Definitions

secretive or illicit method

Major depressive disorder

Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, 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, and 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 of the disorder 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. Major depression appears significantly more often in women than men.

Both psychological and biological causes have been proposed, and the question of whether there are two separate conditions or a continuum of a single disorder has been hotly debated since the 1920s. Current classification has favored the latter theory 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. However, the relief of symptoms usually occurs several weeks or more after changes in neurotransmitter levels, which suggests that the precise role of neurotransmitter levels in depressive illness is still murky. A host of psychological factors has also been implicated, and various forms of psychotherapy are used to address them. Hospitalization may be necessary in cases associated with self-neglect or a significant risk of suicide, and electroconvulsive therapy is sometimes used in severe cases.

Ideas about what causes and constitutes depression have evolved over the centuries. The term depression is commonly used to describe a temporary depressed or sad mood. By contrast, 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, authorities such as Australian psychiatrist Gordon Parker have proposed it may be overdiagnosed, and current diagnostic standards arguably have the effect of medicalizing 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.

Signs and symptoms

Major depression is a serious condition that significantly 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 congestive heart failure.

A person suffering a major depressive episode almost always 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 reports waking very early and being 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 agitated or slowed down. Older people with major depression are more likely than younger people with the condition to show cognitive symptoms such as forgetfulness, and a more noticeable slowing of movements. In severe cases, depressed people may experience psychotic symptoms such as delusions or, less commonly, hallucinations, which are usually unpleasant.

Children may display a mostly irritable rather than depressed mood, and show different symptoms depending on age and situation. Most will exhibit a loss of interest in school and decline in academic performance. Those older than 12 years may also begin abusing drugs or alcohol, or exhibit disruptive behavior. Diagnosis may be delayed or missed as symptoms may be interpreted as normal moodiness. Thoughts or attempts of suicide are rare in children with major depression under 12 years of age.

Diagnosis

Physical investigations

Before diagnosing a major depressive disorder, a medical practitioner generally performs a medical examination and selected investigations to rule out a medical illness as a cause of the 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. An EEG may be ordered to rule out the early dementia that can present with depressive symptoms in older patients. 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.

Clinical assessment

A psychiatric assessment may be conducted by a general medical practitioner or by referral to a psychiatrist or psychologist. 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 an assessment of the person's current mood and an exploration of thought content, in particular thoughts of hopelessness, self-harm or suicide.

Specialist mental health services are rare in rural areas, and thus diagnosis and management is largely left to primary care clinicians. The issue is even more marked in developing countries.

Rating scales

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, and there is strong evidence routine screening does little to improve detection rates.

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. Originally designed by psychiatrist Aaron T. Beck in 1961, it is a 21-question patient-completed survey that covers symptoms such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, fatigue, weight loss, and lack of interest in sex. Other scales commonly used include the Geriatric Depression Scale in older populations, which is also valid in patients with mild to moderate dementia, the widely used 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, and are frequently referenced in research studies.

Major depressive disorder is classified as a mood disorder in DSM IV-TR; the diagnosis hinges on the presence of a major depressive episode, which may be either single or recurrent. 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); the term recurrent may be added if there have been multiple episodes without mania.

Major depressive episode

A major depressive episode is a severely depressed mood that persists for at least two weeks. 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 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 characteristic features develop. The criteria have been criticized for not taking 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. There are in fact a range of related diagnoses of differing severity and duration, 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:

  • 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.
  • 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. The criteria have been questioned by Australian psychiatrist Gordon Parker, who has proposed greater emphasis on motor disturbance in diagnosis of this subtype.
  • 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.
  • 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%, 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 MDD, 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 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.

Causes

Most experts believe that both biological and psychological (including social) factors play a role in causing depression, in what is often described as the biopsychosocial model. There is much overlap and integration, and the precise causes vary depending on the individual and their circumstances. The heritability of depression—the degree to which it is genetically determined—has been estimated at around 40% for women and 30% for men. 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.

