Major depressive disorder
Specialty	Psychiatry

Major depressive disorder, also known as major depression, unipolar depression, clinical depression, or simply depression, is a mental disorder characterized by a pervasive low mood and loss of interest or pleasure in usual activities. The diagnosis is made if a person has suffered one or more major depressive episodes. Diagnosis is based on the patient's self-reported experiences and observed behavior. There is no laboratory test for major depression, although physicians often test for physical conditions that may cause similar symptoms before arriving at a diagnosis. The course varies widely, from a one-off occurrence to a lifelong disorder with recurrent episodes. The most common time of onset is between the ages of 30 and 40, with a later peak between 50 and 60. The condition appears to be more common in women.

Both psychological and biological causes have been proposed, and the question of whether there are two separate conditions, a biological and a reactive depression, or a continuum of a single entity, has been hotly debated since the 1920s. Current classification has favored the latter since the creation of the term major depressive disorder in 1980. The neurotransmitters serotonin and noradrenaline have been implicated, and most antidepressants work to increase the active levels of these in the brain. A host of psychological factors has also been implicated, and various forms of psychotherapy are used to address them. Electroconvulsive therapy is sometimes used in severe cases. Hospitalization may be necessary in cases with a significant risk of suicide or self-neglect.

The term depression is commonly used to describe a temporary depressed mood, when a person may feel sad or "down". Ideas about what causes and constitutes depression have evolved over the centuries. Major depression can be a serious and often disabling condition that can significantly affect a person's work, family and school life, sleeping and eating habits, and general health. However, it may be overdiagnosed, and current diagnostic standards arguably have the effect of medicalising sadness or misery.

Around 3.4 percent of people with major depression commit suicide. Up to 60 percent of all people who commit suicide have a mood disorder, such as depression, and their risk may be especially high if they feel a marked sense of hopelessness or have both depression and borderline personality disorder. Depressed people have a shortened life expectancy, being more susceptible to and likely to die from conditions such as heart disease than the non-depressed.

A person suffering a major depressive episode almost always reports a pervasive low mood, and loss of interest or pleasure in favorite activities. They may ruminate over or be preoccupied with feelings of worthlessness, inappropriate or exaggerated guilt or regret, helplessness or hopelessness.^[1] Other symptoms include poor concentration and memory, withdrawal from social situations, family gatherings and activities with friends, reduced libido (sex drive), and thoughts of death or suicide. Insomnia is a common symptom; the typical pattern is one of early morning wakening where the person reports waking up very early and being unable to get back to sleep.^[2] Hypersomnia, or oversleeping, is less common.^[2] Appetite is often decreased, with resulting weight loss, although increase and weight gain occasionally occurs.^[1] The patient may report persistent physical symptoms such as fatigue, headaches, digestive problems, or chronic pain, or describe feeling "slowed down" or sluggish. Family or friends may note the person appears agitated or slowed down.^[2]

People are most likely to suffer their first depressive episode between the ages of 30 and 40.^[3] The risk is increased in the first year after childbirth (post-natal depression), and after cardiovascular and neurological illnesses such as stroke,^[4] Parkinson's disease,^[4] and multiple sclerosis.^[4] Depressive episodes following a heart attack might even correspond with an increased risk of further cardiac complications, including death.^[5] There is a second, smaller peak of incidence later in life between the ages of 50 and 60;^[3] older people are more likely to present with cognitive symptoms such as forgetfulness and a more noticeable slowing of movements. The term pseudodementia was coined for this syndrome, due to its clinical resemblance to dementia.^[6]

Diagnosis in children or adolescents may be delayed or missed as the symptoms are dismissed as normal moodiness. Their mood may be predominantly irritable rather than depressed.^[1] Children may show different symptoms depending on age and situation;^[7] most will exhibit a loss of interest in school and decline in academic performance.^[2] Those older than 12 years may also begin abusing drugs or alcohol, or exhibit disruptive behaviour. Thoughts or attempts of suicide are rare in children with major depression under 12 years of age.

Major depression frequently co-occurs with other psychiatric problems; the National Comorbidity Survey (US) reports that 58% of those with major depression also suffer from lifetime anxiety. Even mild anxiety symptoms can have a major impact on the course of a depressive illness, and the commingling of any anxiety symptoms with the primary depression is important to consider. Psychiatrist Ellen Frank found that depressed patients with lifetime panic symptoms experienced significant delays in their remission, and had higher levels of residual impairment.^[8] Robert Sapolsky similarly argues that the relationship between stress, anxiety, and depression could be measured and demonstrated biologically.^[9] There are increased rates of alcohol and drug abuse and particularly dependence,^[10] and around a third of individuals diagnosed with attention-deficit hyperactivity disorder develop comorbid depression.^[11]

