, or military serving. We also can not forget about social determinants of health as a risk factor when it comes to developing depression. Access to education, healthy food and quality water, socioeconomic status, or race. Health and social inequality are strongly linked with each other. Experiencing racism contributes to chronic stress and low-grade inflammation, both risk factors for depression (Nuru-Jeter et al., 2018; Allen et al., 2019).

2. Genetics

Data shows a two- to threefold increase in the risk of depression in first-degree offspring of patients with depression and estimated heritability rate for depression of 37% (McGuffin et al., 2007; Sullivan et al., 2000; Menke et al., 2012). Moreover, depression severity depends on whether illness is inherited maternally or paternally (Kendler et al., 2001; Kendler et al., 2006).

Scientists are now starting to focus on an environmental factors and environment-gene interaction as a contributing factor to the etiology of depression. These include exposure in the womb (e.g., viruses, toxins, alcohol and drugs), social deprivation (e.g., poverty, child maltreatment), and enrichment (e.g., psychosocial interventions and treatments) (reviewed in Dunn et al., 2015).

3. Environmental toxins

Indoor exposure to mould and mycotoxins (any toxic substance produced by a fungus) can trigger the release of inflammatory molecules (cytokines) and impair brain plasticity leading to symptoms of depression (Shenassa et al., 2007; Doi and Uetsuka, 2011; Scafuri et al., 2017; Kritas et al., 2018; Ratnaseelan et al., 2018). Ambient air pollution can also lead to activation of inflammatory pathways in the nervous system that have been shown to cause depression-like symptoms (Khan et al., 2019). Those effects appear to be especially significant for people who encountered air pollution during the first 10 years of their lives (Khan et al., 2019). Several studies have also suggested a low-intensity microwave frequency electromagnetic fields as a cause of diverse psychiatric symptoms including depression (reviewed in Pall, 2016).

4. Infections

Immune system supports brain health in several ways. Therefore, activation of certain immune system cells in response to an infection may contribute to mental illness. Indeed, several chronic infections have been shown to associate with depression. These include bacterial infections as Lyme borreliosis, Clostridium difficile, Toxoplasma gondii, and Chlamydophila trachomatis commonly known as chlamydia, or viral infection like herpes simplex virus-1 and Epstein-Barr virus (Purslow, 2013; Hsu et al., 2014; Wang et al., 2014; Bransfield, 2018).

5. Gut dysbiosis and leaky gut

The idea that the gut microbes influence the brain biochemistry, and therefore human behaviour, is widely understood and accepted. As much as 90% of the nerve impulses that follow the path of the vagus nerve are sent from the gut to the brain. Therefore, gut plays an important role in regulating our mental health. Metabolic products of gut microbes like short-chain fatty acids possess neuroactive properties influencing serotonin release and brain function (Tan et al., 2014; Stilling et al., 2016; Fung et al., 2017; Dalile et al., 2019). Disturbance in the gut flora and gut-brain axis is believed to be involved not only in the development of several gastrointestinal disorders, but also mental diseases including depression (Cryan and Dinan, 2012; Appleton, 2018). Altered gut flora can lead to leaky gut, another risk factor for depression development (Stevens et al., 2018). Leaky gut, or intestinal permeability, is a condition in which the lining of the small intestine becomes damaged, causing undigested food particles, toxic waste products and bacteria to "leak" through the intestines to the blood stream. Excessive sugar, gluten and alcohol intake, nutrient deficiencies (vit. A, D, zinc), stress, bacterial /yeast overgrowth, or use of non-steroidal anti-inflammatory drugs are other causative factors. In recent years, balancing the brain-gut axis via improving gut flora has become an important therapeutic target for depression (Evrensel and Ceylan, 2015).

6. Hypothyroidism

Depression can also by a symptoms of other health conditions. Low thyroid hormone levels, called hypothyroidism, slows down many organs and internal systems and creates a wide range of symptoms - including depression. Once thyroid dysfunctions are corrected, depression symptoms improve dramatically. Depressive disorders may also occur in 31 to 61% people with overactive thyroid function (hyperthyroidism) (reviewed in Hage and Azar, 2012).

7. Sleep problems

Sleep and depression are strongly linked with each other. About 75% of patients with depression have trouble sleeping (insomnia), and 40-50% of patients experience excessive sleepiness during the day (hypersomnia). Our circadian rhythm regulates the body and brain functions, and it is markedly affected by light and to some extent by temperature. Light exposure suppresses the production of melatonin, a hormone that controls the sleep-wake cycle (Figueiro et al., 2011; Gooley et al., 2011). As people spend more and more time in front of a screen, they are more exposed to artificial light affecting their physical and mental health. Especially light exposure at night is an independently associated with risk of depression development (Obayashi et al., 2018).