Biological

Most antidepressants increase synaptic levels of monoamine neurotransmitter serotonin. They may 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 the deficit of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." The proponents of this theory recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. The anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs.

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 stressful life events, but even more so for people with one or two short alleles of the 5-HTT gene. Serotonin may help to 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.

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. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known 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 the symptoms in depressed patients. Already limited, the monoamine theory has been further oversimplified when presented to the general public.

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, 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.

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.

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.

Psychological

Psychological factors include the complex development of personality and how a person has learned to cope with external environmental factors, such as stress.

Low self-esteem, learned helplessness, and self-defeating or distorted thinking are connected with depression. It is unclear whether these are causes or effects of depression, but in either case depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem. A depressive episode may also be triggered by a loss of religious faith.

Cognitive psychology and cognitive behavioral 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. 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 perceived to be uncontrollable. On the other hand, depressed people often blame themselves for negative events, and believe that the relevance of these events persists through time and pervades their entire lives. This tendency is characteristic of a "depressive attributional style", or "pessimistic explanatory style". 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. A related idea, Aaron T. Beck's cognitive triad, is that depression entails "cognitive errors" about oneself, one's world, and one's future. 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.

A large body of research has documented the salience of interpersonal factors, including strained or critical relationships, in the onset of depressive symptoms and major depression in young and middle-aged adults. For older adults, the factors are often health problems, a change in relationship with spouse or adult children because of transition to a care-giving or 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. Vulnerability factors—namely early maternal loss, lack of a confiding relationship, several young children at home, and unemployment—can interact with 'provoking agents' to increase the risk of depression.

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." 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.'"

Existential psychologist Rollo May stated that "depression is the inability to construct a future. From the existential perspective, in order to construct a future, people must be 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", whereas the lack of these things leads to "neurotic anxiety," "self-alienation," "inauthentic" living, and depression. Humanistic psychologists agree with many facets of existentialism, but argue that depression results from an incongruity between society and the individual's innate drive to self-actualize.

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

Family disruption and low socioeconomic status in early childhood are long-term risks for developing major depression. The risk is independent of parental status, is related to various social inequalities, and possibly affects women more than men. Childhood emotional, physical, and sexual abuse are also associated with increased risk of developing depressive disorders for decades after their occurrence. Such events are more likely to occur in dysfunctional households, for example when the parents have problems with alcoholism. Such early adverse events may be linked to the later development of depression as stressful conditions persist through childhood and adolescence. 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 consistently found and is probably causal, although the specific mechanisms are unclear. Negative events such as assault, divorce or separation, legal issues, or major problems with work, finances, housing, health, or friends and confidants, have been found to precede episodes if they represent a long-term threat and particularly a loss or humiliation that devalues an individual in a core role. A first major depressive episode is more likely than recurrent ones to be immediately preceded by severe life events. Social isolation has also been found to predict onset of a first episode. There is evidence that neighborhood social disorder, due to crime or illicit drugs for example, is a risk factor, and that higher neighborhood socioeconomic status, with better amenities, is a protective factor. There is some mixed evidence regarding a role of social capital (features of social organization including interpersonal trust, civic engagement and cooperation for mutual benefit). There is also some evidence of a risk from psychosocial stressors in the workplace, for example where work is demanding yet involves little scope for decision-making.

Treatment

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. Patients are usually assessed and managed as outpatients, and only admitted to an inpatient mental health unit if they are considered to pose a risk to themselves or others.

Treatment options are much more limited in developing countries; with access to mental health staff, and medication and psychotherapy difficult, particularly so in poorer countries. Development of mental health services is minimal in many countries as depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and as not an inherently life-threatening condition.

Psychotherapy

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. In people under 18, medication is offered only in conjunction with psychotherapy, not as a first line agent.

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.

For the treatment of adolescent depression, CBT performed no better than placebo, and significantly worse than the antidepressant fluoxetine. 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 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.

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, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.

Medication

To find the most effective pharmaceutical 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 its therapeutic effects can be fully discovered. 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 need to take the 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.