Before a diagnosis of major depressive disorder is made, a physician generally performs a medical examination and selected investigations to rule out a medical illness as a cause of symptoms. These include blood tests measuring TSH to exclude hypo- or hyperthyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and full blood count including ESR to rule out a systemic infection or chronic disease.^[12] Testosterone levels may be used to diagnose hypogonadism, a cause of depression in men.^[13] Two commonly ordered investigations are EEG to exclude epilepsy, and a CT scan of the head to exclude brain lesions.^[14] Early dementia may present with depressive symptoms in older patients. No biological tests are used to confirm major depression as such.^[15] Investigations are not generally repeated for a subsequent episode unless there is a specific medical indication. These may include measuring serum sodium to rule out hyponatremia (low sodium) if the person presents with increased frequency of passing urine, a common side effect of selective serotonin reuptake inhibitor (SSRI) antidepressants.^[16]

If no medical cause is found, a psychiatric assessment may be done by the physician, or by referral to a psychiatrist or psychologist.^[17] Assessment is usually done on an outpatient basis; admission to an inpatient mental health unit is considered for patients who pose a risk to themselves or others. This will include a complete history of the person's current circumstances, biographical history and current symptoms, a discussion of alcohol and drug use, and a family medical history to see if other family members have suffered from a mood disorder. A mental state examination will include assessing the person's current mood and exploring thought content, in particular thoughts of hopelessness, self-harm or suicide.^[17]

Several rating scales are used in research or as screening tools, and have been widely promoted in primary healthcare to improve detection of depression. However, their benefit has been questioned,^[18] and there is strong evidence routine screening does little to improve detection rates.^[19]

The Beck Depression Inventory is one of the most widely used diagnostic tools for self-diagnosis of depression, although its main purpose is not the diagnosis of depression, but determining the presence and severity of symptoms.^[20] Originally designed by psychiatrist Aaron T. Beck in 1961, it is a 21-question patient-completed survey that covers items related to the basic symptoms of depression, such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex.^[21]

Two Patient Health Questionnaires available are self-administered questionnaires. The PHQ-2 has only two questions that asks about the frequency of depressed mood and a loss of interest in doing things, with a positive to either question indicating the need for further testing.^[22] The PHQ-9 is a slightly more detailed nine question survey covering some of the major symptoms of depression and the frequency a person has experienced them. It is based directly on the diagnostic criteria listed in the DSM-IV and often used as a follow up to a positive PHQ-2 test.^[23]

Other scales commonly used include the Geriatric Depression Scale in older populations, which is also valid in patients with mild to moderate dementia,^[24] the widely used Hamilton Depression Rating Scale (HRSD-21) designed by psychiatrist Max Hamilton in 1960,^[25] and the Montgomery-Åsberg Depression Rating Scale (MADRS).^[26]

The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD-10). The latter system is typically used in European countries, while the former is used in the USA and many other non-European nations,^[27] and are frequently referenced in research studies.

Major depressive disorder is classified as a mood disorder in DSM IV-TR;^[28] the diagnosis hinges on the presence of a major depressive episode, which may be either single or recurrent.^[1] Further qualifiers are used to classify both the episode itself and the course of the disorder. There is also a category of Depressive Disorder Not Otherwise Specified. The ICD-10 system does not use the term Major depressive disorder, but lists similar criteria for the diagnosis of a Depressive episode (mild, moderate or severe); multiple episodes without mania may be classed as Recurrent Depressive Disorder.^[29]

A major depressive episode has been defined as a severely depressed mood that persists for at least two weeks.^[1] Episodes may be isolated or recurrent and categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning); any episode with psychotic features is automatically rated as severe. If the patient has already had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead.^[30] Depression without periods of mania is sometimes referred to as unipolar depression because the mood remains at one emotional state or "pole".^[31] The DSM excludes cases where the symptoms are a result of bereavement, although it is possible for normal bereavement to evolve into a depressive episode if characteristic features develop.^[32]

Diagnosticians recognize several subtypes or course specifiers:

• Atypical depression is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite ("comfort eating"), excessive sleep or somnolence (hypersomnia), an sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.^[33] Difficulties in measuring this subtype have led to questions of its validity and prevalence.^[34]

• Melancholic depression is characterized by a loss of pleasure (anhedonia) 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.^[35]

• Psychotic depression is the term for a major depressive episode, particularly of melancholic nature, where the patient experiences psychotic symptoms such as delusions or, less commonly, hallucinations. These are most commonly mood-congruent (content coincident with depressive themes).^[36]

• 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 stuporose, and either immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia, a manic episode, or be due to neuroleptic malignant syndrome.^[37]

• Postpartum depression is listed as a course specifier in DSM-IV-TR; it refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression, which has incidence rate of 10–15%, typically sets in within three months of labor, and lasts as long as three months.^[38]

• Seasonal affective disorder is a specifier. Some people have a seasonal pattern, with depressive episodes coming on in the autumn or winter, and resolving 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.^[39]

In the process of differential diagnosis, alternative diagnoses are ruled out so that the applicable condition can be identified. Some potential diagnoses that may be considered before diagnosing MDD include the following:

• Dysthymia, which is a chronic, milder mood disturbance where a person reports a low mood almost daily over a span of at least two years. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression).^[40]

• Recurrent brief depression (RBD), distinguished from Major Depressive Disorder primarily by differences in duration. People with RBD have depressive episodes about once per month, with individual episodes lasting less than two weeks and typically less than 2–3 days. Diagnosis of RBD requires that the episodes occur over the span of at least one year and, in female patients, independently of the menstrual cycle.^[41] People with clinical depression can develop RBD, and vice versa, and both illnesses have similar risks.^[42]

• Minor depression, which refers to a depression that does not meet full criteria for major depression but in which at least two symptoms are present for two weeks.^[43]

• Adjustment disorder with depressed mood, is a term given to a psychological response to identifiable event or stressor; the resulting emotional or behavioral symptoms, in this case low mood, are significant, but do not meet the criteria for a major depressive episode.^[44]

Current theories regarding the risk factors and causes of major depression fall into two categories, the psychological and the biological, although there is much overlap and integration. Debate has persisted for most of the twentieth century over whether a unitary or binary model of depression is a truer reflection of the syndrome;^[45] in the former, there is a continuum of depression ranked only by severity and the result of a "psychobiological final common pathway",^[46] whereas the latter conceptualizes a distinction between biological and reactive depressive syndromes.^[47] The publishing of DSM-III has seen the unitarian model gain a more universal acceptance.^[45]

Psychological factors include the complex development of personality and how a person has learned to cope with external environmental factors, such as stress.^[48] Events such as the death of a parent or loved one, issues with biological development, school related problems, abandonment or rejection, neglect, chronic illness, and physical, psychological, or sexual abuse increase the risk of depression later in life. Post-traumatic stress disorder (PTSD) and depression often co-occur, and both can result from childhood trauma.^[49]

Stressful or traumatic life experiences or circumstances, including rape, assault, combat, or the death of a relative or friend, may trigger a depressive episode directly—although temporary grief-related depression is not considered a disorder. A depressive episode may also be triggered by other major changes such as unemployment, divorce, or a loss of religious faith.^[50] Ongoing issues, such as financial difficulties or poverty, major health problems, addictions such as problem gambling or drug addiction, marital or sexual difficulties, or work-related stress can also contribute to depression. According to sociologist George W. Brown and psychologist Tirril Harris,^[51] "certain 'vulnerability factors'—namely early maternal loss, lack of a confiding relationship, greater than three children under the age of 14 at home and unemployment—can interact with 'provoking agents' to increase the risk of depression."^[52] Among these factors, confiding relationships appear to be especially important.^[52] Low self-esteem, learned helplessness, and self-defeating or distorted thinking are connected with depression. There is debate as to whether these are causes or effects of depression. In either case, it is known that depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem.^[53]

Cognitive psychology and cognitive behavioural theory take the view that depression arises from deficits in memory and information processing which give rise to cognitive biases and distortions. According to psychologist Martin Seligman, depression in humans may be similar to learned helplessness in other animals, who remain in unpleasant situations from which they could escape, but over which they had initially had no control.^[54] Learned helplessness and depression may be related to what psychologist Julian Rotter called an external locus of control, a tendency to attribute outcomes to external events outside one's control.^[55] However, depressed people tend to blame themselves for negative events in particular, and to believe that the relevance of these events persists through time and pervades their entire lives and selfhoods.^[56][57] This tendency is characteristic of a "depressive attributional style," or "pessimistic explanatory style," and the causal attributions made in such a style have been termed "internal, stable, and global,"^[56] or "personal, permanent, and pervasive."

According to psychologist Albert Bandura, people become depressed through a distorted self-concept and a lack of self-efficacy, in other words a habitual sense of inability to influence events and achieve personal goals.^[58][59] A related idea, Aaron T. Beck's cognitive triad, is that depression entails "cognitive errors" about oneself, one's world, and one's future.^[56] Milder depression, however, has been associated with what has been called depressive realism, or the "sadder-but-wiser effect," a view of the world that is relatively undistorted by positive biases.^[60][61]

From the psychoanalytic perspective, depression may be intertwined with self-criticism. In particular, wrote Sigmund Freud, the "super-ego becomes over-severe, abuses the poor ego, humiliates it and ill-treats it, threatens it with the direst punishments."^[62] Freud also argued that objective loss, as occurs through death or a romantic break-up, could result in subjective loss as well, when the depressed subject had identified with the object of its affection through an unconscious but narcissistic process called the "libidinal cathexis of the ego." Such loss results in "a profoundly painful dejection, cessation of interest in the outside world, loss of the capacity to love, inhibition of all activity, and a lowering of self-regarding feelings" that is more severe than mourning. "In mourning 'it is the world that has become poor and empty; in [depression] it is the ego itself.'"^[63]

Existential psychologist Rollo May stated that "depression is the inability to construct a future."^[64] From the existential perspective, in order to construct a future, people must become acutely aware of both their mortality and their freedom, and they must exercise the latter within the explicit framework of the former. This awareness and responsibility produce "normal anxiety,"^[65] whereas the lack of these things leads to "neurotic anxiety,"^[65] "self-alienation,"^[66] "inauthentic" living,^[67] and depression. Humanistic psychologists agree with many facets of existentialism, but argue that depression results from a specific incongruity between society and the individual's innate drive to self-actualize.^[68]

Evolutionary psychology suggests that major depression can result from the overactivation or dysfunction of psychological mechanisms that are sensitive to certain kinds of material or social loss or defeat.^[69][70][71] Some aspects of this approach have received empirical support and clinical application;^[72][73] other components are still at a hypothetical stage.

