Major depressive disorder

Major depressive disorder, also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introduced by a group of US clinicians in the mid-1970s, the term was adopted by the American Psychiatric Association for this symptom cluster under mood disorders in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders, and has become widely used since. The disorder causes the second-most years lived with disability, after low back pain.
The diagnosis of major depressive disorder is based on the person's reported experiences, behavior reported by family or friends, and a mental status examination. There is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms. The most common time of onset is in a person's 20s, with females affected about three times as often as males. The course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent episodes.
Those with major depressive disorder are typically treated with psychotherapy and antidepressant medication. While a mainstay of treatment, the clinical efficacy of antidepressants is controversial. Hospitalization may be necessary in cases with associated self-neglect or a significant risk of harm to self or others. Electroconvulsive therapy, ketamine, esketamine, and psilocybin are the most effective and safe first-line treatments for treatment-resistant depression, though regulatory approval and clinical availability vary by country.
Major depressive disorder is believed to be caused by a combination of genetic, environmental, and psychological factors, with about 40% of the risk being genetic. Risk factors include a family history of the condition, major life changes, childhood traumas, environmental lead exposure, certain medications, chronic health problems, and substance use disorders. It can negatively affect a person's personal life, work life, or education, and cause issues with a person's sleeping habits, eating habits, and general health.

Signs and symptoms

A person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities. Depressed people may be preoccupied with or ruminate over thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness.
Other symptoms of depression include poor concentration and memory, withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common; in the typical pattern, a person wakes very early and cannot get back to sleep. Hypersomnia, or oversleeping, can also happen, as well as day-night rhythm disturbances, such as diurnal mood variation. Some antidepressants may also cause insomnia due to their stimulating effect. In severe cases, depressed people may have psychotic symptoms. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. People who have had previous episodes with psychotic symptoms are more likely to have them with future episodes.
A depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the World Health Organization's criteria for depression. Appetite often decreases, resulting in weight loss, although increased appetite and weight gain occasionally occur.
Major depression significantly affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health. Family and friends may notice agitation or lethargy. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements.
Depressed children may often display an irritable rather than a depressed mood; most lose interest in school and show a steep decline in academic performance. Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness". Elderly people with depression may not present with classical depressive symptoms. Diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases.

Cause

The etiology of depression is not yet fully understood. The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis–stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The preexisting vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood. American psychiatrist Aaron Beck suggested that a triad of automatic and spontaneous negative thoughts about the self, the world or environment, and the future may lead to other depressive signs and symptoms.

Genetics

Genes play a major role in the development of depression. Family and twin studies suggest that genetic factors account for nearly 40% of the variation in risk for major depressive disorder. Like most psychiatric disorders, major depression is likely shaped by a combination of many individual genetic influences. In 2018, a genome-wide association study discovered 44 genetic variants linked to risk for major depression; a 2019 study found 102 variants in the genome linked to depression. However, it appears that major depression is less heritable compared to bipolar disorder and schizophrenia. Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings. There are also other efforts to examine interactions between life stress and polygenic risk for depression.

Environmental

markedly increase the risk of major depression, especially if more than one type. Childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness. Some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility. Couples in unhappy marriages have a higher risk of developing clinical depression.
There appears to be a link between air pollution and depression and suicide. There may be an association between long-term PM2.5 exposure and depression, and a possible association between short-term PM10 exposure and suicide.
In a review, people who lived alone were found to have a 42% greater risk of depression.

Evolutionary

ary explanations propose that low mood may sometimes represent an adaptive response, such as conserving energy during adverse circumstances or promoting rumination on complex problems. Other models emphasize the potential social functions of depressive symptoms, including signaling a need for support. Recent reviews highlight both the heuristic value and limitations of these perspectives, noting that empirical support remains mixed.

Pathophysiology

The pathophysiology of depression is not completely understood, but current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA-axis dysfunction, and structural or functional abnormalities of emotional circuits.
Derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. First, acute depletion of tryptophan—an amino acid and a necessary precursor of the monoamine serotonin—can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression. Second, the correlation between depression risk and polymorphisms in the 5-HTTLPR gene, which codes for serotonin receptors, suggests a link. Third, decreased size of the locus coeruleus, reduced activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptors, and evidence from rat models suggest decreased adrenergic neurotransmission in depression. Furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor D₁ binding in the striatum, and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression. Lastly, increased activity of monoamine oxidase, an enzyme that degrades monoamines, has been associated with depression. However, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway.
One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is that a desensitization of self-inhibition in raphe nuclei by the increased serotonin, mediated by antidepressants, occurs before the therapeutic efficacy of the drugs can be realized. However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls; the finding of increased jugular 5-HIAA in people who are depressed that normalized with selective serotonin reuptake inhibitor treatment, and the preference for carbohydrates in people who are depressed. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. A 2022 review found no consistent evidence supporting the serotonin hypothesis linking serotonin levels and depression.
HPA-axis abnormalities have been suggested in depression given the association of CRHR1 with depression and the increased frequency of dexamethasone test non-suppression in people who are depressed. However, this abnormality is not adequate as a diagnosis tool because its sensitivity is only 44%. These stress-related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed. Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors. Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.
There is also a connection between the gut microbiome and the central nervous system, otherwise known as the Gut–Brain axis, which is a two-way communication system between the brain and the gut. Experiments have shown that microbiota in the gut can play an important role in depression, as people with MDD often have gut-brain dysfunction. One analysis showed that those with MDD have different bacteria in their guts. Bacteria Bacteroidetes and Firmicutes were most affected in people with MDD, and they are also impacted in people with irritable bowel syndrome. Another study showed that people with IBS have a higher chance of developing depression, which shows the two are connected. There is even evidence suggesting that altering the microbes in the gut can have regulatory effects on developing depression.
Theories unifying neuroimaging findings have been proposed. The first model proposed is the limbic-cortical model, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing. Another model, the cortico-striatal model, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures result in depression. Another model proposes hyperactivity of salience structures in identifying negative stimuli and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies.