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Major depressive disorder (also known as major depression, unipolar depression, unipolar disorder, or clinical depression) is a mental disorder characterized by a pervasive low mood and loss of interest or pleasure in usual activities. The general term depression is often used to describe a temporary depressed or sad mood. By contrast, major depression is 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. In Western countries, approximately 3.4% of people with major depression eventually commit suicide. Up to 60% of all people who commit suicide have depression or another mood disorder. Depressed individuals have a shorter life expectancy than those without depression, being more susceptible to medical conditions such as heart disease. However, depression may be overdiagnosed, and current diagnostic trends arguably have the effect of medicalizing sadness. The diagnosis of major depressive disorder is based on the patient's self-reported experiences and behavior reported by relatives or friends. There is no laboratory test for major depression, although physicians generally test for physical conditions that may cause similar symptoms. The course of the disorder varies widely, from a once only occurrence to a lifelong disorder with recurrent major depressive episodes. The most common time of onset is between the ages of 30 and 40 years, with a later peak between 50 and 60 years. Major depression occurs more often in women than men, although men are at higher risk for suicide. Most patients are treated in the community with antidepressant medication and supportive counselling, and admission to hospital may be necessary in cases associated with self-neglect or a significant risk of harm to self or others. A minority with severe illness may be treated with electroconvulsive therapy (ECT) under a short general anaesthetic. The understanding of the nature and causes of depression has evolved over the centuries; nevertheless, many aspects of depression including the precise role of neurotransmitters are not fully understood, and are the subject of debate and research. Both psychological and biological causes have been proposed, and the determination of whether there are two separate conditions or a continuum of a single disorder has been researched since the 1920s. Current classification has favored a single disorder since the creation of the term major depressive disorder in 1980. The neurotransmitters serotonin and norepinephrine have been implicated, and most antidepressants work to increase their active levels in the brain.

Psychological factors have also been implicated, and forms of psychotherapy can be used to address them.

Signs and symptoms Major depression is a serious condition that affects a person's work, family and school life, sleeping and eating habits, and general health. The impact on functioning and well-being has been equated to that of chronic medical conditions such as diabetes. A person suffering a major depressive episode usually experiences a pervasive low mood, or loss of interest or pleasure in favored activities. Depressed people may be preoccupied with feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness. Other symptoms include poor concentration and memory, withdrawal from social situations and activities, reduced libido (sex drive), and thoughts of death or suicide. Insomnia is common: in the typical pattern, a person wakes very early and is unable to get back to sleep. Hypersomnia, or oversleeping, is less common. Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur. The person may report persistent physical symptoms such as fatigue, headaches, digestive problems, or chronic pain; this is a typical presentation in developing countries. Family and friends may perceive that the person is either agitated or slowed down. Older people with major depression are more likely than younger people to show cognitive symptoms such as forgetfulness and to show a more noticeable slowing of movements. In severe cases, depressed people may experience psychotic symptoms such as delusions or, less commonly, hallucinations, usually of an unpleasant nature. Children may display an irritable rather than depressed mood, and show different symptoms depending on age and situation. Most exhibit a loss of interest in school and a decline in academic performance. Children with depression may be described as clingy, demanding, dependent, or insecure.

