Major depressive disorder

Major depressive disorder
Specialty	Psychiatry

Major depressive disorder (also known as major depression, unipolar depression, unipolar disorder, or clinical depression) is a mental disorder typically characterized by a pervasive low mood, low self-esteem, and loss of interest or pleasure in usual activities. The term was selected by the American Psychiatric Association for the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) classification for the symptom cluster, and has become widely used since. The general term depression is often used to describe the disorder, but since it is also used to describe a temporary sad or depressed mood, more precise terminology is preferred in clinical use and research. Major depression is often a disabling condition which adversely affects a person's family, work or school life, sleeping and eating habits, and general health. In the United States around 3.4% of people with major depression commit suicide, and up to 60% of all people who commit suicide have depression or another mood disorder.

The diagnosis of major depressive disorder is based on the patient's self-reported experiences, behavior reported by relatives or friends, and mental state. There is no laboratory test for major depression, although physicians generally request tests for physical conditions that may cause similar symptoms. The most common time of onset is between the ages of 30 and 40 years, with a later peak between 50 and 60 years. Major depression occurs about twice as frequently 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 some may undertake psychotherapy. 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-acting general anaesthetic. The course of the disorder varies widely, from a once-only occurrence lasting months to a lifelong disorder with recurrent major depressive episodes. Depressed individuals have a shorter life expectancy than those without depression, being more susceptible to medical conditions such as heart disease. Sufferers and former patients may be stigmatized.

The understanding of the nature and causes of depression has evolved over the centuries; nevertheless, many aspects of depression are still not fully understood, and are the subject of debate and research Psychological, psycho-social and biological causes have been proposed. Psychological theories and treatments are based on ideas about the personality, interpersonal communication, and unduly negative thoughts. The monoamine chemicals serotonin, norepinephrine, and dopamine are naturally present in the brain and assist communication between nerve cells. Monoamines have been implicated in depression, and most antidepressants work to increase the active levels of at least one.

Symptoms and signs

Major depression is a serious illness that affects a person's family, work or school life, sleeping and eating habits, and general health; its 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, or ruminatate over thoughts of worthlessness, inappropriate guilt or regret, helplessness or hopelessness. Other symptoms include poor concentration and memory, withdrawal from social situations and activities, reduced 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 multiple persistent physical symptoms such as fatigue, headaches, or digestive problems; this is a typical presentation of depression, according to the World Health Organization's criteria of depression, in developing countries. Family and friends may perceive that the person's behavior is either agitated or slowed down. Older people with depression are more likely to show cognitive symptoms of recent onset, 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

The biopsychosocial model proposes that biological, psychological, and social factors all play a role to varying degrees in causing depression. The diathesis–stress model posits that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. This predisposition can be either genetic, implying an interaction of nature and nurture, or schematic, involving a lasting influence of mental structures formed in childhood. This approach to understanding the causes of depression has garnered empirical support. For example, a prospective, 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, worse yet, two short alleles of the 5-HTT gene. A Swedish study estimated the heritability of depression (the degree to which individual differences in occurrence are associated with genetic differences) to be approximately 40% for women and 30% for men.

Biological

Main article: Biology of depression

Most antidepressants increase synaptic levels of serotonin, one of a group of neurotransmitters known as monoamines. Serotonin is thought to help regulate other neurotransmitter systems, and decreased serotonin activity may allow these systems to act in unusual and erratic ways. According to this "permissive hypothesis", depression can arise when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter. Some antidepressants also enhance the levels of norepinephrine directly, whereas others raise the levels of dopamine, a third monoamine neurotransmitter. These observations gave rise to the monoamine hypothesis of depression. In its contemporary formulation, the monoamine hypothesis postulates that a deficiency of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." 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.