Most experts believe that both biological and psychological factors play a role in causing depression. The heritability of depression—the degree to which it is genetically determined—has been estimated at around 40% for women and 30% for men.^[74] From the evolutionary standpoint, major depression might be expected to reduce the reproductive fitness of the individual suffering from it. Some evolutionary explanations for the apparent contradiction between this hypothesis and the high heritability and prevalence of major depression rest on the idea that some components of depression are adaptations.^[75][71]

Many modern antidepressant drugs change synaptic levels of certain neurotransmitters, especially serotonin and norepinephrine; this has implicated neurochemical factors. Serotonin in particular may regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties of this dysregulation.^[76] However, the precise relationships between serotonin, Selective serotonin reuptake inhibitors, and depression are largely unknown, and tend to be greatly oversimplified when presented to the public.^[77]

Many depressed individuals exhibit markedly higher levels of monoamine oxidase A (MAO-A) in the brain compared to people without depression.^[78] MAO-A is an enzyme that decreases the concentration of monoamines such as serotonin, norepinephrine and dopamine.

There may be a link between depression and neurogenesis of the hippocampus,^[79] 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.^[80][81] Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior.^[82] 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, more than threefold, reduced as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although the decreased plasma BDNF levels have been found in many other disorders, there are indications of BDNF involvement in the causes of depression and the mechanism of the action of antidepressants.^[83]

Depression may also be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.^[84]

Depression may be affected by variations in the circadian rhythm. The REM stage of sleep, in which dreaming occurs, tends to be especially quick to arrive, and especially intense, for depressed people. Although the precise relationship between sleep and depression is mysterious, the relationship appears to be particularly strong among those whose depressive episodes are not precipitated by unusual stress. In such cases, clients may be especially unaffected by therapeutic intervention.^[85]

The three most commonly indicated treatments for depression are psychotherapy, medication, and electroconvulsive therapy. Psychotherapy is the treatment of choice for people under 18, while electroconvulsive therapy is only used as a last resort in severe cases or in emergencies. The term refractory- or treatment-resistant depression is used to describe cases that do not respond to adequate courses of least two antidepressants.^[86]

There are a number of different psychotherapies for depression, which may be provided to individuals or groups. Psychotherapy can be delivered by a variety of mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. With more complex and chronic forms of depression the most effective treatment is often considered to be a combination of medication and psychotherapy.^[87] Psychotherapy is the treatment of choice in people under 18; medication is offered only in conjunction with the former and generally not as a first line agent. ^[88]

The most studied form of psychotherapy for depression is Cognitive behavioral therapy (CBT), thought to work by teaching clients to learn a set of cognitive and behavioral skills, which they can employ on their own. Earlier research suggested that cognitive-behavioral therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression.^[89]

For the treatment of adolescent depression, CBT performed no better than placebo, and significantly worse than the antidepressant fluoxetine.^[90] Combining fluoxetine with CBT appeared to bring no additional benefit^[91][92] or, at the most, only marginal benefit.^[93]

Two randomized, controlled trials of mindfulness-based cognitive therapy (MBCT), which includes elements of meditation, have been reviewed. MBCT was significantly more effective than "usual care" for the prevention of recurrent depression in patients who had had three or more depressive episodes. According to the review, the "usual care" did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected the non-specific or placebo effects.^[94]

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT, however the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.^[95]

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts,^[96] is used by its practitioners to treat clients presenting with major depression.^[97] A more widely practiced, eclectic technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus.^[98] In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.^[99]

To find the most effective pharmaceutical treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressant changed. Response rates to the first agent administered may be as low as 50%.^[100] It may take anywhere from three to eight weeks after the start of medication before its therapeutic effects can be fully discovered. Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four months to prevent the chance of recurrence. People with chronic depression need to take the medication for the rest of their lives.^[17]

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine, and citalopram are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety. Those who do not respond to the first SSRI tried can be switched to another; such a switch results in improvement in almost 50% of cases.^[101] Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy;^[102] this strategy is possibly more effective.^[103][104] It is not uncommon for SSRIs to cause or worsen insomnia; the sedating antidepressant mirtazapine (Zispin, Remeron) can be used in such cases.^{[105][106][107]} Venlafaxine (Effexor) may be moderately more effective than SSRIs;^[108] however, it is not recommended as a first-line treatment because of the higher rate of side effects,^[109] and its use is specifically discouraged in children and adolescents.^[110] Fluoxetine is the only antidepressant recommended for people under the age of 18.^[111]

Tricyclic antidepressants have more side effects than SSRIs and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective.^[112][113] A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy and life-threatening adverse effects. They are still used only rarely, although newer agents of this class, with a better side effect profile, have been developed.^[114]

Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant.^[115] Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.^[116] Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.^[117] Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent side effects.^[118] There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.^[119]

Two recent meta-analyses of clinical trial results submitted to the FDA concluded that antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence criteria for a "clinically significant" effect. In particular, the effect size was very small for moderate depression but increased with severity reaching "clinical significance" for very severe depression.^[120][121] These result were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment.^{[122][123][124]} Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there "seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit."^[120] The other author agreed that "antidepressant 'glass' is far from full" but disagreed "that it is completely empty". He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.^[125]

Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD.^[126][127] In contrast, medication gives better results for dysthymia.^[126][127] The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants.^[126] Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional "booster" sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.^[127]

Electroconvulsive therapy (ECT) is a treatment where seizures are electrically induced in anesthetized patients for therapeutic effect. ECT is most often used as a last resort intervention for severe major depression which has not responded to other treatment.^[128] It is also works more quickly than antidepressant therapy, and is thus the treatment of choice in emergencies such as catatonic depression where the patient has ceased oral intake of fluid or nutrients, or severe suicidality.^[128] Strong evidence suggests it is the most effective treatment for depression^[129] and results in improved quality of life in both the short- and long-term.^[130] Antidepressant therapy is generally continued after treatment, although some patients require maintenance monthly ECT to remain well. Short-term memory loss, disorientation, and headache are common side effects. Long-term memory loss may occur in some instances.^[131] The American Psychiatric Association and the National Institute for Health and Clinical Excellence have concluded that the procedure does not cause brain damage.^[132][133]

• St John's wort extract is used extensively in Europe to treat mild and moderate depression. It is a prescription antidepressant in several European countries but is classified as herbal supplement and sold over the counter in the US. Opinions on its efficacy for major depression differ. A systematic meta-analysis of 37 trials conducted by Cochrane Collaboration indicated statistically significant weak-to-moderate effect as compared to placebo. The same meta-analysis found that St John's wort efficacy for major depression is not different from prescription antidepressants.^[134] NCCAM and other NIH-affiliated organizations hold that St John's wort has minimal or no effects beyond placebo in the treatment of major depression, based primarily on one study with negative outcome conducted by NCCAM.^[135][136]

• S-Adenosyl methionine (SAM-e) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Fairly strong evidence from 16 clinical trials suggests it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.^[137][138]

• Repetitive transcranial magnetic stimulation (rTMS), used in treatment-resistant depression, is supported by multiple controlled studies; it has been approved for this indication in Europe, Canada and Australia, but not in the US.^[139] A 2008 meta-analysis based on 32 trials found a robust effect of this method on depression, and it appeared similarly effective for both uncomplicated depression and depression resistant to medication.^[140] However, it was inferior to ECT in a side-by-side randomized trial.^[141]

• Vagus nerve stimulation (VNS) is an approved therapy for treatment-resistant depression and is used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit.^[139] The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favorable for the secondary outcome.^[142]

• A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found it to be more effective than placebo—usually, dim light—for both seasonal affective disorder and for nonseasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective.^[143] A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration studied a different set of trials, in which light was used mostly as an addition to medication or sleep deprivation. A moderate statistically significant effect of light therapy was found; however, it disappeared if a different statistical technique was used.^[144] Both analyses noted poor quality of most studies and their small size and urged caution in the interpretation of their results. The short duration (1–2 weeks) of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

• A 2004 Cochrane Review concluded that there was insufficient evidence to judge the efficacy of acupuncture in the management of depression. Although acupuncture showed no difference in the improvement of depression compared with conventional medication, the methodological quality of the evidence base was found to be poor.^[145]

• Exercise, when used in conjunction with medication by non-suicidal patients, can have beneficial effects in preventing the return of depression. Patients who completed 30 minutes of brisk exercise at least three times a week were found to have a significantly lower incidence of relapse.^[146]

• The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage.^[139]

• Tryptophan and 5-hydroxytryptophan may be more effective than placebo in alleviating depression according to the Cochrane Collaboration meta-analysis. However, only two out of 108 trials were of sufficient quality to be included in this analysis.^[147]

• Omega-3 fatty acids have been studied in clinical trials for major depression primarily as an adjunctive to antidepressant therapy. A meta-analysis of eight such trials indicated a statistically significant superiority of combinations with omega-3 fatty acids over single antidepressants; however, the authors warned that, due to multiple problems with these trials, a reliable conclusion is difficult to achieve.^[148]

• Dehydroepiandrosterone (DHEA), available as a supplement in the US, has been shown to be more effective than placebo for major depression in two small double-blind trials: in one as an adjunctive to antidepressant treatment^[149], and in another as monotherapy.^[150]

• Chromium picolinate was found to be equivalent to placebo for atypical depression overall but possibly efficacious in the sub-group of patients with severe carbohydrate craving.^[151]

• Zinc supplementation was found in a small study to augment the effect of antidepressants.^[152]