Diagnosis may be delayed or missed when symptoms are interpreted as normal moodiness. Causes In the biopsychosocial model, both biological and psychological (including social) factors play a role in causing depression. There is overlap, and the precise causes vary depending on individual circumstances. The heritability of depression—the degree to which it is genetically determined—has been estimated to be approximately 40% for women and 30% for men. From the evolutionary standpoint, major depression might be expected to reduce an individual's ability to reproduce. Some evolutionary explanations for the apparent contradiction between biopsychosocial, psychological and psychosocial hypotheses and the high heritability and prevalence of major depression are explained by the proposal that certain components of depression are adaptations. Biological causes Most antidepressants increase synaptic levels of the monoamine neurotransmitter serotonin. Some also enhance the levels of two other neurotransmitters, norepinephrine and dopamine. This observation gave rise to the monoamine theory of depression. In its contemporary formulation, the monoamine theory 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; serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." The proponents of this theory recommend choosing the antidepressant with the mechanism of action impacting 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. Major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells. Consistent with the monoamine theory, a longitudinal study uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow such events, but even more so in people with one or two short alleles of the 5-HTT gene. Serotonin is thought to help regulate other neurotransmitter systems, and decreased serotonin activity may allow these systems to act in unusual and erratic ways. Facets of depression may be emergent properties of this dysregulation. In the past two decades, research has uncovered multiple limitations of the monoamine theory, and its inadequacy has been criticized within the psychiatric community. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. Antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known about for a long time. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people nor does it worsen symptoms in depressed patients. Already limited, the monoamine theory has been further oversimplified when presented to the general public. MRI scans of patients with major depressive disorder have reported a number of differences in brain structure compared to those without the illness. Although there is some inconsistency in the results, meta-analyses have shown there is strong evidence for smaller hippocampal volumes and increased rates of hyperintensities in depressed patients. Hyperintensities have been associated with patients with a late age of onset have led to the development of the theory of vascular depression. There may be a link between depression and neurogenesis of the hippocampus, a center for both mood and memory. Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood. Drugs may increase serotonin levels in the brain, stimulating neurogenesis and thus increasing the total mass of the hippocampus. This increase may help to restore mood and memory. Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior. One of the neurotrophins responsible for neurogenesis is the brain-derived neurotrophic factor (BDNF). The level of BDNF in the blood plasma of depressed subjects is drastically reduced (more than threefold) as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although decreased plasma BDNF levels have been found in many other disorders, there is some evidence that BDNF is involved in the cause of depression and the mechanism of action of antidepressants. Depression may also be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that is similar to the neuro-endocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function. 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, in 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, patients may be especially unaffected by therapeutic intervention. Psychological causes Various aspects of personality and its development are integral in the occurrence and persistence of depression. Although episodes are strongly correlated with adverse events, how a person copes with stress also plays a role. Low self-esteem, learned helplessness, and self-defeating or distorted thinking are related to depression. Depression may also be connected to feelings of religious alienation; conversely, depression is less likely to occur among those with high levels of religious involvement. It is unclear as to which factors are causes or effects, but in any case depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem. Cognitive psychology and cognitive behavioral therapy are based on the theory that depression arises from cognitive biases and distortions stemming from deficits in memory and information processing. According to psychologist Martin Seligman, depression in humans is similar to learned helplessness in laboratory animals, who remain in unpleasant situations when they are able to escape, but do not because they initially learned they had no control. Learned helplessness and depression may be related to what psychologist Julian Rotter called an external locus of control, a tendency to attribute outcomes to events outside of personal control. A related idea, Aaron T. Beck's cognitive triad, proposes that depression entails cognitive errors about oneself, one's world, and one's future. On the other hand, depressed individuals often blame themselves for negative events. According to one study, depressed adolescents, while feeling responsible for negative events, do not take credit for positive outcomes. This tendency is characteristic of a depressive attributional, or pessimistic explanatory style. According to psychologist Albert Bandura, depressed individuals have a negative self-concept and lack a sense of self-efficacy; in other words they do not believe they can influence events or achieve personal goals. Milder depression 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. A large body of research has documented the importance of interpersonal factors, including strained or critical personal relationships, in the onset of depressive symptoms and major depression in young and middle-aged adults. Vulnerability factors—such as early maternal loss, lack of a confiding relationship, responsibility for the care of several young children at home, and unemployment—can interact with life stressors to increase the risk of depression. For older adults, the factors are often health problems, changes in relationships with a spouse or adult children due to the transition to a care-giving or care-needing role, the death of a significant other, or a change in the availability or quality of social relationships with older friends because of their own health-related life changes. According to psychoanalytic theory, depression may be intertwined with self-criticism. Sigmund Freud, the father of psychoanalysis, wrote that the "super-ego becomes over-severe, abuses the poor ego, humiliates it and ill-treats it, threatens it with the direst punishments". He theorized that objective loss, such as the loss of a valued relationship through death or a romantic break-up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, 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 it is the ego itself.'" Existential psychologist Rollo May stated that "depression is the inability to construct a future". From the existential perspective, in order to construct a future, individuals must be acutely aware of both their mortality and their freedom to act, and they must exercise their freedom within the explicit framework of an acute awareness of their mortality. This awareness produces "normal" anxiety, whereas the lack of awareness leads to neurotic anxiety, self-alienation, inauthentic living, guilt, and depression. Humanistic psychologists agree with many facets of existentialism, but argue that depression can result from an incongruity between society and the individual's innate drive to self-actualize. The father of humanistic psychology, Abraham Maslow, believed that depression is especially likely to arise when the world precludes a sense of "richness" or "totality" for the self-actualizer. Evolutionary psychology suggests that major depression can result from overactivation of psychological mechanisms that evolved to produce adaptive responses to material or social loss or defeat. Some aspects of this approach have received empirical support and clinical application; other components are still at a hypothetical stage. Social causes Long-term risks for developing major depression include family disruption and low socioeconomic status in early childhood. The risk is independent of later adult social status and is related to various social inequalities. Childhood emotional, physical, sexual abuse, or neglect are also associated with increased risk of developing depressive disorders later in life. Such events are more likely to occur in dysfunctional families, for example, one with an alcoholic parent. Early adverse events and stressful conditions that persist through childhood and adolescence may be linked to the later development of depression. Social rejection also predicts later depression, and adolescents who are victimized by peers are more vulnerable to developing depressive symptoms if it impacts on the development of their identity, although family cohesion and emotional involvement are protective factors. In adulthood, a correlation between stressful life events and the onset of major depressive episodes has been found consistently and is likely causal, although the specific mechanisms are unclear. Negative events such as assault, divorce or separation, legal issues, major problems with work, finances, housing, health, or friends and confidants, have been found to precede episodes if they represent a long-term threat, particularly if the threat is of a loss or humiliation that devalues an individual in a core role. The first episode of major depressive is more likely to be immediately preceded by stressful life events than are recurrent ones. Social isolation has also been found to predict onset of a first episode. There is evidence that neighborhood social disorder, for example, due to crime or illicit drugs, is a risk factor, and that a high neighborhood socioeconomic status, with better amenities, is a protective factor. There is some evidence of risk from psychosocial stressors in the workplace, such as working at a job that is demanding but involves little opportunity for decision-making. There is mixed evidence regarding the role of social capital (features of social organization including interpersonal trust, civic engagement and cooperation for mutual benefit). Diagnosis Clinical assessment A diagnostic assessment may be conducted by a general practitioner or by a psychiatrist or psychologist, who will record the person's current circumstances, biographical history and current symptoms, and a family medical history to see if other family members have suffered from a mood disorder, and discuss the person's alcohol and drug use. A mental state examination includes an assessment of the person's current mood and an exploration of thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans.