8. Sedentary lifestyle

Epidemiological studies have shown a significantly positive association between sedentary lifestyle (mental and physical) and potential for depression (Huang et al., 2020). Sedentary behaviours like watching television or using a computer can hinder direct communication between people, resulting in reduction in social interaction and increasing the risk of depression (Kraut et al., 1998). Moreover, it also decreases the time spent in physical exercise, an effective way to improve mental health.

9. Poor diet and alcohol use

Poor diet with an increased consumption of ultra-processes, high in refined sugar foods impairs brain function and even worsen symptoms of depression. It is also an independent factor associated with a greater likelihood risk for depression due to its inflammatory and oxidative properties (Jacka et al., 2010, Sánchez-Villegas et al., 2011; Sánchez-Villegas et al., 2012). So called the Standard American Diet harms the gut microbiome and can lead to leaky gut, another risk factor for depression development (Stevens et al., 2018). Nutritional deficiencies are also a concern with this diet. Low intake or low absorption (due to low stomach acid, poor gut health, etc.) of the following nutrients increases risk for depression and are most common nutritional deficiencies seen in patients with mental disorders: omega-3 fatty acids, vitamin D, vitamins B2, B6, B12, folate, magnesium, iron, zinc, copper (reviewed in Rao et al., 2008). Increased intake of food containing above nutrients, or an extra supplementation decrease depression symptoms (reviewed in Rao et al., 2008). Alco clcohol is a depressant itself as it can harm the nervous system. According to studies, 64% of people who are alcohol dependent have depression and nearly one-third of people with depression have also an alcohol problem (Kuria et al., 2012). Often, the depression comes first. Drinking alcohol frequently can make symptoms of depression worse. It can aggravate the problem when acting on impulse and making worse life decisions when drunk. As a result, it can lead to financial problems, ruin a relationship, and worsen the illness even more.

10. Mitochondrial dysfunction and oxidative stress

A growing body of evidence suggests that mitochondrial dysfunction may play a role in the development of depression. Mitochondria, organelles presented in nearly all cells, are responsible for energy generation, maintaining calcium level in the cells, regulating controlled cell death (apoptosis) and balancing the reactive oxygen species (ROS). ROS are highly reactive molecules that impair the structures of proteins, lipids, and DNA, and cause cell and tissue damage. Patients with depressive disorder and chronic physical conditions demonstrate decreased mitochondrial energy production rates (Gardner et al., 2003). Moreover, depression associates with an increase production of ROS and oxidative stress (Maes et al., 2009).

11. Chronic inflammation

All above mentioned factors are the powerful sources of inflammation. Environmental factors like psychosocial stress, early life adversity, and processed-food are uniformly pro-inflammatory. Inflammation is a normal response of the body to injury, toxins, and infections. It has a regenerative purpose and is purported to be short-lived. However, when prolonged it can affect the brain and nervous system. Numerous studies have found that patients with depression have high level of inflammatory markers in their peripheral blood and cerebrospinal fluid, a clear fluid that surrounds the brain and spinal cord (reviewed in Millerand Raison, 2016). Inflammatory illnesses are associated with greater rates of depressive disorder and patients treated with cytokines are at greater risk of developing depression (Capuron and Miller, 2011).


Depression is a complex disorder which can disable person’s ability to function in daily life. The symptoms vary in respect to their presence and intensity and include e.g., persistent sadness, feelings of hopelessness and worthlessness, decreased energy or fatigue, and cognitive dysfunction. There is no one cause of this illness - experts think that biological processes, psychological factors, major events in a person’s life and personal circumstances can all play a role. The treatments strategies should therefore focus all causative factors. Addressing hidden health issues, altering the diet and using supplement when necessary, exercising regularly, reducing toxins exposure, and practicing stress-management techniques should all be included in the recovery plan. Let’s not forget a number of herbs for depression that science supports as making a significant impact on the condition - most of which have no side effects.



· Adjibade, M., Julia, C., Allès, B. et al. (2019). Prospective association between ultra-processed food consumption and incident depressive symptoms in the French NutriNet-Santé cohort. BMC Med. 17:78

· Allen, A.M., Wang, Y., Chae, D.H., Price, M.M., Powell, W., Steed, T.C., Rose Black, A., Dhabhar, F.S., Marquez-Magaña, L. and Woods-Giscombe, C.L. (2019). Racial discrimination, the superwoman schema, and allostatic load: exploring an integrative stress-coping model among African American women. Annals of the New York Academy of Sciences. 1457(1):104-127.

· Appleton, J. (2018). The Gut-Brain Axis: Influence of Microbiota on Mood and Mental Health. Integrative medicine (Encinitas, Calif.). 17(4):28-32.

