Causes of Depression
Research spanning the last 20 to 30 years has examined a range of influences that contribute to depression. These include genetics, brain chemistry, early life trauma, negative thinking, one’s personality and temperament, stress, and difficulty relating to others.7 Moreover, emerging scientific research suggests that metabolic phenomenon such as inflammation, oxidative stress, and hormonal imbalances can cause or exacerbate depression as well.8,9
Impaired Stress Response
When a person experiences stress—whether it’s physical or emotional, internal or external—the body copes through a complex system of adaptive reactions. This response involves the release of glucocorticoids, or stress hormones, which stimulate adaptive changes throughout the body.
A stress response is designed to help us confront or escape danger by redirecting blood flow to the muscles, dilating the pupils, inhibiting digestion, and releasing stored fatty acids and glucose (blood sugar) to be used by the muscles. This process is known as the fight-or-flight response.
The fight-or-flight response originates in the brain. When the hypothalamus, the brain’s “control tower,” perceives a threat, it sends chemical signals to the brain’s pituitary gland, also known as the master hormone gland. The pituitary gland then sends chemical signals to the adrenal glands, which sit atop the kidneys. The adrenal glands then release the stress hormone cortisol, which triggers many of the physiological responses to danger.
Almost all animals share the fight-or-flight response, as it is paramount for survival. Although we were designed to undergo this response on only an occasional basis, modern humans cope with relentless stress. Such things as financial worries, deadline pressures at work or school, emotional challenges, excessive caloric intake, poor diet, obesity, inactivity, and environmental toxins chronically activate the hypothalamic-pituitary-adrenal axis, keeping us in a perpetual fight-or-flight response. The result is an increased rate of cardiovascular disease, diabetes, and mood disorders such as depression and anxiety.
The relationship between chronic stress, depression, and anxiety is complex, but incredibly powerful. For instance, the chronic elevation of glucocorticoids (primarily cortisol) caused by chronic stress actually changes the physical structure of the brain.
Chronic exposure to glucocorticoids shifts dendrites, the branches of neurons that receive signals from other neurons, into less functional patterns. Research links this phenomenon with alterations in mood, short-term memory, and behavioral flexibility.10 Glucocorticoids blunt the brain’s sensitivity to serotonin, the mood-regulating neurotransmitter most often associated with depression.11,12 Chronic stress also increases one’s susceptibility to neuronal damage and impairs neurogenesis, the process by which new neurons are “born.”10
Interestingly, emerging research suggests that drugs used to treat anxiety and depression may stabilize mood not only by acting on neurotransmitters, but also by regulating the brain’s receptors for stress hormones.13 These new findings strongly support the importance of controlling the stress response in order to alleviate mood disorders. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to adapt efficiently to stress, with increased rates of anxiety and depression.14-16
Fortunately, a number of relaxation techniques and coping styles can improve depression, further emphasizing the role of stress in depression. These approaches include Mindfulness-Based Stress Reduction,17 meditation,18 biofeedback,19 progressive muscle relaxation20 and an integrative health approach that combines relaxation, nutrition, and exercise.21
Recent studies suggest some of these techniques influence genetic activity regulating depression.20 Brain imaging techniques show meditation significantly affects neurotransmitter levels and the activity of various parts of the brain that facilitate relaxation.18
Traumatic Events and Post-Traumatic Stress Disorder
Research establishes that trauma, such as the sudden loss of a family member, sexual abuse, or war-related traumas, contributes significantly to prolonged periods of depression. The effects are more pronounced when the trauma occurs in childhood; childhood trauma can considerably alter the structure and function of the brain, increasing susceptibility to depression and anxiety later in life.22
Social Network and Personal Relationships
Lack of meaningful social contact with others has been linked to depression, while evidence increasingly shows that close personal relationships and social networks positively affect mood and health.23 Loving relationships, social connection and support, work-related passion and recognition, and a good marriage help prevent depression.24,25 Interestingly, it also has been shown that while a good marriage benefits both men and women, it seems to be more important for men from an overall health standpoint.