Before diagnosing a 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 to exclude hypo- or hyperthyroidism; 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. Testosterone levels may be used to diagnose hypogonadism, a cause of depression in men. 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. Depression is also a common initial symptom of dementia. Conducted in older depressed people, screening tests such as the mini-mental state examination, or a more complete neuropsychological evaluation, can rule out cognitive impairment. A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms. No biological tests confirm major depression. Investigations are not generally repeated for a subsequent episode unless there is a specific medical indication, in which case serum sodium can 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. Specialist mental health services are rare in rural areas, and thus diagnosis and management is largely left to primary care clinicians. This issue is even more marked in developing countries. Rating scales Diagnostic screening programs have been advocated to improve detection of depression, but there is evidence that the use of screening instruments does little to improve detection rates. A study in the U.K. concluded that screening alone is costly and does not improve the treatment or outcome of depression. Several rating scales are used in research or as screening tools. The Beck Depression Inventory is a widely used tool in the diagnosis of depression, although its main purpose is not diagnosis, but determining the presence and severity of symptoms. Originally designed by psychiatrist Aaron T. Beck in 1961, it is a 21-question self-report inventory that covers symptoms such as irritability, fatigue, weight loss, lack of interest in sex and thoughts including feelings of guilt, hopelessness or of being punished. Other scales include the Geriatric Depression Scale in older populations, which is also valid in patients with mild to moderate dementia; the Hamilton Depression Rating Scale (HRSD-21) designed by psychiatrist Max Hamilton in 1960; and the Montgomery-Åsberg Depression Rating Scale (MADRS). The Patient Health Questionnaires are two self-administered questionnaires for use in primary care. The PHQ-2 has two screening questions about the frequency of depressed mood and a loss of interest in activities; a positive to either question indicates further testing is required. The PHQ-9 is a slightly more detailed nine-question survey for assessing symptoms of major depressive disorder in greater detail, and is often used to follow up a positive PHQ-2 test. DSM IV-TR and ICD-10 criteria 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. Major depressive disorder is classified as a mood disorder in DSM IV-TR. The diagnosis hinges on the presence of a single or recurrent major depressive episode. Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Depressive Disorder Not Otherwise Specified is diagnosed if the depressive episode's manifestation does not meet the criteria for a major depressive episode. 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); the term recurrent may be added if there have been multiple episodes without mania. Major depressive episode A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks. 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. 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". 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 the mood persists and the characteristic features of a major depressive episode develop. The criteria have been criticized because they do not take into account any other aspects of the personal and social context in which depression can occur. 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: excluded are a range of related diagnoses, including dysthymia which involves a chronic but milder mood disturbance, Recurrent brief depression which involves briefer depressive episodes, Minor depressive disorder which involves only some of the symptoms of major depression, and Adjustment disorder with depressed mood which involves low mood resulting from a psychological response to an identifiable event or stressor.