• Cranial electrotherapy stimulation (CES, electrosleep) devices currently on the market have been granted marketing authorization by the FDA based on the legacy waver, that is because a sufficiently similar device had been marketed before 1976, when the new regulations requiring controlled testing were introduced.^[153] The FDA considers them to be the class III devices—"devices for which insufficient information exists to ... provide reasonable assurance of safety and effectiveness"^[154] The effects of CES on depression were inconclusive or negative in multiple double-blind studies of psychiatric patients.^{[155][156][157][158][156][159]} In one of them, four out of six clinically depressed patients dropped out of the study because of the massive worsening of depressive symptoms, with two of them becoming actively suicidal.^[159] One of the authors of the latter study cautioned that CES “should not be used as a treatment of choice” for the patients with the primary diagnosis of depression, “and should be used with caution if this diagnosis is suspected.”^[160] Nevertheless, the CES practitioners continue to employ it as a treatment of choice for depression.^[161][162]

Major depressive episodes often tend to resolve over time whether they are treated or not. Outpatients on a waiting list show a 10–15% decrease in symptoms over a few months, and around 20% will no longer meet full criteria.^[163] The median duration of an episode has been estimated to be at least 23 weeks, with the highest rate of recovery in the first three months.^[164]

Studies recruiting from the general population indicate around half those who have a major depressive episode (whether treated or not) do not have any further episodes, but around half have at least one more and a minority experience chronic recurrence.^[165] Studies recruiting from selective inpatient sources suggest low recovery and high chronicity, but studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Recurrence occurs in 40% to 70% within several years, however, and overall about one tenth have poor, one third have intermediate, and one half have favorable outcomes. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence.^[166][167]

There is a higher-than-average suicide risk in major depression. Articles and textbooks have often quoted a suicide rate of 15%, based on reviews of more severely depressed hospitalized patients. However, this was generalized to all people with major depression, both in and out of hospital. A reexamination indicated an approximate figure of 3.4%, with differing rates of around 7% for men and 1% for women.^[168][169] Up to 60% of people who commit suicide have a mood disorder such as major depression, and their risk is especially high if they feel a marked sense of hopelessness or have both depression and borderline personality disorder.^[170] Depressed people also have a higher rate of dying from other causes.^[171] Major depression can be a serious and disabling condition that can significantly affect a person's work, family and school life, sleeping and eating habits, and general health.^[17]

Recurrence is more likely if symptoms have not fully resolved with treatment. Current guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse. Combined evidence from many randomized controlled trials indicates that continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use. Thus in a significant minority of patients depression recurs despite the prolonged treatment with antidepressants.^[172] The reason for recurrence in these cases is poorly understood and could be a "true pharmacologic failure or a worsening of the disease, a relapse that overrides medication." Because of the difficulties of carrying out controlled clinical trials of longer duration, the approval of most antidepressants for the prevention of recurrence is based on trials that lasted up to a year.^[173]

The National Comorbidity Survey Replication (NCS-R), conducted from 2001 through 2002, found that 16.2% of people had suffered a major depressive episode in their lives.^[174] Lifetime prevalence estimates in community epidemiological surveys carried out by the World Health Organization in ten countries varied widely, from 3% in Japan to 16.9% in the US, with the majority between 8% to 12%.^[175] North American population studies have shown that 3–5% of males and 8–10% of females are suffering from a major depressive episode over a 12 month period.^[176][177] Overall, major depression annually affects about 8.2% of the Canadian population and about 8.7% of the US population. Researchers who compared epidemiological factors in Canada and the US found the rate of major depression to be twice as high for Americans without medical insurance than either for Americans with insurance or for Canadians—for whom health care is publicly funded—in general.^[178]

Population studies have consistently shown major depression to be more common in women, although it is unclear why this is so, and whether factors unaccounted for are contributing to this.^[179]

Major depression is currently the leading cause of disease burden in North America and high-income countries, and fourth leading cause worldwide. In the year 2030, it is predicted to be the second leading cause of disease burden worldwide (after HIV), according to the World Health Organization.^[180]

Notes in the Ancient Egyptian document known as the Ebers papyrus appear to refer to emotional distress of the heart or mind, which has been interpreted as sadness or depression.^[181] Passages of the Hebrew Bible (Old Testament), composed and compiled between the 12th and 2nd centuries BC, have been interpreted as describing mood disorders in figures such as Job, King Saul and in the psalms of David.^[182]

The modern idea of depression appears similar in some ways to the much older concept of melancholia, which derives its name from the Greek theory of the four humours: disease being caused by an imbalance in the four basic bodily fluids, or humors. Personality types were similarly thought to be determined by the dominant humor in a particular person. The theory was first put forward by Greek scholar Empedocles (490–430 BC), and was influentially adopted by Hippocrates (460–377 BC). Melancholia was thought to be caused by an excess of black bile; derived literally from the Ancient Greek μέλας, melas, "black", + χολή, kholé, "bile";^[183] a person whose constitution tended to have a preponderance of black bile was thought to have a melancholic disposition.

