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Introduction & epidemiology
The World Health Organization estimates that approximately 322 million people – more than 4 percent of the global population – currently live with depression, the most common mental health disorder worldwide. Between 2005 and 2015, rates of depression increased by more than 18 percent, and public health experts predict that by the year 2020, depression likely will rank second in the global burden of disease, measured by the number of years lost due to poor health, disability, or early death. 
Often referred to as major depressive disorder in the research or clinical setting, depression is characterized by profound sadness, fatigue, altered sleep and appetite, and feelings of guilt or low self-worth. The condition is often accompanied by perturbations in metabolic, hormonal, and immune function and inflammatory responses. 
A number of adverse medically and socially significant outcomes are associated with depression, many of which may elicit multigenerational effects due to both genetic and epigenetic influences. People who have depression are at greater risk of developing numerous chronic diseases, including cardiovascular disease, type 2 diabetes, cognitive decline, and osteoporosis. Part of this increased risk may be mediated by decreased telomere length. Findings from multiple studies demonstrate that people with depression have shorter telomeres, which are associated with increased morbidity and mortality.    In addition, chronic, severe depression that is untreated or accompanied by severe physical complaints is associated with an increased risk of suicide. In fact, more than half (56 to 87 percent) of people who commit or attempt suicide have depression.
The global prevalence of depression among women is nearly twice that in men, with an annual prevalence of 5.5 percent and 3.2 percent, respectively. This difference persists across races, cultures, and socioeconomic status, suggesting that the risk may stem from biological sex differences. Women also experience specific forms of depression-related illness, including premenstrual dysphoric disorder, postpartum depression, postmenopausal depression, and anxiety, which often coincide with periods of major hormonal changes, such as those that occur during puberty, prior to menstruation, following pregnancy, and at perimenopause, indicating female hormonal fluctuations may serve as a trigger for depression.
Animal studies consistently implicate female hormones in the etiology of depression. For example, in studies involving small groups of female macaques – monkeys that tend to form lifelong relationships with defined social orders comprised of dominant and subordinate members –subordinate females tend to develop behavioral patterns and physiological characteristics commonly observed in human depression, including low activity levels, increased heart rate, stress-response disturbances, and higher death rates. These phenotypic traits were associated with lower serotonin receptor levels and lower hippocampal volume, the latter of which was more extensive in postmenopausal monkeys, suggesting that ovarian hormones, including estrogen, may ameliorate depression risk.  Some evidence indicates that hormone replacement therapy, particularly during the perimenopausal period, may be useful in preventing postmenopausal depression in women.
Children & adolescents
Approximately 2 to 4 percent of children and 8 percent of adolescents living in the United States report having depression in any given year. Children and adolescents who experience a depressive episode are more likely to have recurrent depression as adults and are at greater risk for suicide. Depression risk factors for this population are varied and include female sex, family history of depression, chronic health conditions, overweight or obesity, experiencing a traumatic event (including natural disasters), witnessing or being a victim of violence, uncertainty about sexual orientation or gender identity, and living with family members who have mental or substance abuse disorders, among others.
Depression is less common in older adults (65 years and older) than in younger adults. Suicide rates, however, are higher among older adults than any other demographic. Depression in older adults may be masked by other health conditions, complicating diagnosis and treatment. The common practice of polypharmacy – the simultaneous use of multiple drugs (typically five or more) by a single patient – in older adults may increase their risk of developing depression.
Despite the recent increase in its prevalence, depression is not a newly identified condition. References to depressive illness were common among the medical texts of the ancient Greek physicians, who believed that depression arises from disturbances in the natural balance of the body's four fluids, or humors, which included blood, phlegm, yellow bile, and black bile. To their thinking, too much of the latter – the black bile – produced a dark state of melancholia, a construct that dominated medical thought until the 1600s.