Subtypes Diagnosticians recognize several subtypes, which are sometimes called "course specifiers":

   * 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.
   * 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.
   * 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 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.

   * Postpartum depression refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth.

Postpartum depression, which has incidence rate of 10–15% among new mothers, typically sets in within three months of labor, and lasts as long as three months.

   * Seasonal affective disorder 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. Differential diagnoses In order to diagnose major depressive disorder, several other potential diagnoses must be ruled out, including the following:

   * Dysthymia is a chronic, milder mood disturbance in which 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).

   * Adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode.
   * Bipolar disorder, previously known as manic-depressive disorder, is a condition in which depressive phases alternate with periods of mania or hypomania.

Although depression is currently categorized as a separate disorder, there is ongoing debate because individuals diagnosed with major depression often experience some hypomanic symptoms, indicating a mood disorder continuum.

   * Loneliness and depression have enough features in common that loneliness may be viewed as a differential diagnosis.

In general, depression is likely to coexist with loneliness if the loneliness is chronic rather than transient. If the individual has global concerns that do not focus strictly on interpersonal relationships, feels a high degree of guilt, or is particularly vegetative, then the person is likely to be depressed; if these conditions are not met, he or she may be lonely instead. Treatment For a fuller discussion of standard, rarer and more experimental treatments, see Treatment for depression. The three most common 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. Care is usually given on an outpatient basis, while treatment in an inpatient unit is considered if there is a significant risk to self or others. Treatment options are much more limited in developing countries, where access to mental health staff, medication, and psychotherapy are often difficult. Development of mental health services is minimal in many countries; depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and not as an inherently life-threatening condition. Psychotherapy