Melancholia was described as a distinct disease with particular mental and physical symptoms by Hippocrates in his Aphorisms, where he characterized all "fears and despondencies, if they last a long time" as being symptomatic of melancholia.^[184] Between 150–200 AD, Aretaeus of Cappadocia noted that sufferers were "dull or stern; dejected or unreasonably torpid, without any manifest cause". Although humoral theory fell out of favor in some quarters, it was later revived in Greece and the Roman Empire when Galen (AD 129–ca. 200) proposed that melancholy was caused by "animal spirits". Such accounts show similarities to more modern concepts that developed from the 19th century. Prominence was given to a clustering of sadness, dejection, and despondency symptoms, but also often included fear, anger, delusions and obsessions.^[185]

Influenced by Greek and Roman texts, physicians in the Persian and then the Muslim empire developed ideas about melancholia during the Islamic Golden Age. Ishaq ibn Imran (d. 908), known as "Isaac" in the West, combined the concepts of melancholia and phrenitis.^[186] In The Canon of Medicine (1020s), Avicenna described melancholia as a depressive type of mood disorder in which the person may become suspicious and develop certain types of phobias.^[187] The Canon of Medicine became the standard of medical science in Europe for centuries, together with works of Hippocrates and Galen.^[188]

Galen's ideas about medicine dominated Western medical thinking from the medieval era until the Renaissance, in part because the Catholic church supported them. In addition to viewing mental illness through the lens of Galen's "four humors", medieval Europeans viewed mental illness as the entry of demons or evil spirits into the body^[189] and either a punishment for sin or a test of faith and character.^[190] The Franciscan monk Bartholomeus Anglicus (ca. 1203–1272) described a condition which resembles depression in his encyclopedia, De Proprietatibis Rerum, and he suggested that music would help people with this condition. In Christian settings, a spiritual malaise called "acedia" (sloth or absence of caring) was described, involving low spirits and lethargy, especially related to isolation. It was viewed as a "spiritual disease", vice, or "undesirable trait of character".^[191][190]

The seminal scholarly work of the 17th century was Robert Burton's The Anatomy of Melancholy, drawing on numerous theories and the author's own experiences. Burton suggested that melancholy could be combated with a healthy diet, sufficient sleep, music, and "meaningful work", along with talking about the problem with a friend.^[192][193] Shakespeare's plays, such as Hamlet and King Lear, described characters with deep melancholy.

There was increasing medical dissatisfaction with the concept of melancholia. During the 18th century its connections to humoral theory were increasingly challenged by mechanical and electrical explanations; references to dark and gloomy states gave way to ideas of slowed circulation and depleted energy.^[194] The German physician Johann Christian Heinroth (1773–1843), however, argued that melancholia was a disturbance of the soul due to moral conflict within the patient. Eventually various authors proposed up to 30 different subtypes of melancholia, and alternative terms were suggested and discarded. Hypochondria came to be seen as a separate disorder. "Melancholia" and "Melancholy" had been used interchangeably until the 19th century, but the former came to refer to a pathological condition and the latter to a temperament.^[185]

The term depression was derived from the Latin verb deprimere, "to press down".^[195] From the 14th century, "to depress" meant to subjugate or to bring down in spirits. An early published instance of a psychological usage of the noun was in 1665 in Richard Baker's "Chronicle", referring to someone having "a great depression of spirit", and Samuel Johnson used the term in a similar sense in 1753.^[196] The term also came in to use in physiology and economics. One of the earliest uses to refer to a psychiatric symptom was by Louis Delasiauve in 1856; by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function.^[197] Since Aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. The newer concept abandoned these associations and, through the 19th century, became more associated with women.^[185]

Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and by the end of the century it had become a synonym of melancholia; the German psychiatrist Emil Kraepelin (1855–1926) may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states.^[182] English psychiatrist Henry Maudsley proposed an overarching category of affective disorder.^[198]

The influential system put forward by Emil Kraepelin unified nearly all types of mood disorder into manic–depressive insanity, with a separate category of Dementia praecox (now known as schizophrenia). Kraepelin worked from an assumption of underlying brain pathology, but also promoted a distinction between endogenous and exogenous types.^[182] Kurt Schneider honed the terms and coined endogenous depression, commonly associated with prominent psychomotor slowing and seen in inpatients, and reactive depression, more usually seen in outpatients, in 1920.^[47] The latter was so named for reactivity in mood and not reaction to outside events and was frequently misinterpreted. This view was challenged in 1926 by British psychiatrist Edward Mapother, who found a continuum of severity, and noted no clear differences in cause, prognosis or treatment response.^[199] The unitarian view became more popular in the United Kingdom, while the binary view held sway in the US, influenced by the work of Adolf Meyer and before him Sigmund Freud.^[200]

Freud had emphasized early life experiences and conflicting psychological drives; he associated melancholia with psychological loss and self-criticism.^[185] Meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individual's life, and argued that the term depression should be used instead of melancholia.^[198] The DSM-I (1952) contained depressive reaction and the DSM-II (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, as well as including a depressive type of manic-depressive psychosis within Major affective disorders.^[201] The depressive reaction of the 1950s was distinguished from endogenous depression, purportedly a rare biological condition, which borrowed as a synonym the longstanding term, melancholic.^[202]

In the mid-20th century, researchers theorized that depression was caused by a chemical imbalance in transmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms.^[203] During the 1960s and 70s, manic-depression came to refer to just one type of mood disorder (now most commonly known as bipolar disorder) which was distinguished from (unipolar) depression. The terms unipolar and bipolar had been coined by Karl Kleist.^[182]

The term Major depressive disorder was introduced by a group of US psychiatrists in the mid-1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the "Research Diagnostic Criteria", building on earlier Feighner Criteria), and was incorporated in to the DSM-III in 1980.^[204] In order to maintain consistency the ICD-10 used the same criteria, with only minor alterations, but using the DSM diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes.^[204][205] The ancient idea of melancholia still survives in the notion of a melancholic subtype.