· Billings A.G. and Moos R.H. (1984). Chronic and nonchronic unipolar depression: The differential role of environmental stressors and resources. Journal of Nervous & Mental Disease. 172:65-75.

· Bransfield, R.C. (2018). Neuropsychiatric Lyme Borreliosis: An Overview with a Focus on a Specialty Psychiatrist's Clinical Practice. Healthcare (Basel, Switzerland). 6(3):104.

· Capuron, L. and Miller, A.H. (2011). Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 130:226-238.

· Copeland, W.E., Wolke, D., Lereya, S.T., Shanahan, L., Worthman, C. and Costello, E.J. (2014). Childhood bullying involvement predicts low-grade systemic inflammation into adulthood. Proc Natl Acad Sci U S A. 111(21):7570-7575.

· Cryan, J.F. and Dinan, T.G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 13(10):701-712.

· Dalile, B., Van Oudenhove, L., Vervliet, B. and Verbeke, K. (2019). The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol. 16:461-478.

· Doi, K. and Uetsuka, K. (2011). Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways. International Journal of Molecular Sciences. 12(8):5213-5237.

· Dunn, E.C., Brown, R.C., Dai, Y., Rosand, J., Nugent, N.R., Amstadter, A.B. and Smoller, J.W. (2015). Genetic determinants of depression: recent findings and future directions. Harvard review of psychiatry. 23(1):1-18.

· Evrensel, A. and Ceylan. M.E. (2015). The gut-brain axis: the missing link in depression. Clin Psychopharmacol Neurosci. 13:239-244.

· Ferrari, A.J., Norman, R.E., Freedman, G., Baxter, A.J., Pirkis, J.E., Harris, M.G., Page, A., Carnahan, E., Degenhardt, L., Vos, T. and Whiteford, H.A. (2014). The burden attributable to mental and substance use disorders as risk factors for suicide: findings from the Global Burden of Disease Study 2010. PLoS One. 9(4):e91936.

· Figueiro, M.G., Wood, B., Plitnick, B. and Rea, M.S. (2011). The impact of light from computer monitors on melatonin levels in college students. Neuro Endocrinol Lett. 32(2):158-163.

· Fung, T.C., Olson, C.A. and Hsiao, E.Y. (2017). Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 20:145–155.

· Gardner A., Johansson A., Wibom R., Nennesmo I., von Döbeln U., Hagenfeldt L., et al. (2003). Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J. Affect. Disord. 76:55-68.

· Gooley, J.J., Chamberlain, K., Smith, K.A., Khalsa, S.B., Rajaratnam, S.M., Van Reen, E., Zeitzer, J.M., Czeisler, C.A. and Lockley, S.W. (2011). Exposure to room light before bedtime suppresses melatonin onset and shortens melatonin duration in humans. The Journal of clinical endocrinology and metabolism. 96(3):E463-E472 .

· Gujral, S., Aizenstein, H., Reynolds, C.F. 3rd, Butters, M.A. and Erickson, K. I. (2017). Exercise effects on depression: possible neural mechanisms. Gen. Hosp. Psychiatry. 49:2-10.

· Hage, M.P. and Azar, S.T. (2012). The Link between Thyroid Function and Depression. Journal of thyroid research. 590648.

· Hsu, P.C., Groer, M. and Beckie, T. (2014). New findings: depression, suicide, and Toxoplasma gondii infection. J Am Assoc Nurse Pract. 26(11):629-637.

· Huang, Y., Li, L., Gan, Y. et al. (2020). Sedentary behaviors and risk of depression: a meta-analysis of prospective studies. Transl Psychiatry. 10:26.

· 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(3):305–311.

· Kendler, K.S., Gardner, C.O., Neale, M.C. and Prescott, C.A. (2001). Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med. 31:605-616.

· Kendler, K.S., Gatz, M., Gardner, C.O. and Pedersen, N.L. (2006). A Swedish national twin study of lifetime major depression. Am J Psychiatry. 163:109-114.

· Khan, A., Plana-Ripoll, O., Antonsen, S., Brandt, J., Geels, C., Landecker, H., et al. (2019). Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark. PLoS Biol. 17(8):e3000353.

· Kraut, R. et al. (1998). Internet paradox. A social technology that reduces social involvement and psychological well-being? Am. Psychol. 53:1017-1031.

· Kritas, S.K., Gallenga, C.E., Ovidio, C.D., Ronconi, G., Caraffa, A., Toniato, E., Lauritano, D. and Conti, P. (2018). Impact of mold on mast cell-cytokine immune response. J Biol Regul Homeost Agents. 32(4):763-768.

· Kuria, M.W., Ndetei, D.M., Obot, I.S., Khasakhala, L.I., Bagaka, B.M., Mbugua, M.N. and Kamau, J. (2012). The Association between Alcohol Dependence and Depression before and after Treatment for Alcohol Dependence. ISRN psychiatry. 482802.