Psychotherapy can be delivered, to individuals or groups, 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. In people under 18, medication is usually offered only in conjunction with psychotherapy, not as a first line treatment. The most studied form of psychotherapy for depression is cognitive behavioral therapy (CBT), thought to work by teaching clients to learn a set of useful cognitive and behavioral skills. Earlier research suggested that cognitive-behavioral therapy was not as effective as antidepressant medication; however, more recent research suggests that it can perform as well as antidepressants in patients with moderate to severe depression. Overall, systematic review reveals CBT to be an effective treatment in depressed adolescents, although possibly not for severe episodes. Combining fluoxetine with CBT appeared to bring no additional benefit or, at the most, only marginal benefit. 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. Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment. 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. Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced, eclectic technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, Short Psychodynamic Supportive Psychotherapy (SPSP) was found to be as effective as medication for mild to moderate depression. Medication 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 one SSRI can be switched to another; such a switch results in improvement in almost 50% of cases. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. Venlafaxine (Effexor), and other serotonin-norepinephrine reuptake inhibitors, may be modestly more effective than SSRIs; however, Venlafaxine is not recommended as a first-line treatment because of evidence suggesting its risks may outweigh benefits. Its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18. Isoniazid, the first compound called antidepressant 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. 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. To find the most effective treatment, the dosages of antidepressants must often be adjusted, or different medications and combinations tried. Response rates to the first agent administered may be as low as 50%. It may take anywhere from three to eight weeks after the start of medication before the therapeutic effects are fully revealed. Patients are 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 usually need to take medication for the rest of their lives. The term refractory- or treatment-resistant depression is used to describe cases that do not respond to adequate courses of least two antidepressants. A doctor may add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance. Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. Addition of a thyroid hormone, triiodothyronine may work as well as lithium, even in patients with normal thyroid function. 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. Efficacy of medication and psychotherapy Two recent meta-analyses of clinical trial results submitted to the U.S. Food and Drug Administration (FDA) concluded that antidepressants are statistically superior to placebo but their overall effect is low to moderate; 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 although did increase with severity and reach clinical significance for very severe depression. These results 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. 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". The other author agreed that the "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. Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of major depression. In contrast, medication gives better results for dysthymia. 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. 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. Electroconvulsive therapy Electroconvulsive therapy (ECT) is a procedure in which seizures are electrically induced in anesthetized patients. Hospital psychiatrists prescribe ECT in cases of severe major depression which has not responded to trials of antidepressant or, less often, psychotherapy or supportive interventions. It has a quicker effect than antidepressant therapy, and thus may be the treatment of choice in emergencies such as catatonic depression where the patient has ceased oral intake of fluid or nutrients, or where there is severe suicidality. Some evidence suggests it is the most effective treatment for depression in the short-term and one study without a comparison group or assessment of additional treatments given, suggested remission is related to improved self-rated quality of life in both the short-term (correlated with the degree of amnesia) and after six months. However, ECT has been found to have much lower remission rates in real-world practice and on its own does not have a sustained benefit as nearly everyone relapses. The relapse rate in the first six months may be reduced by the use of psychiatric medications or further ECT (although some authorities, such as NICE, do not recommend the latter), but remains high. Common initial adverse effects include short-term memory loss, disorientation, headache; long-term memory and other cognitive deficits may persist. According to the American Psychiatric Association and the National Institute for Health and Clinical Excellence, available evidence suggests that the procedure, when administered according to their standards and without complications, does not cause brain damage in adults. Other methods of treatment Two products, St John's wort and S-Adenosyl methionine, are available as prescription antidepressants in several European countries, but in the US are classified as herbal supplements and sold over-the-counter. There is inconsistent evidence on the effect of St John's wort extract on major depression. The pharmaceutical quality of the extract has an effect on the safety and efficacy for the treatment of any type of depression. Clinical trials of S-Adenosyl methionine (SAM-e) have shown that it is equivalent to tricyclic antidepressants in effectiveness, although the safety and efficacy of over-the-counter versions is unknown. Other supplements such as omega-3 fatty acids, tryptophan, and 5-hydroxytryptophan (5-HTP), have shown no effect beyond those of placebo. Bright light therapy is sometimes used to treat depression, especially in its seasonal form. Repetitive transcranial magnetic stimulation (rTMS) utilizes powerful magnetic fields which applied to the brain from outside the head. Multiple controlled studies support the use of this method in treatment-resistant depression; it has been approved for this indication in Europe, Canada and Australia, but not in the US. It was inferior to ECT in a side-by-side randomized trial. Other therapeutic approaches have been used to treat depression. Bright light therapy has been found to be an effective treatment for the winter depression produced by seasonal affective disorder. There has been some conflicting evidence as to its effectiveness for non-seasonal depression. Exercise has not been shown to reduce the symptoms of depression. Prognosis Major depressive episodes often resolve over time whether they are treated or not. Outpatients on a waiting list show a 10–15% reduction in symptoms over a few months, and around 20% will no longer meet full criteria. The median duration of an episode has been estimated at least 23 weeks, with the highest rate of recovery in the first three months. General population studies indicate around half those who have a major depressive episode (whether treated or not) recover and remain well, while 35% will have at least one more, and around 15% experience chronic recurrence. Studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence. 