The mainstream view on the cause of depression relies largely on the monoamine hypothesis - a theory proposing that deregulation in neurotransmitter signalling is the sole cause of depression. This has been the ground for the primary utilisation of antidepressant drugs in the management of depression for decades. However, this theory fails to take into account various other well-studied causes, and partly explains the poor success rate of antidepressant medications in some cases. Conventional medicine overlooks several important biological factors that influence depression, thereby undermining the likelihood that a holistic strategy will be employed to thoroughly manage a patient’s depression. If left unchecked, aberrations among these under-appreciated factors may work together to create metabolic and neurochemical imbalances that provoke mood changes and initiate depression.Critical omissions from conventional assessment of depression include: Hormonal imbalances Nutritional Deficiencies Oxidative stress and mitochondrial dysfunction Insulin resistance and chronic inflammation Hormonal influencesBalanced and youthful concentrations of hormones can help control depression, and astute clinicians often find hormonal imbalances in patients with depression. Because a wide range of hormones can influence depression, it is important to discern which hormone(s) may be an underlying factor when considering depression. For example, thyroid function directly affects metabolism and brain function, and low thyroid activity can contribute to depression. Conventional medicine relies on overly broad thyroid lab ranges, failing to recognize many cases of sub-optimal thyroid function. Overt hypothyroidism has been shown to perturb serotonin signalling in the brain, which can contribute to depression. Furthermore, because the brain requires sufficient thyroid hormones to function optimally, a low thyroid hormone status can contribute to overall loss of function and degeneration in the brain, including the areas of the brain that govern mood. Hashimoto’s thyroiditis, an autoimmune thyroid disease, can cause a person’s metabolism to swing between overly active to overly depressed. These swings can mimic the symptoms of bipolar disorder and cause misdiagnosis and inappropriate treatment.Sex hormones also influence mood and depression. Women are more susceptible to anxiety than men and also experience more depression when they are pregnant, postpartum, premenstrual and menopausal than at other times in life. These general observations have piqued the interest of scientists and given rise to an expanding body of research linking depression with sex hormone imbalances. By now, it is well known that most steroid hormones (e.g., pregnenolone, estrogen, progesterone, testosterone, and DHEA) are neurologically active. In fact, the brain contains large numbers of receptors for DHEA, estrogen, and progesterone. These hormones affect many functions in the brain, including the regulation of mood. In the follicular phase of menses, when estrogen levels are high, women produce more serotonin and experience an improved mood. When estrogen decreases during the premenstrual period, serotonin levels drop, contributing to the negative mood and personality shifts associated with PMS. Likewise, the drop in estrogen during menopause is associated with reduced serotonin production and a negative impact on mood and cognition. This is evidenced by the fact that SSRIs have been shown to improve mood and cognitive function in menopausal women. In addition, testosterone deficiency has been linked with depression in men, which is not surprising since testosterone plays an important role in brain function, including mood regulation. In studies, select populations of men were more likely to be depressed if their total and/or free testosterone levels are low; these included those with heart disease, HIV/AIDS, and the elderly. Medical research acknowledges the link between hormonal imbalances and depression; however, conventional doctors rarely evaluate and address hormone status when treating depression. Instead, they frequently dismiss such imbalances as a normal part of aging, while in truth, restoring youthful hormonal status may effectively combat multiple health deficits associated with aging, including mood imbalances. Medical research acknowledges the link between hormonal imbalances and depression; however, conventional doctors rarely evaluate and address hormone status when treating depression. Instead, they frequently dismiss such imbalances as a normal part of aging, while in truth, restoring youthful hormonal status may effectively combat multiple health deficits associated with aging, including mood imbalances. Nutritional deficiency or insufficiency Nutrition plays an essential role in brain function, and poor nutrition significantly increases one’s risk for depression. Dietary nutrients influence nervous system function in multiple ways. Important dietary