Today, the etiology of depression remains unknown but is widely believed to be multifactorial, stemming from a confluence of psychological, physiological, and environmental elements. In addition, having a chronic medical condition increases a person's risk of developing depression. Conversely, depression can be a symptom of certain medical conditions, such as Parkinson's disease, multiple sclerosis, hypothyroidism, or Cushing's disease.   
Emotional or physical trauma, especially early in life, plays a key role in the pathophysiology of depression. It is a robust risk factor for developing depression in adulthood, especially in response to additional stress.
The body responds to stress by activating a complex set of self-regulating, adaptive processes that include both behavioral and physiological components to ensure survival. A key element in the stress response is the activation of the hypothalamus-pituitary-adrenal, or HPA, axis, a complex set of interactions that sits at the interface between stress and brain function.
Activation of the HPA axis begins when the hypothalamus releases the neurohormones corticotropin-releasing factor and arginine vasopressin into the blood vessels that connect the hypothalamus and the pituitary gland. The two neurohormones stimulate the anterior pituitary gland to produce and secrete adrenocorticotropic hormone into the bloodstream, which in turn promotes the synthesis and release of glucocorticoid hormones – primarily cortisol – from the adrenal glands. Prolonged cortisol secretion increases the risk of developing depression. Several neurotransmitters, including gamma-aminobutyric acid, endogenous opioids, norepinephrine, and serotonin, among others, work in concert in a series of negative feedback loops to modulate the activation of the HPA axis.
Hyperactivity of the HPA axis, however, is commonly observed in psychiatric disorders, including depression. For example, in animal studies involving rodents and non-human primates, young animals that are separated from their mothers for long periods exhibit HPA axis activity changes that persist into adulthood and resemble those observed in depressed people, including hyperactivity of the HPA axis. Similarly, clinical studies of women who are sexually or physically abused in childhood exhibit enhanced HPA axis activation in adulthood.
Another key player in the pathophysiology of depression is inflammation, a critical element of the body's immune system. Inflammation is a conserved biological response that developed during humans' ancient past, when regular exposure to pathogens dictated highly coordinated behavioral and immunological responses to ensure survival. The fallout of these responses is an "inflammatory bias"– a propensity for the body to launch an indiscriminate response to a stressor, regardless of its source.
Inflammation involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Whereas acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever, chronic inflammation occurs on the cellular level in response to internal and external stressors and is often “invisible.” Chronic inflammation is instrumental in the development of many diseases, including depression. Elevated biomarkers of inflammation, which are commonly observed in people who have depression, chronically activate the body's inflammatory response system, promoting the development of depressive symptoms and inducing changes in brain and neuroendocrine function. 
Compelling evidence suggests that the relationship between inflammation and depression is indeed causal. At least two double-blinded, placebo-controlled studies investigated the effects of injecting healthy adults with either lipopolysaccharide (also known as endotoxin – a component of bacterial cell membranes that elicits an immune response) or interferon-gamma, a proinflammatory cytokine.  Injection of either the endotoxin or the interferon-gamma increased the study participants' circulating levels of proinflammatory cytokines, including IL-6 and tumor necrosis factor-alpha. Interestingly, in both studies, participants also experienced an acute increase in depressive symptoms, anxiety, feelings of social disconnection, and anhedonia (a lack of reactivity to pleasurable stimuli)  that coincided with the peak of the proinflammatory response.
Whereas the early view of the mammalian central nervous system presumed that it was a fairly static complex, incapable of change, a growing body of evidence suggests that it retains its capacity for synaptic pruning – the process by which extra neurons and synaptic connections are eliminated and new neural circuits are established as a means to increase the efficiency of neuronal transmissions – throughout life.
The establishment of these new circuits is dependent upon adequate neurogenesis, the process of forming new neurons. Neurogenesis is essential during embryonic development but also continues in certain brain regions throughout human lifespan. In particular, areas within the hypothalamus and the olfactory bulb serve as "neurogenic niches," where nascent neurons can undergo differentiation and integration. Derangements in adult neurogenesis and subsequent connectivity losses or failures have been implicated in depression, and may further impede responsiveness to antidepressant therapies. 