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. Evidence from many randomized controlled trials indicates 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, depression recurs despite the prolonged antidepressant treatment in a significant minority of patients; 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. Epidemiology Depression is a major cause of morbidity worldwide. Lifetime prevalence varies widely, from 3% in Japan to 17% in the US. In most countries the number of people who would suffer from depression during their lives falls within an 8–12% range. In North America the probability of having a major depressive episode within a year-long period is 3–5% for males and 8–10% for females. 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. People are most likely to suffer their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60. The risk of major depression is increased in the first year after childbirth (postpartum depression), and after cardiovascular and neurological illnesses such as stroke, Parkinson's disease, and multiple sclerosis. Depressive episodes following a heart attack might even correspond with an increased risk of further cardiac complications, including death. World map of suicide rates per 100,000. Depression is often associated with unemployment and poverty. A 2007 study that 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. Major depression is currently the leading cause of disease burden in North America and other high-income countries, and the 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. Up to 60% of people who commit suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality disorder. Depressed people also have a higher rate of dying from other causes. The suicide rate in major depression has often been quoted as 15% but this was taken from a review of studies of hospitalized patients, who were the most severely depressed. A broader reexamination has indicated an approximate figure of 3. 4%, with differing rates of around 7% for men and 1% for women. Comorbidity 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. Robert Sapolsky similarly argues that the relationship between stress, anxiety, and depression could be measured and demonstrated biologically. There are increased rates of alcohol and drug abuse and particularly dependence, and around a third of individuals diagnosed with attention-deficit hyperactivity disorder develop comorbid depression. Post-traumatic stress disorder and depression often co-occur, and both can result from childhood trauma. History Prehistory to medieval periods The four temperaments (clockwise from top right; choleric; melancholic; sanguine; phlegmatic), according to an ancient theory of mental states 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. 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. In Ancient Greece, disease was thought due to 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. Derived from the Ancient Greek melas, "black", and kholé, "bile", 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 the ailment. Aretaeus of Cappadocia later noted that sufferers were "dull or stern; dejected or unreasonably torpid, without any manifest cause". The humoral theory fell out of favor but was revived in Rome by Galen. Melancholia was a far broader concept than today's depression; prominence was given to a clustering of the symptoms of sadness, dejection, and despondency, and often fear, anger, delusions and obsessions were included. 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) combined the concepts of melancholia and phrenitis. Avicenna described melancholia as a depressive type of mood disorder in which the person may become suspicious and develop certain types of phobias. His work, the Canon of Medicine, became the standard of medical thinking in Europe alongside those of Hippocrates and Galen. Moral and spiritual theories also prevailed, and in Christian settings a malaise called acedia (sloth or absence of caring) was identified, involving low spirits and lethargy typically linked to isolation. 17th to 19th centuries 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. During the 18th century, the humoral theory of melancholia was increasingly challenged by mechanical and electrical explanations; references to dark and gloomy states gave way to ideas of slowed circulation and depleted energy. The German physician Johann Christian Heinroth, however, argued 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. The term depression was derived from the Latin verb deprimere, "to press down". From the 14th century, "to depress" meant to subjugate or to bring down in spirits. It was used in 1665 in Richard Baker's Chronicle to refer to someone having "a great depression of spirit", and by Samuel Johnson in a similar sense in 1753. The term also came in to use in physiology and economics. An early usage referring to a psychiatric symptom was by Louis Delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function. 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. Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; the German psychiatrist Emil Kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states. English psychiatrist Henry Maudsley proposed an overarching category of affective disorder. 20th century to the present day The influential system put forward by 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 (internally caused) and exogenous (externally caused) types. Kurt Schneider coined the terms endogenous depression and reactive depression in 1920, the latter referring to reactivity in mood and not reaction to outside events, and therefore frequently misinterpreted. The division was challenged in 1926 by British psychiatrist Edward Mapother who found no clear distinction between the types. 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.