· Lowrance, S.A., Ionadi, A., McKay, E., Douglas, X. and Johnson, J.D. (2016). Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress. Psychoneuroendocrinology. 68:163-170.

· Maes, M., Mihaylova, I, Kubera, M., Uytterhoeven, M., Vrydags, N. and Bosmans, E. (2009). Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 30(4):462-469.

· Mazure C.M. (1985). Life stressors as risk factors in depression. Clinical Psychology: Science & Practice. 5:291-313.

· McGuffin, P., Cohen, S. and Knight, J. (2007). Homing in on depression genes. Am J Psychiatry. 164:195-197.

· Menke, A., Klengel, T. and Binder, E.B. (2012). Epigenetics, depression and antidepressant treatment. Curr Pharm Des. 18:5879-5889.

· Menke, A., Lehrieder, D., Fietz, J., Leistner, C., Wurst, C., Stonawski, S., Reitz, J., Lechner, K., Busch, Y., Weber, H., Deckert, J. and Domschke, K. (2018). Childhood trauma dependent anxious depression sensitizes HPA axis function. Psychoneuroendocrinology. 98:22-29.

· Miller, A.H. and Raison, C.L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews. Immunology. 16(1):22-34.

· Monroe S.M. and Depue R.A. (1991). Life stress and depression. In: Becker J, Kleinman A, editors. Psychosocial aspects of depression. Hillsdale, NJ: Erlbaum; pp. 1101–1130.

· Nuru-Jeter, A., Chae, D.H., Price, M., Telesford, J., Mendoza-Denton, R. and Woods-Giscombe, C. (2018). Anticipatory Racism Threat and Superwoman Schema: Elucidating the Relationship Between Racial Discrimination and Chronic Inflammation. Circulation. 128:A9550.

· Obayashi, K., Saeki, K. and Kurumatani, N. (2018). Bedroom Light Exposure at Night and the Incidence of Depressive Symptoms: A Longitudinal Study of the HEIJO-KYO Cohort. Am J Epidemiol. 187(3):427-434.

· Pall, M.L. (2016). Microwave frequency electromagnetic fields (EMFs) produce widespread neuropsychiatric effects including depression. J Chem Neuroanat. 75(Pt B):43-51.

· Purslow, C. (2013). Linking Clostridium difficile infection with depression. Expert Rev Anti Infect Ther. 11(8):763

· Rao, T.S., Asha, M.R., Ramesh, B.N. and Rao, K. S. (2008). Understanding nutrition, depression and mental illnesses. Indian journal of psychiatry. 50(2): 77-82.

· Ratnaseelan, A.M., Tsilioni, I. and Theoharide, T.C. (2018). Mycotoxins on neuropsychiatric symptoms and immune processes. Clinical Therapeutics. 40(6):903-917.

· Sánchez-Villegas, A., Toledo. E., De Irala. J. et al. (2012). Fast-food and commercial baked goods consumption and the risk of depression. Public Health Nutr. 15(3):424-432.

· Sánchez-Villegas, A., Verberne, L., De Irala, J. et al. (2011). Dietary fat intake and the risk of depression: the SUN Project. PLoS One.6(1):e16268.

· Scafuri, B., Varriale, A., Facchiano, A., D’Auria, S., Raggi, M.E. and Marabotti, A. (2017). Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation. Sci Rep. 7:15156.

· Shenassa, E.D., Daskalakis, C., Liebhaber, A., Braubach, M. and Brown, M. (2007). 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. American journal of public health. 97(10):1893-1899.

· Stevens, B.R., Goel, R., Seungbum, K., Richards, E.M., Holbert, R.C., Pepine, C.J. and Raizada, M.K. (2018). Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut. 67(8):1555-1557.

· Stilling, R.M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T.G. and Cryan, J.F. (2016). The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis?Neurochem Int.99:110-132.

· Sullivan, P.F., Neale, M.C. and Kendler, K.S. (2000). Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 157:1552-1562.

· Tan, J., McKenzie, C., Potamitis, M., Thorburn, A.N., Mackay, C.R. and Macia, L. (2014). The role of short-chain fatty acids in health and disease. In: Advances in Immunology. Alt FW. editor. Cambridge, MA: Academic Press Inc. p. 91-119.

· Wang, P.S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M.C., Borges, G., Bromet, E.J., Bruffaerts, R., et al. (2007). Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys. Lancet. 370(9590):841-850.

· Wang, X., Zhang, L., Lei., Y., Liu, X., Zhou, X., Liu, Y., Wang, M., Yang, L., Zhang, L., Fan, S. and Xie, P. (2014). Meta-analysis of infectious agents and depression. Sci Rep. 4:4530.

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