Major depressive disorder

Major depressive disorder (MDD) (also known as recurrent depressive disorder, 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 by loss of interest or pleasure in normally enjoyable activities. This cluster of symptoms (syndrome) was named, described and classified as one of the mood disorders in the 1980 edition of the American Psychiatric Association's diagnostic manual. The term "depression" is ambiguous. It is often used to denote this syndrome but may refer to other mood disorders or to lower mood states lacking clinical significance. Major depressive disorder is a disabling condition that adversely affects a person's family, work or school life, sleeping and eating habits, and general health. In the United States, around 3.4% of people with major depression commit suicide, and up to 60% of people who commit suicide had depression or another mood disorder.^[1]

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 examination. 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 20 and 30 years, with a later peak between 30 and 40 years.^[2]

Typically, patients are treated with antidepressant medication and, in many cases, also receive psychotherapy or counseling, although the effectiveness of medication for mild or moderate cases is questionable. 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). The course of the disorder varies widely, from one episode lasting weeks 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 and suicide. It is unclear whether or not medications affect the risk of suicide. Current and former patients may be stigmatized.

The understanding of the nature and causes of depression has evolved over the centuries, though this understanding is incomplete and has left many aspects of depression as the subject of discussion and research. Proposed causes include psychological, psycho-social, hereditary, evolutionary and biological factors. Certain types of long-term drug use can both cause and worsen depressive symptoms. Psychological treatments are based on theories of personality, interpersonal communication, and learning. Most biological theories focus on the monoamine chemicals serotonin, norepinephrine and dopamine, which are naturally present in the brain and assist communication between nerve cells.

Symptoms and signs

Major depression significantly affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health.^[3] Its impact on functioning and well-being has been compared to that of chronic medical conditions such as diabetes.^[4]

A person having a major depressive episode usually exhibits a very low mood, which pervades all aspects of life, and an inability to experience pleasure in activities that were formerly enjoyed. Depressed people may be preoccupied with, or ruminate over, thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness, hopelessness, and self-hatred.^[5] In severe cases, depressed people may have symptoms of psychosis. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant.^[6] Other symptoms of depression include poor concentration and memory (especially in those with melancholic or psychotic features),^[7] withdrawal from social situations and activities, reduced sex drive, and thoughts of death or suicide. Insomnia is common among the depressed. In the typical pattern, a person wakes very early and cannot get back to sleep.^[8] Insomnia affects at least 80% of depressed people.^[9] Hypersomnia, or oversleeping, can also happen.^[8] Some antidepressants may also cause insomnia due to their stimulating effect.^[10]

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.^[11] Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur.^[5] Family and friends may notice that the person's behavior is either agitated or lethargic.^[8] Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness,^[7] and a more noticeable slowing of movements.^[12] Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson's disease, and chronic obstructive pulmonary disease.^[13]

Depressed children may often display an irritable mood rather than a depressed mood,^[5] and show varying symptoms depending on age and situation.^[14] Most lose interest in school and show a decline in academic performance. They may be described as clingy, demanding, dependent, or insecure.^[8] Diagnosis may be delayed or missed when symptoms are interpreted as normal moodiness.^[5] Depression may also coexist with attention-deficit hyperactivity disorder (ADHD), complicating the diagnosis and treatment of both.^[15]

Causes

The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression.^[23] 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,^[24][25] implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.^[26]

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. To be specific, depression may follow such events, but seems more likely to appear in people with one or two short alleles of the 5-HTT gene.^[24] In addition, a Swedish study estimated the heritability of depression—the degree to which individual differences in occurrence are associated with genetic differences—to be around 40% for women and 30% for men,^[27] 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 drug abuse, or to withdrawal from certain sedative and hypnotic drugs.^[28][29]

Biological

Monoamine hypothesis

Most antidepressant medications increase 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 regulate other neurotransmitter systems; decreased serotonin activity may allow these systems to act in unusual and erratic ways.^[31] According to this "permissive hypothesis", depression arises when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter.^[32] 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."^[33] 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.^[33]

Besides the clinical observations that drugs that increase the amount of available monoamines are effective antidepressants, recent advances in psychiatric genetics indicate that phenotypic variation in central monoamine function may be marginally associated with vulnerability to depression. Despite these findings, the cause of depression is not simply monoamine deficiency.^[34] In the past two decades, research has revealed multiple limitations of the monoamine hypothesis, and its explanatory inadequacy has been highlighted within the psychiatric community.^[35] A counterargument is that the mood-enhancing effect of MAO inhibitors and SSRIs takes weeks of treatment to develop, even though the boost in available monoamines occurs within hours. Another counterargument is based on experiments with pharmacological agents that cause depletion of monoamines; while deliberate reduction in the concentration of centrally available monoamines may slightly lower the mood of unmedicated depressed patients, this reduction does not affect the mood of healthy people.^[34] The monoamine hypothesis, already limited, has been further oversimplified when presented to the general public as a mass marketing tool, usually phrased as a "chemical imbalance".^[36]

In 2003 a gene-environment interaction (GxE) was hypothesized to explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR);^[37] a 2009 meta-analysis showed stressful life events were associated with depression, but found no evidence for an association with the 5-HTTLPR genotype.^[38] Another 2009 meta-analysis agreed with the latter finding.^[39] A 2010 review of studies in this area found a systematic relationship between the method used to assess environmental adversity and the results of the studies; this review also found that both 2009 meta-analyses were significantly biased toward negative studies, which used self-report measures of adversity.^[40]

Other theories

MRI scans of patients with depression have revealed a number of differences in brain structure compared to those who are not depressed. Recent meta-analyses of neuroimaging studies in major depression, reported that compared to controls, depressed patients had increased volume of the lateral ventricles and adrenal gland and smaller volumes of the basal ganglia, thalamus, hippocampus, and frontal lobe (including the orbitofrontal cortex and gyrus rectus).^[41][42] Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.^[43]

There may be a link between depression and neurogenesis of the hippocampus,^[44] 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