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Major depressive disorder (MDD), also known simply as depression, is a mental disorder characterized by at least two weeks of pervasive low mood. Low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause are common symptoms.[1] Those affected may also occasionally have delusions or hallucinations.[1] Some people have periods of depression separated by years, while others nearly always have symptoms present.[3] Major depression is more severe and lasts longer than sadness, which is a normal part of life.[3] The diagnosis of major depressive disorder is based on the person's reported experiences and a mental status examination.[7] There is no laboratory test for the disorder,[3] but testing may be done to rule out physical conditions that can cause similar symptoms.[7] Those with major depressive disorder are typically treated with counseling and antidepressant medication.[1] Medication appears to be effective, but the effect may only be significant in the most severely depressed.[8][9] Types of counseling used include cognitive behavioral therapy (CBT) and interpersonal therapy,[1][10] and electroconvulsive therapy (ECT) may be considered if other measures are not effective.[1] Hospitalization may be necessary in cases with a risk of harm to self and may occasionally occur against a person's wishes.[11] The most common time of onset is in a person's 20s and 30s,[3][4] with females affected about twice as often as males.[3][4] Major depressive disorder affected approximately 163 million people (2% of the world's population) in 2017.[6] The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France.[4] Lifetime rates are higher in the developed world (15%) compared to the developing world (11%).[4] The disorder causes the second-most years lived with disability, after lower back pain.[12] The term major depressive disorder was introduced by a group of US clinicians in the mid-1970s.[13] The cause of major depressive disorder is believed to be a combination of genetic, environmental, and psychological factors,[1] with about 40% of the risk related to genetics.[3] Risk factors include a family history of the condition, major life changes, certain medications, chronic health problems, and substance abuse.[1][3] It can negatively affect a person's personal life, work life, or education as well as sleeping, eating habits, and general health.[1][3] Those currently or previously affected with the disorder may be stigmatized.[14]

1. 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.[15] Its impact on functioning and well-being has been compared to that of other chronic medical conditions, such as diabetes.[16] 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.[17] In severe cases, depressed people may have symptoms of psychosis. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant.[18] Other symptoms of depression include poor concentration and memory (especially in those with melancholic or psychotic features),[19] withdrawal from social situations and activities, reduced sex drive, irritability,[20] 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.[21] Hypersomnia, or oversleeping, can also happen.[21] Some antidepressants may also cause insomnia due to their stimulating effect.[22] 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.[23] Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur.[17] Family and friends may notice that the person's behavior is either agitated or lethargic.[21] Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness,[19] and a more noticeable slowing of movements.[24] Depressed children may often display an irritable mood rather than a depressed one,[17] and show varying symptoms depending on age and situation.[25] Most lose interest in school and show a decline in academic performance. They may be described as clingy, demanding, dependent, or insecure.[21] Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness."[17].

Associated conditions

Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reports that half of those with major depression also have lifetime anxiety and its associated disorders such as generalized anxiety disorder.[26] Anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicide attempts.[27] There are increased rates of alcohol and drug abuse and particularly dependence,[28][29] and around a third of individuals diagnosed with ADHD develop comorbid depression.[30] Post-traumatic stress disorder and depression often co-occur.[15] Depression may also coexist with attention deficit hyperactivity disorder (ADHD), complicating the diagnosis and treatment of both.[31] Depression is also frequently comorbid with alcohol abuse and personality disorders.[32] Depression can also be exacerbated during particular months (usually winter) for those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, digital media may also be utilised in some situations to improve mood.[33][34] Depression and pain often co-occur. One or more pain symptoms are present in 65% of depressed patients, and anywhere from 5 to 85% of patients with pain will be suffering from depression, depending on the setting; there is a lower prevalence in general practice, and higher in specialty clinics. The diagnosis of depression is often delayed or missed, and the outcome can worsen if the depression is noticed but completely misunderstood.[35] Depression is also associated with a 1.5- to 2-fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. People with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, which further increases their risk of medical complications.[36] In addition, cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care.[37] Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson's disease, and chronic obstructive pulmonary disease.[38]

2. Cause

The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression.[3][40] 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,[41][42] implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.[43] Childhood abuse, either physical, sexual or psychological, are all risk factors for depression, among other psychiatric issues that co-occur such as anxiety and drug abuse. Childhood trauma also correlates with severity of depression, lack of response to treatment and length of illness. However, some are more susceptible to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.[44]

Genetics

Family and twin studies find that nearly 40% of individual differences in risk for major depressive disorder can be explained by genetic factors.[45] Like most psychiatric disorders, major depressive disorder is likely to be influenced by many individual genetic changes. In 2018, a genome-wide association study discovered 44 variants in the genome linked to risk for major depression.[46] This was followed by a 2019 study that found 102 variants in the genome linked to depression.[47] The 5-HTTLPR, or serotonin transporter promoter gene's short allele has been associated with increased risk of depression. However, since the 1990s, results have been inconsistent, with three recent reviews finding an effect and two finding none.[41][48][49][50][51] Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. There is no conclusive effects of candidate gene on depression, either alone or in combination with life stress.[52] Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings.[53] There are also other efforts to examine interactions between life stress and polygenic risk for depression.[54]

