Major depressive disorder

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Major depressive disorder (also known as clinical depression, major depression, unipolar depression, or unipolar disorder) is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities. The term "major depressive disorder" was selected by the American Psychiatric Association to designate this symptom cluster as a mood disorder in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) classification, and has become widely used since. The general term depression is often used to describe the disorder, but as it can also be used to describe other types of psychological depression, more precise terminology is preferred for the disorder in clinical and research use. Major depression is a disabling condition which adversely affects a person's family, work or school life, sleeping and eating habits, and general health. In the United States, approximately 3.4% of people with major depression commit suicide, and up to 60% of people who commit suicide have depression or another mood disorder.

The diagnosis of major depressive disorder is based on the patient's self-reported experiences, behavior reported by relatives or friends, and a mental status exam. There is no laboratory test for major depression, although physicians generally request tests for physical conditions that may cause similar symptoms. The most common time of onset is between the ages of 30 and 40 years, with a later peak between 50 and 60 years. Major depression is reported about twice as frequently in women as in men, although men are at higher risk for committing suicide.

Most patients are treated in the community with antidepressant medication and some with psychotherapy or counseling. Hospitalization may be necessary in cases with associated self-neglect or a significant risk of harm to self or others. A minority are treated with electroconvulsive therapy (ECT), under a short-acting general anaesthetic. The course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent major depressive episodes. Depressed individuals have shorter life expectancies than those without depression, in part because of greater susceptibility to medical illnesses. Current and former patients may be stigmatized.

The understanding of the nature and causes of depression has evolved over the centuries, though many aspects of depression remain incompletely understood and are the subject of discussion and research. Psychological, psycho-social, hereditary, evolutionary and biological causes have been proposed. Psychological treatments are based on theories of personality, interpersonal communication, and learning. Most biological theories focus on the monoamine chemicals serotonin, norepinephrine, and dopamine that are naturally present in the brain and assist communication between nerve cells. Monoamines have been implicated in depression, and most antidepressants work to increase the active levels of at least one.

Symptoms and signs

Major depression is a serious illness that affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health. Its impact on functioning and well-being has been equated to that of chronic medical conditions such as diabetes.

A person suffering a major depressive episode usually exhibits a very low mood that pervades all aspects of life and an inability to experience pleasure in activities that formerly were enjoyed. Depressed people may be preoccupied with, or ruminate over, thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness, hopelessness, and self-hatred.Other symptoms include poor concentration and memory (especially in those with melancholic or psychotic features), withdrawal from social situations and activities, reduced sex drive, and thoughts of death or suicide. Insomnia is common: in the typical pattern, a person wakes very early and is unable to get back to sleep. Hypersomnia, or oversleeping, is less common. Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur. The 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 of depression Family and friends may notice that the person's behavior is either agitated or lethargic.

Older depressed persons may have cognitive symptoms of recent onset, such as forgetfulness and a more noticeable slowing of movements. Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson's disease, and chronic obstructive pulmonary disease

In severe cases, depressed people may have symptoms of psychosis such as delusions or, less commonly, hallucinations, usually of an unpleasant nature.

Depressed children often display an irritable rather than a depressed mood, and show varying symptoms depending on age and situation. Most exhibit a loss of interest in school and a decline in academic performance. They may be described as clingy, demanding, dependent, or insecure. Diagnosis may be delayed or missed when symptoms are interpreted as normal moodiness Depression may also coincide with attention-deficit hyperactivity disorder, complicating the diagnosis and treatment of both.


The biopsychosocial model proposes that biological, psychological, and social factors all play a role to varying degrees in causing depression The diathesis–stress model posits 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. These interactive models have gained empirical support. For example, researchers in New Zealand took a prospective approach to studying depression, by documenting over time how depression emerged among an initially normal cohort of people. The researchers concluded that variation among the serotonin transporter (5-HTT) gene affects the chances that people who have dealt with very stressful life events will go on to experience depression. Specifically, depression may follow such events, but seems more likely to appear in people with one or two short alleles of the 5-HTT gene.

A Swedish study estimated the heritability of depression—the degree to which individual differences in occurrence are associated with genetic differences—to be approximately 40% for women and 30% for men, and evolutionary psychologists have proposed that the genetic basis for depression lies deep in the history of naturally selected adaptations. A substance-induced mood disorder resembling major depression has been causally linked to long-term drug use or abuse, or to withdrawal from certain sedative and hypnotic drugs.[17][18]


Monoamine hypothesis

Most antidepressant medications work by increasing the levels of one or more of the monoamines—the neurotransmitters serotonin, norepinephrine and dopamine—in the synaptic cleft between neurons in the brain. Some medications affect the monoamine receptors directly.