Mice with impaired adult neurogenesis exhibit sustained stress hormone levels and display depressive-like symptoms. In addition, when mice were exposed to an acute psychosocial stressor at the time of nerve cell generation, fewer new cells were produced. Furthermore, if the stressor occurred after nerve cell generation, the cells were less likely to survive long-term.
Several factors contribute to impaired neurogenesis, including hyperactivity of the HPA axis; insufficient production of neurotrophins (neural growth factors), in particular, brain-derived neurotrophic factor, or BDNF; inflammation; and perturbed gut microbial signaling.
Circadian rhythms, the body’s 24-hour cycles of biological, hormonal, and behavioral patterns, modulate a wide array of physiological processes, including the production of hormones that regulate sleep, hunger, metabolism, and others. Roughly 10 to 40 percent of gene expression in mammals is under circadian control, including genes in the brain, liver, and muscle. As such, circadian rhythmicity may have profound implications for mental health and mood.
External cues, termed zeitgebers, or "time givers," provide cues to the body's internal clocks to regulate behavioral, hormonal, and biochemical processes. Food intake and light exposure are the two most powerful zeitgebers, and alterations in a person's exposure to these cues, whether from shift work, late-night eating, or other variations from the normal day-night cycles of activity to which our bodies are entrained, elicit deleterious effects on human health.
For example, light directly influences the production of melatonin, a hormone that regulates the body's response to darkness and ultimately influences mood. People who experience seasonal affective disorder, commonly known as SAD, show significant improvement following the administration of melatonin. In addition, people who have depression often exhibit cyclical patterns of depressive symptoms, typically manifesting more severe symptoms in the morning hours. 
Genetic factors contribute to a person's susceptibility to depression. Findings from a meta-analysis that investigated the genetic epidemiology of depression indicate that roughly one-third to one-half of the risk for developing depression is due to genetic influences. Environmental exposures, such as early life trauma, parenting styles, socioeconomic status, and others – also play a role. These exposures are unique to each individual, however, suggesting that depression is likely due to gene-environment interactions. A different meta-analysis that used data on more than 800,000 people from three large genome-wide association studies of depression identified 269 genes, 102 independent variants, and 15 gene sets that were associated with depression, some of which influence synaptic structure and neurotransmission.
Interestingly, genetic factors and circadian rhythms are intrinsically linked. For example, the NPAS2 gene encodes for the protein Npas2, which functions in the brain as a generator and maintainer of circadian rhythm. It descends from the same ancestral gene as the CLOCK gene, which encodes for the protein Clock, a key regulator of circadian rhythms. In the absence of Clock, production of Npas2 increases to maintain rhythms in the suprachiasmatic nucleus, the part of the brain that acts as the master regulator or "pacemaker" of circadian rhythm. Mice that lack the NPAS2 gene exhibit sleep disturbances.
Furthermore, in a study of more than 500 Spanish adults, those who carried two of the G alleles (G;G) for the NPAS2 gene had a 2.88-fold increased risk of major depression or bipolar disorder. Carriers of only one allele experienced a similar effect, but of lesser magnitude, with a 1.44-fold increased risk.
Depression is a side effect of many prescription drugs, especially isotretinoin (an anti-acne drug); varenicline (commonly known as Chantix®, a smoking-cessation drug); rimonabant and taranabant (anti-obesity drugs); and many classes of cardiovascular drugs, including beta-blockers, calcium channel blockers, and angiotensin II inhibitors. Cardiovascular drugs are commonly prescribed for older adults, and, as mentioned above, the widespread practice of polypharmacy among many older adults places this population at greater risk of developing depression.