nutrients include: B-complex vitamins: B-complex vitamins serve as cofactors for the production of neurotransmitters. Inadequate levels of B vitamins, especially folate, vitamin B12, niacin, and vitamin B6, can disrupt neurotransmitter synthesis. This not only may lead to mood alterations, but also can impact overall brain function, memory, and cognition. An Optimal balance of omega-3 and omega-6 fatty acids: Fatty acids are critical components of nerve cell membranes and play an important role in neuronal communication. Fatty acid imbalances can impair the transmission of messages between nerve cells, leading to cognitive deficits and mood alterations, including depression. A Vitamin D activity: A vitamin-D insufficiency, which is very common even among dedicated supplement users, is linked with seasonal depression. Recent evidence suggests that it also may contribute to general depression through its considerable influence on genetic activity, its ability to control inflammation, and other mechanisms. It is important to remember that optimal brain function necessitates all of these nutritional aspects be addressed simultaneously. Oxidative Stress and Mitochondrial Dysfunction Brain tissue is particularly susceptible to oxidative damage due to its high concentrations of phospholipids and the exhaustive metabolic rate among neurons. A growing body of research suggests that oxidative stress contributes to depression and other brain-related disorders. This is thought to result from either an increase in damaging reactive oxygen species (ROS), a decrease in antioxidant defence mechanisms, or a combination of the two. These mechanisms become especially important with advancing age. Newer research sheds light on the critical role of mitochondria and neurotransmission and mood regulation. Mitochondria are the “powerhouses” in each cell that generate energy. In an intriguing study, researchers measured the content of mitochondrial DNA within white blood cells in aging patients who were depressed, and in an age-matched group who were not depressed. The subjects with depression had significantly fewer mitochondria than non-depressed controls, leading researchers to suggest, “Mitochondrial dysfunction could be a mechanism of geriatric depression”. In a similar study, greater numbers of mitochondria in peripheral cells were associated with improved cognitive function in healthy elderly women. Preliminary research suggests that two nutrients, coenzyme Q10 and acetyl-L-carnitine, which support mitochondrial function, may influence depression. A small study of 35 depressed patients in comparison to 22 healthy volunteer controls showed that plasma CoQ10 levels were significantly lower in the depressed patients. Levels were also lower in treatment-resistant patients, as well as those with chronic fatigue. Several studies of geriatric depression have investigated acetyl-L-carnitine. Acetyl-L-carnitine also has been found to relieve depression and improve quality of life in patients with liver disease and to ease depressive symptoms significantly in patients with fibromyalgia. Insulin Resistance Recent data suggest a direct link between insulin resistance and depression. Evidence suggests that a popular glucose control agent, Metformin, may influence psychiatric health. Individuals who are overweight, have suboptimal glucose control, or have diabetes with concurrent depression may find that losing weight and gaining control over their glucose levels eases their depressive symptoms. Scientific literature indicates that for optimal health, fasting glucose levels should fall between 4.0 and 5.0 mmol/l and 2-hour postprandial (2 hours after a meal) glucose levels should not exceed 6.7 mmol/l.Chronic Inflammation Several studies support the role of inflammation and immune system deregulation in depression. Studies have found elevated levels of inflammatory cytokines (signalling molecules with which immune cells communicate) in patients suffering from major depression, late-life depression, and in patients who do not respond to SSRIs. These cytokines include the interleukins IL-1beta and IL-6, as well as the cytokines INF-gamma and TNFalpha. Studies show an association between the systemic inflammation marker C-reactive protein (C-RP) and major depression. Moreover, elevated CRP levels are associated with a number of other significant health problems such as cardiovascular disease. Health Renewal suggests that women target a CRP blood level of less than 1.0 mg/L and men target a level of less than 0.55 mg/L. In prospective studies involving patients being treated with recombinant cytokines for immune-related conditions, depression is observed to develop after inflammation initiates several other undesirable metabolic cascades. This has led some researchers to identify depression as a late-stage consequence of chronic inflammation. Research innovations even suggest that future antidepressant medications may be anti-inflammatory in nature.