Serotonin is hypothesized to help regulate other neurotransmitter systems; decreased serotonin activity may allow these systems to act in unusual and erratic ways. According to this "permissive hypothesis", depression arises when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter. Some antidepressants enhance the levels of norepinephrine directly, whereas others raise the levels of dopamine, a third monoamine neurotransmitter. These observations gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that a deficiency of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life."The proponents of this theory recommend the choice of an antidepressant with mechanism of action that impacts the most prominent symptoms. Anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and those experiencing a loss of energy and enjoyment of life with norepinephrine- and dopamine-enhancing drugs.

Schematic of a synapse between an axon of one neuron and a dendrite of another. Synapses are specialized gaps between neurons. Electrical impulses arriving at the axon terminal trigger release of packets of chemical messengers (neurotransmitters), which diffuse across the synaptic cleft to receptors on the adjacent dendrite temporarily affecting the likelihood that an electrical impulse will be triggered in the latter neuron. Once released the neurotransmitter is rapidly metabolised or pumped back into a neuron. Antidepressants influence the overall balance of these processes.

In the past two decades, research has revealed multiple limitations of the monoamine hypothesis, and its explanatory inadequacy has been criticized within the psychiatric community.Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The medications tianeptine and opipramol have long been known to have antidepressant properties despite the fact that the former is a serotonin reuptake enhancer and the latter has no effect on the monoamine system. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people nor does it worsen symptoms in depressed patients—although an intact monoamine system is necessary for antidepressants to achieve therapeutic effectiveness. According to an essay published by the Public Library of Science (PLoS), the monoamine hypothesis, already limited, has been further oversimplified when presented to the general public as a mass marketing tool.

 Other theories

MRI scans of patients with depression have reported a number of differences in brain structure compared to those without the illness. Although there is some inconsistency in the results, meta-analyses have shown there is evidence for smaller hippocampal volumes and increased numbers of hyperintensive lesions. Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.

There may be a link between depression and neurogenesis of the hippocampus, a center for both mood and memory. Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood. Drugs may increase serotonin levels in the brain, stimulating neurogenesis and thus increasing the total mass of the hippocampus. This increase may help to restore mood and memory. Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior. One of the neurotrophins responsible for neurogenesis is the brain-derived neurotrophic factor (BDNF). The level of BDNF in the blood plasma of depressed subjects is drastically reduced (more than threefold) as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although decreased plasma BDNF levels have been found in many other disorders, there is some evidence that BDNF is involved in the cause of depression and the mechanism of action of antidepressants.

Major depression may also be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that is similar to the neuro-endocrine response to stress. Investigations reveal increased levels of the hormone cortisol and enlarged pituitary and adrenal glands, suggesting disturbances of the endocrine system may play a role in some psychiatric disorders, including major depression. Oversecretion of corticotropin-releasing hormone from the hypothalamus is thought to drive this, and is implicated in the cognitive and arousal symptoms.

Depression may be related to the same brain mechanisms that control the cycles of sleep and wakefulness.

Depression may be related to abnormalities in the circadian rhythm, or biological clock. For example, the REM stage of sleep, the one in which dreaming occurs, may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotoninergic tone in brain stem structures.Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.

Research on the effects of light therapy on treating seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in hospitalized patients.

The hormone estrogen has been implicated in depressive disorders due to the increase in risk of depressive episodes after puberty, the antenatal period, and reduced rates after menopause Conversely, the premenstrual and postpartum periods of low estrogen levels are also associated with increased risk. The use of estrogen has been under-researched, and although some small trials show promise in its use to prevent or treat depression, the evidence for its effectiveness is not strong. Estrogen replacement therapy has been shown to be beneficial in improving mood in perimenopause, but it is unclear if it is merely the menopausal symptoms that are being reversed.

Other research has explored potential roles of molecules necessary for overall cellular functioning: cytokines and essential nutrients. The symptoms of major depressive disorder are nearly identical to those of sickness behavior, the response of the body when the immune system is fighting an infection. This raises the possility that depression can result from a maladaptive manifestation of sickness behavior as a result of abnormalities in circulating cytokines.Deficiencies in certain essential dietary nutrients, particularly vitamin B12 and folic acid, have been associated with depression;other agents such as the elements copper and magnesium, and vitamin A have also been implicated.


Various aspects of personality and its development appear to be integral to the occurrence and persistence of depression.Although depressive episodes are strongly correlated with adverse events, a person's characteristic style of coping may be correlated with their resilience Additionally, low self-esteem and self-defeating or distorted thinking are related to depression. Depression may be less likely to occur, as well as quicker to remit, among those who are religious It is not always clear which factors are causes or which are effects of depression; however, depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem.

American psychiatrist Aaron T. Beck developed what is now known as a cognitive model of depression in the early 1960s. He proposed that three concepts underlie depression: a triad of negative thoughts composed of cognitive errors about oneself, one's world, and one's future; recurrent patterns of depressive thinking, or schemas; and distorted information processing.From these principles, he developed the structured technique of cognitive behavioral therapy (CBT).According to American psychologist Martin Seligman, depression in humans is similar to learned helplessness in laboratory animals, who remain in unpleasant situations when they are able to escape, but do not because they initially learned they had no control.