The gut-brain axis, a bidirectional signaling pathway between the gastrointestinal tract and the nervous system, is a critical component of mental health. Key elements of this pathway are the tens of trillions of bacteria, viruses, and fungi that comprise the intestinal microbiota. Stress, diet, and mood can work together or independently to influence the gut microbial population, ultimately promoting dysbiosis – an imbalance in its overall composition – and a lack of microbial diversity. Dysbiosis and low diversity contribute to altered immune function, deranged appetite and metabolism, and mood changes.
Gut microbes also influence dietary choices, which, in turn, influence which microbes survive.  Adherence to a Western diet, which is high in processed foods, refined sugar, and saturated fats, promotes a misfit population of microbes that chronically activates the body's immune system.  This cycle of stress, poor dietary choices, and immune responses sets the stage for self-sustaining systemic inflammation and low mood.
Research demonstrates that people with depression are often deficient in several key nutrients involved in modulating inflammation, neurogenesis, and aspects of metabolism, including folate, vitamins B6 and B12, and omega-3 fatty acids.   A prospective study of more than 16,000 people in Spain demonstrated that deficiency in more than four essential micronutrients was associated with increased risk for developing depression.
Depressed people often exhibit unhealthy dietary patterns, such as poor or excessive appetite, skipping meals, "emotional eating," or preferential consumption of sweet foods. Some of these behaviors are likely due to derangements in brain function. For example, whereas depression-related loss of appetite is associated with poor interoception (the ability to perceive sensations from inside the body, including hunger) depression-related increases in appetite are associated with hyperactivity in the brain's reward circuitry.
Multiple studies have found low serum levels of zinc in people with depression.  This association has also been noted among cases of treatment-resistant depression and the level of zinc deficiency appears to be directly linked to the severity of depressive symptoms.    In one preclinical study, zinc supplementation was found to significantly improve symptoms when used in combination with a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant. Zinc supplementation combined with the use of a multivitamin has also been shown to reduce anger and depression compared to the use of a multivitamin alone.
Nearly everyone has experienced an episode of low mood and has simultaneously recovered. Clinical depression, however, is more often a chronic disorder that may last months, years, or even a lifetime. In fact, the long-term prognosis is not favorable, and few people with depression experience full recovery. Despite the overly optimistic view of depression and recovery in the lay world and even in the medical field, more than 80 percent of people who experience an episode of depression will likely still suffer from the disorder six years later.
Managing depressive symptoms
Selective serotonin reuptake inhibitors (SSRIs) in conjunction with cognitive behavioral therapy are typically the first line of treatment for people who have depression. The response to treatment with SSRIs is moderate and variable, however, ranging from 40 to 60 percent, with remission rates ranging from 30 to 45 percent.
Several non-pharmacological adjunct therapies have demonstrated effectiveness in modulating the symptoms of depression (including treatment-resistant depression), and include public health interventions, physical activity, dietary modification, meditation, sauna use, and light therapy, among others.
Public health interventions
Strategies for treating older adults with depression that utilize structured activities (such as exercise) and problem-solving strategies, in conjunction with psychotherapy and/or antidepressants, have been effective in reducing the number of days the participants experienced depressive symptoms. In a study involving more than 400 older adults seen in primary care clinics, those randomized to intervention programs involving exercise or problem-solving strategies experienced an average of 115 more depression-free days per year than those who received the typical care.
Exercise, particularly endurance or high-intensity aerobic exercise, may impact kynurenine metabolism in a way that is beneficial for creating resilience against stress-induced depression.
Several observational studies have found that people who are physically active are less likely to develop depression. For example, a Mendelian randomization study – a type of research method that provides evidence of links between modifiable risk factors and disease based on genetic variants within a population – demonstrated that higher levels of physical activity may be causally linked with a reduced risk for depression. In addition, numerous randomized-controlled trials have found that exercise mitigates depressive symptoms, facilitates recovery from depressive disorders, and prevents relapse. For example, a meta-analysis of 25 randomized controlled trials comparing exercise versus control groups found that exercise reduced depressive symptoms, and this effect was particularly strong for moderate- to vigorous-intensity aerobic exercise.