Freud had emphasized early life experiences and conflicting psychological drives; he associated melancholia with psychological loss and self-criticism. 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. 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, and also included a depressive type of manic-depressive psychosis within Major affective disorders. 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. 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; in the former, there is a continuum of depression ranked only by severity and the result of a "psychobiological final common pathway", whereas the latter conceptualizes a distinction between biological and reactive depressive syndromes. The publishing of DSM-III saw the unitarian model gain a more universal acceptance. 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. 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. 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. 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. The ancient idea of melancholia still survives in the notion of a melancholic subtype. The new definitions of depression were widely accepted, albeit with some conflicting findings and views. There have been some continued empirical arguments for a return to the diagnosis of melancholia. There has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s. Sociocultural aspects Samuel Johnson described his depression as "the black dog" 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." There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or is an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle. The diagnosis is less common in some countries, such as China. It has been argued that the Chinese traditionally deny or somatize emotional depression (although since the early 1980s the Chinese denial of depression may have modified drastically). Alternatively, it may be that Western cultures reframe and elevate some expressions of human distress to disorder status. Gordon Parker and others have argued that the Western concept of depression "medicalizes" sadness or misery. Evolutionary theorists view depression as an adaptation to regulate relationships or resources, although it may be unwanted or disordered in modern environments. 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". 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. These insights may be helpful in counselling therapy. There is discussion in Western countries that depression and mental illness in general may be linked to creativity in the arts. British literature gives many examples of reflections on depression. English 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." English essayist and wit Samuel Johnson used the term "the black dog" in 1780s to describe his own depression. Subsequently popularized by depression sufferer former British Prime Minister Sir Winston Churchill, 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. 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 and American president Abraham Lincoln. Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen and American playwright and novelist Tennessee Williams. Even some pioneering psychologists, such as William James and John B. Watson, dealt with depression in their adulthoods. Both William James and John Stuart Mill found relief from their depression in literature. For James, who was nearly driven to suicide during his depression, the choice to believe in free will was instrumental in overcoming this condition. This choice was inspired by an essay about free will by French philosopher Charles-Bernard Renouvier. Upon reading this essay, James no longer felt that "suicide the most manly form to put daring into," and declared, "now I will go a step further with my will, not only act with it, but believe as well; believe in my individual reality and creative power." Mill took solace in the work of English poet William Wordsworth. Mill wrote that, "What made Wordsworth's poems a medicine for my state of mind, was that they expressed, not mere outward beauty, but states of feeling, and of thought coloured by feeling, under the excitement of beauty."