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. 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), a serotonin-norepinephrine reuptake inhibitor, may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18.

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.

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 good 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 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 "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 MDD. 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 where seizures are electrically induced in anesthetized patients for therapeutic effect. ECT is most often used as a last resort (from the perspective of hospital psychiatrists) for 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 (though the latter is not recommended by some authorities, such as NICE), but remains high. Short-term memory loss, disorientation, headache and other adverse effects are common, as are long-term memory and other neurocognitive deficits, which may persist. The American Psychiatric Association and the National Institute for Health and Clinical Excellence have concluded that the evidence they had suggested that the procedure, when administered according to their standards and without complications, does not cause brain damage in adults.

Other methods of treatment

Several other less widely used treatments have been officially approved either in the US or Europe. St. John's wort extract is available as a prescription antidepressant in several European countries, but is classified as an herbal supplement and sold over the counter in the US. A systematic meta-analysis of 37 trials conducted by Cochrane Collaboration indicated statistically significant weak-to-moderate effect compared to placebo. The same meta-analysis found that St John's wort efficacy for major depression is not significantly different from that of prescription antidepressants. 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. S-Adenosyl methionine (SAM-e) is another drug available as a prescription antidepressant in Europe, and as an over-the-counter dietary supplement in the US. Fairly strong evidence from 16 clinical trials indicates it to be as effective as standard antidepressant medication for the treatment of major depression.

In repetitive transcranial magnetic stimulation (rTMS), powerful magnetic fields are 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. 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. However, it was inferior to ECT in a side-by-side randomized trial.

A number of other therapeutic approaches have sometimes been used although they are not officially sanctioned. Bright light therapy has been found to be an effective treatment for the winter depression produced by seasonal affective disorder. In the analysis commissioned by APA it appeared to be moderately effective for non-seasonal depression, although it did not improve the outcome when combined with standard antidepressant therapy. Another 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 was found, although it disappeared if a different statistical technique was used. 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 benefit of light therapy could be sustained in the longer term.

People who exercise regularly often sense the activity is beneficial to their mood. Some empirical support for this comes from a Duke University study, in which exercise used in conjunction with medication had 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.

Population studies show that countries with high consumption of omega-3 fatty acids may have a lower rate of depression. A meta-analysis of eight such trials indicated a statistically significant superiority of addition of omega-3 fatty acids to antidepressants over antidepressants alone; however, the authors warned that, due to multiple problems with these trials, a reliable conclusion was difficult to achieve.

Tryptophan and 5-hydroxytryptophan (5-HTP) are obvious candidates for antidepressants, because they are metabolic precursors for serotonin. The Cochrane Collaboration analyzed the combined set of trials for the both of these treatments. Although the results appeared to indicate better than placebo efficacy, only two out of 108 trials were of sufficient quality to be included in the analysis.

Several other treatments deserve a brief mention. Acupuncture has been tried, but a 2004 Cochrane Review concluded that there was insufficient evidence to judge its effectiveness for managing depression. Deep brain stimulation is currently in a very early investigational stage, and data are available only from a handful of case studies. Vagus nerve stimulation is an FDA-approved therapy for treatment-resistant depression. However, the support for this method comes mainly from open-label trials and the only large double-blind trial yielded inconclusive results.

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 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) will have at least one more and a minority 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. 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.

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 the world over. 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 8% to 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. 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.

People are most likely to suffer their first depressive episode between the ages of 30 and 40. There is a second, smaller peak of incidence later in life between the ages of 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.

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. Depression is often associated with unemployment and poverty.

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.

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.

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

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 sadness, dejection, and despondency symptoms, but often also to fear, anger, delusions and obsessions.

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. Shakespeare's plays, such as Hamlet and King Lear, described characters with deep melancholy.

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. 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. 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

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 an indicator of the need to address social problems, structural determinants 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, or alternatively 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 ongoing debate about the extent to which depression and mental illness in general may be linked to creativity in arts. 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.

References

Cited texts

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