Exercise and physical activity promote a wide range of neurogenic and neuroprotective responses that mediate depressive symptoms, such as increases in tryptophan transport into the brain to support serotonin synthesis; prevention of the formation of neurotoxins associated with depression; increases in anti-inflammatory factors; and increases in the neurotrophin BDNF.    
- Learn more about how exercise prevents or reduces the symptoms of depression in this podcast from Dr. Rhonda Patrick
An abundance of scientific studies suggests that adherence to a diet that is rich in fruits, vegetables, and fatty fish is associated with reduced depressive symptoms.   In a 12-week randomized controlled trial involving people who had moderate to severe depression who received either dietary support that encouraged the consumption of healthy foods versus social support only, those who received the dietary support had fewer symptoms of depression at the end of the trial.
Fruits and vegetables provide essential nutrients such as folate and B vitamins, but, perhaps more importantly, they deliver bioactive compounds such as polyphenols, isothiocyanates, stilbenes, and others. These compounds elicit hormetic responses in the body that trigger mild cellular stress, which, in turn, induces beneficial stress response pathways that reduce inflammation and protect cells from damage.
Omega-3 fatty acids
Fatty fish (such as salmon) provide omega-3 fatty acids, which have important anti-inflammatory, immunomodulatory, and neuroprotective properties. Eicosapentaenoic acid and docosahexaenoic acid, omega-3 fatty acids that are found in fatty fish and fish oil supplements, promote the production of anti-inflammatory mediators such as resolvins and protectins. In a trial involving 28 people with depression, participants who took an omega-3 fatty acid supplement had significant improvements in their depressive symptoms compared to those who took a placebo. In a separate trial involving 20 people with recurrent depression, participants who took an omega-3 fatty acid supplement in conjunction with their antidepressant therapy showed marked reductions in their symptoms. Findings from a meta-analysis of studies investigating the therapeutic value of omega-3 fatty acids suggest that administration of high dose supplemental omega-3 fatty acids in conjunction with antidepressant therapies offer the greatest promise in treating the symptoms of depression.
Probiotics, which can be obtained in fermented foods and dietary supplements, are live microorganisms that impart health benefits when consumed. A randomized, triple-blind, placebo-controlled trial involving 20 healthy adults who took a probiotic supplement containing 2.5 billion bacteria per gram of Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) for four weeks experienced reduced reactivity to sad mood, as evidenced by reduced rumination and aggressive thoughts. These findings suggest that probiotic intake may help reduce negative thoughts associated with a sad mood.
Sauna use has been shown to reduce symptoms of depression, likely through its effects on the expression of heat shock proteins, transcriptional regulators, and pro- and anti-inflammatory factors.
In a randomized controlled trial involving 28 people diagnosed with mild depression, participants who received four weeks of sauna sessions experienced reduced symptoms of depression – such as improved appetite and reduced body aches and anxiety – compared to the control group, which received bed rest instead of sauna therapy. Similarly, in a randomized, double-blind study of 30 healthy adults diagnosed with depression, participants who were exposed to a single session of whole-body hyperthermia in which core body temperature was elevated to 38.5°C (101.3°F) experienced an acute antidepressant effect that was apparent within a week of treatment and persisted for six weeks after treatment.
- Learn more about the health and mood-enhancing benefits associated with sauna use in this topic article from FMF.
Exposure to bright light, particularly blue light, boosts alertness and improves mood by acting as a robust circadian trigger in the morning and daytime hours. A study involving 20 healthy men and women who were kept in an environment free of time cues for about 10 days found that seven hours of exposure to approximately 10,000 lux of bright light, roughly equivalent to the amount of light available at dawn or dusk, reduced participants' cortisol levels. Participants who were exposed to dim light similar to candlelight experienced little change in cortisol levels.
Bright light may interfere with sleep patterns at night, however, by triggering the release of melanopsin, a light-sensitive protein that shifts the activity of cells in the brain’s suprachiasmatic nucleus into an active day pattern. More than 80 percent of depressed patients report poor sleep quality, a common feature of depression. Poor sleep quality is a strong risk factor for suicide.