The new definitions of depression were widely accepted, although there have been conflicting findings and views on the validity of imposing such categorical cut-offs on a continuum,^[206] and of not incorporating any evaluation of the personal and social context (except for grief) in which it occurs.^[207][208] Debate has also continued about whether a categorical distinction between unipolar and bipolar distinction best reflects the evidence.^[209] There are also some continuing empirical arguments for a return to the diagnosis of melancholia.^[210][211]

Many causes for depression have been proposed.^[212] Biological psychiatrists, for example, explored the biological substrates of depression; psychiatrist David Healy wrote about the growth of the diagnosis, along with perspectives on the development and promotion of antidepressants and the biological model since the late 1950s.^[213]

Even today, people's conceptualizations of depression vary widely, both within and among cultures. "Because of the lack of scientific certainty," one commentator has observed, "the debate over depression turns on questions of language. What we call it—'disease,' 'disorder,' 'state of mind'—affects how we view, diagnose, and treat it."^[214] There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or an indicator of the need to address social problems, structural determinants of powerlessness, and emotional struggle.^[215][216] The diagnosis is less common in some countries, such as China. It has been argued that the Chinese traditionally deny or somatize emotional depression, or alternatively that Western cultures reframe and elevate some expressions of human distress to disorder status.^[217] Australian psychiatrist Gordon Parker and others have argued that the Western concept of depression "medicalizes" sadness or misery.^[202][218]

Evolutionary theorists view depression as an adaptation to regulate relationships or resources, although it may be unwanted or disordered in modern environments.^[220] From this perspective, depression can be seen 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."^[73] Like an ageing hunter in our foraging past, an alienated member of today's society may feel and act in ways that 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.^[69] These insights may be helpful in counselling therapy.^[73][221]

There is ongoing debate about the extent to which depression and mental illness in general may be linked to creativity in arts.^[222] The relationship between depression and creativity appears to be especially strong among female poets.^[223][224] Philosopher John Stuart Mill experienced a several-months-long period of what he called "a dull state of nerves," when one is "unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent." He quoted Samuel Taylor Coleridge's "Dejection" as a perfect description of his case: "A grief without a pang, void, dark and drear, / A drowsy, stifled, unimpassioned grief, / Which finds no natural outlet or relief / In word, or sigh, or tear."^[225] English essayist and wit Samuel Johnson used the term "the black dog" in 1780s to describe his own depression.^[226] Subsequently popularised by depression sufferer former British Prime Minister Sir Winston Churchill,^[226] the term lives on in the Black Dog Institute, an Australian facility for research and education into mood disorders such as major depression and bipolar disorder.^[227]

Historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. Nevertheless, analysis or interpretation of letters, journals, artwork, writings or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. People who may have had depression include the British writer Henry James^[228] and American president Abraham Lincoln.^[229][230] Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen^[231] and American playwright and novelist Tennessee Williams.^[232] Even some pioneering psychologists, such as William James^[219][233] and John B. Watson,^[234] dealt with depression in their adulthoods. For more information on historical and contemporary public figures who faced depression, see the List of people with depression.

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• Barlow, DH (2005), Abnormal psychology: An integrative approach (5th ed.), Belmont, CA, USA: Thomson Wadsworth, ISBN 0534633560 {{citation}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

• Kent, Deborah (2003), Snake Pits, Talking Cures & Magic Bullets: A History of Mental Illness, Twenty-First Century Books, ISBN 0761327045

• Hergenhahn, BR (2005), An Introduction to the History of Psychology (5th edition ed.), Belmont, CA, USA: Thomson Wadsworth, ISBN 0534554016 {{citation}}: |edition= has extra text (help)

• Parker, Gordon (1996), Melancholia: A disorder of movement and mood: a phenomenological and neurobiological review, Cambridge: Cambridge University Press, ISBN 052147275X {{citation}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

• Sadock, Benjamin J. (2002), Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (9th ed.), Lippincott Williams & Wilkins, ISBN 0781731836 {{citation}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

• DSM-IV Diagnostic Criteria for Major Depressive Disorder - DSM-IV-TR text from mindsite.com
• Depression at Epocrates Online
• Black Dog Institute – Depression and Bipolar Disorder Information Australia
• Template:Dmoz
• National Alliance on Mental Illness – Depression support, advocacy, and education
• National Depressive and Manic Depressive Association - National Depressive and Manic Depressive Association

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