Depressed individuals often blame themselves for negative events, and a 1993 study of hospitalized adolescents with self-reported depression shows that those who do this may not take credit for positive outcomes.This tendency is characteristic of a depressive attributional, or pessimistic explanatory style.According to Albert Bandura, a Canadian social psychologist associated with social cognitive theory, depressed individuals have negative beliefs about themselves, based on experiences of failure, observing the failure of social models, a lack of social persuasion that they can succeed, and their own somatic and emotional states including tension and stress. These influences may result in a negative self-concept and a perceived lack of self-efficacy; that is, they do not believe they can influence events or achieve personal goals

An examination of depression in women indicates that vulnerability factors—such as early maternal loss, lack of a confiding relationship, responsibility for the care of several young children at home, and unemployment—can interact with life stressors to increase the risk of depression.For older adults, the factors are often health problems, changes in relationships with a spouse or adult children due to the transition to a care-giving or care-needing role, the death of a significant other, or a change in the availability or quality of social relationships with older friends because of their own health-related life changes.

The understanding of depression has also received contributions from the psychoanalytic and humanistic branches of psychology. From the classical psychoanalytic perspective of Austrian psychiatrist Sigmund Freud, depression, or melancholia, may be related to interpersonal loss and early life experiences. Existential therapists have connected depression to the lack of both meaning in the present and a vision of the future. The founder of humanistic psychology, American psychologist Abraham Maslow, suggested that depression could arise when people are unable to attain their needs or to self-actualize, to realize their full potential.


Poverty and social isolation are associated with increased risk of psychiatric problems in general. Child abuse (physical, emotional, sexual, or neglect) is also associated with increased risk of developing depressive disorders later in life.Disturbances in family functioning, such as parental (particularly maternal) depression, severe marital conflict or divorce, death of a parent, or other disturbances in parenting are additional risk factors.In adulthood, stressful life events are strongly associated with the onset of major depressive episodes In this context, life events connected to social rejection appear to be particularly related to depression. Consistent with the hypothesis that people may become increasingly sensitized to life stress over successive recurrences of depression is evidence that a first episode is more likely to be immediately preceded by stressful life events than are recurrent ones.

The relationship between stressful life events and social support has been a matter of some debate; the lack of social support may increase the likelihood that life stress will lead to depression, or the absence of social support may constitute a form of strain that leads to depression directly There is evidence that neighborhood social disorder, for example, due to crime or illicit drugs, is a risk factor, and that a high neighborhood socioeconomic status, with better amenities, is a protective factor.Adverse conditions at work, particularly demanding jobs with little scope for decision-making, are associated with depression, although diversity and confounding factors make it difficult to confirm that the relationship is causal


From the standpoint of evolutionary theory, major depression is hypothesized, in some instances, to increase an individual's ability to reproduce. Evolutionary approaches to depression and evolutionary psychology posit specific mechanisms by which depression may have been genetically incorporated into the human gene pool, accounting for the high heritability and prevalence of depression by proposing that certain components of depression are adaptations,[such as the behaviors relating to attachment and social rank. Current behaviors can be explained as adaptations to regulate relationships or resources, although the result may be maladaptive in modern environments.

From a counseling psychology viewpoint, the therapist may see depression, not as a biochemical illness or disorder, but as "a species-wide evolved suite of emotional programmes that are mostly activated by a perception, almost always over-negative, of a major decline in personal usefulness, that can sometimes be linked to guilt, shame or perceived rejection".This suite may have manifested in aging hunters in humans' foraging past, who were marginalized by their declining skills, and may continue to appear in alienated members of today's society. The feelings of uselessness generated by such marginalization could hypothetically prompt support from friends and kin. Additionally, in a manner analogous to that in which physical pain has evolved to hinder actions that may cause further injury, "psychic misery" may have evolved to prevent hasty and maladaptive reactions to distressing situations.

 Drug and alcohol use

The DSM precludes a diagnosis of major depressive disorder for those presenting with "the direct physiological effects of a substance" because sedative hypnotic drugs such as alcohol and benzodiazepines increase the risk of a syndrome that is similar to major depression. This increased risk may be due in part to the effects of drugs on neurochemistry, such as decreased levels of serotonin and norepinephrine.Alcoholism or excessive alcohol consumption significantly increases the risk of developing this syndrome.Chronic use of benzodiazepines, a class of medication that is commonly used to treat insomnia, anxiety and muscular spasms, also increases the risk. Chronic, severe depression can develop as a result of chronic use of benzodiazepines or as part of a protracted withdrawal syndrome.[18][84][85][86]


Clinical assessment

A diagnostic assessment may be conducted by a general practitioner, or by a psychiatrist or psychologist who records the person's current circumstances, biographical history and current symptoms, and a family medical history to see if other family members have suffered from a mood disorder, and discusses the person's alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans.Specialist mental health services are rare in rural areas, and thus diagnosis and management is largely left to p