- Listen to circadian biologist Dr. Satchin Panda discuss melanopsin and the role of the SCN in circadian rhythm.
Bright light therapy has long been appreciated as a useful intervention for people experiencing seasonal affective disorder. Recent research, however, suggests it may be effective in treating non-seasonal depression. In a randomized controlled trial involving 122 adults with depression, bright light treatment, both as monotherapy and in combination with the SSRI fluoxetine (commonly known as Prozac®) markedly reduced the participants' symptoms of depression. The combination treatment had the most consistent effects.
As described above, emotional stress is a trigger that can increase the risk for developing depression. Some intervention trials have utilized mindfulness and meditation as strategies for mitigating stress and reducing this risk. In a study involving 76 adults who had moderate stress levels, those who received mindfulness meditation training experienced greater improvements in their depressive symptoms than those who received only health education. A meta-analysis of 47 studies involving more than 3,500 people found that mindfulness meditation was moderately effective at reducing anxiety, depression, and pain.
- Learn more about how meditation mediates the effects of stress in this podcast from Dr. Rhonda Patrick
Transcranial direct current stimulation
Non-invasive brain stimulation is emerging as a potential therapy to mitigate symptoms of depression. Transcranial direct current stimulation, or tDCS, utilizes a weak electrical current that is delivered to scalp electrodes via a portable battery-powered stimulator. It modulates brain activity in a desired region or neural network by strengthening or weakening synaptic transmissions between neurons, thereby enhancing the synapses' ability to change their strength – a critical feature of neuronal development and normal brain functions. 
In a double-blind randomized sham-controlled trial involving 30 adults who demonstrated poor response to SSRI therapy, participants who received tDCS showed marked improvements in their depressive symptoms, and these improvements persisted one month after the treatment.
The ability to interpret or "read" emotions such as anger, disgust, or happiness on others' faces is often impaired in people who have depression. A randomized crossover placebo-controlled study involving 17 adults with depression demonstrated that tDCS improved emotion recognition deficits commonly associated with depression.
Psychedelic drugs, a class of hallucinogenic compounds that includes lysergic acid diethylamide, otherwise known as LSD, mescaline, psilocybin, and others, have long been known for their psychoactive properties. These drugs work in part by activating the 5-HT2A serotonin receptors, which modulate a wide range of physiological functions, including mood. Recent research suggests that these drugs may be useful in treating the symptoms of depression.
A randomized, double-blind, cross-over trial that investigated the effects of psilocybin in people diagnosed with life-threatening cancer found that the drug mitigated symptoms of depression and anxiety. Approximately 80 percent of the study participants continued to experience these positive effects on mood six months later. In addition, in an open-label feasibility trial involving 12 adults with treatment-resistant depression, participants experienced marked decreases in symptoms of depression, anxiety, and anhedonia following psilocybin administration.
Modulation of the immune system by psychedelics
Interestingly, a growing body of evidence suggests that psychedelic drugs may also modulate the immune system, a mechanism that may have relevance for depression. Cell studies have demonstrated that an amphetamine psychedelic drug suppresses TNF-alpha-related inflammation and inhibits the production of the pro-inflammatory cytokine, IL-6, and others through its activation of the serotonin 5-HT2A receptor, in the same fashion as other psychedelic drugs. Similar effects were observed in mice following the administration of an amphetamine psychedelic.
- Learn more about the mood-altering effects of psychedelic compounds in this podcast featuring Dr. Roland Griffiths.
Depression is a complex disorder that affects the lives of millions of people worldwide. Its causes are likely multifactorial and involve the interplay between environment, genetics, neuroendocrine systems, and intracellular signaling pathways. Whereas typical treatment options for depressive symptoms include psychological and pharmacological approaches, a growing body of evidence supports the use of non-pharmacological interventions.
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