Magnetic resonance imaging (MRI) shows that the areas of the brain that orchestrate thinking, sleep, mood, appetite, and behavior function abnormally in depressed patients compared to non-depressed individuals. In addition, an imaging technique called single-photon emission computed tomography (SPECT) shows changes in brain blood flow and neurotransmitter activity in the depressed person’s brain.26,27 Although imaging technology can identify neurotransmitter imbalances, it cannot reveal why depression has occurred.
Depression is more common in those with HIV/AIDS,28 heart disease,29 stroke,30 cancer,31 diabetes,32 Parkinson's disease,33 and many other illnesses. Research shows a person with both depression and a serious illness is more likely to experience severe symptoms and find it harder to adapt to the medical condition. Studies also show that treating depression in this population may improve symptoms of the co-occurring illness in some instances.
Additionally, people dependent on alcohol or narcotics are significantly more likely to be depressed.34
Mainstream Medicine Overlooks Factors that Contribute to Depression
The mainstream view on the cause of depression relies largely on the monoamine hypothesis—a theory proposing that deregulation in neurotransmitter signaling is the sole cause of depression. This has been the grounds for the primary utilization 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.
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 underappreciated 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 imbalances. Balanced 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 signaling in the brain, which can contribute to depression.35 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.36 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.37-40
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 (eg, 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.
Accordingly, a number of studies link hormonal imbalances to various depressive disorders.41-44 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.45
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.46
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.47,48 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.49,50
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.
The role of hormones in treating depression will be examined more closely in the section of this protocol entitled “Hormone Restoration.”
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.
- 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.51
- Vitamin D activity. A vitamin-D insufficiency, which is very common even among dedicated supplement users,52 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.53 This is thought to result from either an increase in damaging reactive oxygen species, a decrease in antioxidant defense mechanisms, or a combination of the two. These mechanisms become especially important with advancing age.54
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.”55 In a similar study, greater numbers of mitochondria in peripheral cells were associated with improved cognitive function in healthy elderly women.56
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.57
Several studies of geriatric depression have investigated acetyl-L-carnitine.58 One study compared treatment with acetyl-L-carnitine to the medication amisulpride, an antipsychotic medication commonly used to treat depression. In 204 patients with chronic depression, both acetyl-L-carnitine and the pharmaceutical drug improved symptoms.59 Acetyl-L-carnitine also has been found to relieve depression and improve quality of life in patients with liver disease,60 and to ease depressive symptoms significantly in patients with fibromyalgia.61
Another nutrient, pyrroloquinoline quinine (PQQ), is an enzyme involved in the generation of new mitochondria and the maintenance of antioxidant defense systems.62-64 Supplemental PQQ has been shown to increase mitochondrial activity levels and to be neuroprotective in animal models.65-67 Since fewer mitochondria have been observed in depressed patients,55 PQQ may be supportive in this population.
Insulin resistance. Recent data suggest a direct link between insulin resistance and depression. In a small clinical study, treatment of depressed patients with the insulin-sensitizing drug pioglitazone alleviated depression while simultaneously improving their cardio-metabolic risk profiles.68 Evidence suggests that another popular glucose control agent, metformin, may influence psychiatric health as well.69 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 70 and 85 mg/dL, and 2-hour postprandial (2 hours after a meal) glucose levels should not exceed 120 mg/dL.
Chronic inflammation. Several studies support the role of inflammation and immune system deregulation in depression. Studies have found elevated levels of inflammatory cytokines (signaling molecules with which immune cells communicate) in patients suffering from major depression,70 late-life depression,71 and in patients who do not respond to SSRIs.72 These cytokines include the interleukins IL-1beta and IL-6, as well as the cytokines INF-gamma and TNF-alpha.
Studies show an association between the systemic inflammation marker C-reactive protein (C-RP) and major depression.73 Moreover, elevated CRP levels are associated with a number of other significant health problems such as cardiovascular disease. Life Extension 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.74
Research innovations suggest that future antidepressant medications may be anti-inflammatory in nature.75