3. Pathophysiology

The pathophysiology of depression is not yet understood, but the current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA axis dysfunction and structural or functional abnormalities of emotional circuits. The monoamine theory, derived from the efficacy of monoaminergic drugs in treating depression, was the dominant theory until recently[when?]. The theory postulates that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. Firstly, acute depletion of tryptophan, a necessary precursor of serotonin, a monoamine, can cause depression in those in remission or relatives of depressed patients; this suggests that decreased serotonergic neurotransmission is important in depression.[63] Secondly, 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, decreased activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression.[64] 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,[65] and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression.[66][67] Lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression.[68] However, this theory is inconsistent with the fact that serotonin depletion does not cause depression in healthy persons, the fact 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.[69] One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self-inhibition in raphe nuclei by the increased serotonin mediated by antidepressants.[70] 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 depressed patients that normalized with SSRI treatment, and the preference for carbohydrates in depressed patients.[71] Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.[72] Immune system abnormalities have been observed, including increased levels of cytokines involved in generating sickness behavior (which shares overlap with depression).[73][74][75] The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors in treating depression,[76] and normalization of cytokine levels after successful treatment further suggest immune system abnormalities in depression.[77] 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 depressed patients. However, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%.[78][79] These stress-related abnormalities have been hypothesized to be the cause of hippocampal volume reductions seen in depressed patients.[80] Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors.[81] Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.[82] 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.[83] Another model, the "Corito-Striatal model", suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures results in depression.[84] 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.[85]

4. Diagnosis

Clinical assessment

A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist,[15] who records the person's current circumstances, biographical history, current symptoms, family history, and 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.[15] Specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary-care clinicians.[86] This issue is even more marked in developing countries.[87] Rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose;[88] these include the Hamilton Rating Scale for Depression,[89] the Beck Depression Inventory[90] or the Suicide Behaviors Questionnaire-Revised.[91] Primary-care physicians and other non-psychiatrist physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatric physicians, in part because of the physical symptoms that often accompany depression, in addition to many potential patient, provider, and system barriers. A review found that non-psychiatrist physicians miss about two-thirds of cases, though this has improved somewhat in more recent studies.[92] Before diagnosing major depressive disorder, a doctor generally performs a medical examination and selected investigations to rule out other causes of symptoms. These include blood tests measuring TSH and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including ESR to rule out a systemic infection or chronic disease.[93] Adverse affective reactions to medications or alcohol misuse are often ruled out, as well. Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men.[94] Vitamin D levels might be evaluated, as low levels of vitamin D have been associated with greater risk for depression.[95] Subjective cognitive complaints appear in older depressed people, but they can also be indicative of the onset of a dementing disorder, such as Alzheimer's disease.[96][97] Cognitive testing and brain imaging can help distinguish depression from dementia.[98] A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms.[99] No biological tests confirm major depression.[100] In general, investigations are not repeated for a subsequent episode unless there is a medical indication.

DSM and ICD criteria

Disorders and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems which uses the name depressive episode for a single episode and recurrent depressive disorder for repeated episodes.[101] The latter system is typically used in European countries, while the former is used in the US and many other non-European nations,[102] and the authors of both have worked towards conforming one with the other.[103] Both DSM-5 and ICD-10 mark out typical (main) depressive symptoms.[104] ICD-10 defines three typical depressive symptoms (depressed mood, anhedonia, and reduced energy), two of which should be present to determine the depressive disorder diagnosis.[105][106] According to DSM-5, there are two main depressive symptoms- a depressed mood and loss of interest/pleasure in activities (anhedonia). These symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis.[107] Major depressive disorder is classified as a mood disorder in DSM-5.[108] The diagnosis hinges on the presence of single or recurrent major depressive episodes.[17] Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Unspecified Depressive Disorder is diagnosed if the depressive episode's manifestation does not meet the criteria for a major depressive episode.[108] The ICD-10 system does not use the term major depressive disorder but lists very similar criteria for the diagnosis of a depressive episode (mild, moderate or severe); the term recurrent may be added if there have been multiple episodes without mania.[101]

Major depressive episode

A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks.[17] Episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features—commonly referred to as psychotic depression—is automatically rated as severe.[108] If the patient has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".[109] DSM-IV-TR excludes cases where the symptoms are a result of bereavement, although it is possible for normal bereavement to evolve into a depressive episode if the mood persists and the characteristic features of a major depressive episode develop.[110] The criteria were criticized because they do not take into account any other aspects of the personal and social context in which depression can occur.[111] In addition, some studies have found little empirical support for the DSM-IV cut-off criteria, indicating they are a diagnostic convention imposed on a continuum of depressive symptoms of varying severity and duration.[112] Bereavement is no longer an exclusion criterion in DSM-5, and it is now up to the clinician to distinguish between normal reactions to a loss and MDD. Excluded are a range of related diagnoses, including dysthymia, which involves a chronic but milder mood disturbance;[113] recurrent brief depression, consisting of briefer depressive episodes;[114][115] minor depressive disorder, whereby only some symptoms of major depression are present;[116] and adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor.[117] Three new depressive disorders were added to the DSM-5: disruptive mood dysregulation disorder, classified by significant childhood irritability and tantrums,[118] premenstrual dysphoric disorder (PMDD), causing periods of anxiety, depression, or irritability in the week or two before a woman's menstruation,[119] and persistent depressive disorder.[108]

Subtypes

The DSM-5 recognizes six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:

"Melancholic depression" is characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.[120]

"Atypical depression" is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.[121]

"Catatonic depression" is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome.[122]

"Depression with anxious distress" was added into the DSM-V as a means to emphasize the common co-occurrence between depression or mania and anxiety, as well as the risk of suicide of depressed individuals with anxiety. Specifying in such a way can also help with the prognosis of those diagnosed with a depressive or bipolar disorder.[108]

"Depression with peri-partum onset" refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth or while a woman is pregnant. DSM-IV-TR used the classification "postpartum depression," but this was changed in order to not exclude cases of depressed woman during pregnancy.[123] Depression with peripartum onset has an incidence rate of 10–15% among new mothers. The DSM-V mandates that, in order to qualify as depression with peripartum onset, onset occur during pregnancy or within one month of delivery. It has been said that postpartum depression can last as long as three months.[124]

"Seasonal affective disorder" (SAD) is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer.[125]