Schematic of a chemical synapse between an axon of one neuron and a dendrite of another. Synapses are specialised minute gaps between neurons. The electrical impulses arriving at the axon terminal triggers the release of packets of chemical messengers (neurotransmitters), which diffuse across the synaptic cleft to receptors on the adjacent dendrite temporarily affecting the likelihood that an electrical impulse will be triggered in the latter neuron. Once released the neurotransmitter is rapidly metabolised or is pumped pack into a neuron. Antidepressants influence the overall balance of these processes.

In the past two decades, research has uncovered multiple limitations of the monoamine hypothesis, 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 medications tianeptine and opipramol have long been known to have antidepressant properties despite not acting through the monoamine system. 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. According to an essay published by the Public Library of Science, the monoamine hypothesis, already limited, has been further oversimplified when presented to the general public.

MRI scans of patients with depression 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 numbers of hyperintensive lesions. Hyperintensities have been associated with patients with a late age of onset, and 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.

Diagram of the human biological clock (Source: The Body Clock Guide to Better Health by Michael Smolensky and Lynne Lamberg)

Major 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. Investigations reveal increased levels of the hormone cortisol, enlarged pituitary and adrenal glands, and a weakened circadian rhythm. Oversecretion of corticotropin-releasing hormone from the hypothalamus is thought to drive this, and is implicated in the cognitive and arousal symptoms. 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 unclear, it appears to be particularly strong among those whose depressive episodes are not precipitated by stress. In such cases, patients may be especially unaffected by therapeutic intervention.

The hormone estrogen has been implicated in depressive disorders due to the increase in risk of depressive episodes after puberty, the antenatal period, and reduced rates after menopause. Conversely, the premenstrual and postpartum periods of low estrogen levels are also associated with increased risk. The use of estrogen has been under-researched, and although some small trials show promise in its use to prevent or treat depression, the evidence for its effectiveness is not strong. Estrogen replacement therapy has been shown to be beneficial in improving mood in perimenopause, but it is unclear if it is merely the menopausal symptoms that are being reversed.

Deficiencies in certain essential dietary nutrients, particularly vitamin B12 and folic acid, have been associated with depression; other agents such as the elements copper and magnesium, and vitamin A have also been implicated.

Psychological

Various aspects of personality and its development are integral to the occurrence and persistence of depression. Although episodes are strongly correlated with adverse events, a person's characteristic style of coping with stress also plays a role. Additionally, low lself-esteem and self-defeating or distorted thinking are related to depression. Some eveidence shows that epression may be negatively correlated with with the presence of religious beliefs. It is not always clear which factors are causes or effects of depression; however, depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem.

American psychiatrist Aaron T. Beck developed what is now known as a cognitive model of depression in the early 1960s. He proposed three concepts which underly depression: a triad of negative thoughts comprising cognitive errors about oneself, one's world, and one's future, recurrent patterns of depressive thinking, or schemas, and distorted information processing. From these principles, he developed the structured technique of cognitive behavioral therapy. According to American 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.

Depressed individuals often blame themselves for negative events. According to one study of hospitalized adolescents with self-reported depression, those who felt responsible for negative events did not take credit for positive outcomes. This tendency is characteristic of a depressive attributional, or pessimistic explanatory style. According to Canadian social psychologist Albert Bandura, who is associated with social cognitive theory, depressed individuals have negative perceptions of themselves, including a negative self-concept and lack of self-efficacy; in other words they do not believe they can influence events or achieve personal goals.

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 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 in women. 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.

Generally grouped together, existential and humanistic approaches represent a forceful affirmation of individualism. Austrian existential psychiatrist Viktor Frankl connected depression to feelings of futility and meaninglessness. Frankl's logotherapy is designed to help people fill the "existential vacuum" associated with such feelings, and may be particularly useful for depressed adolescents. American existential psychologist Rollo May has been quoted as saying that "depression is the inability to construct a future". In general, May wrote, "depression ... occur[s] more in the dimension of time than in space," and the depressed individual fails to look ahead in time properly. Thus the "focusing upon some point in time outside the depression ... gives the patient a perspective, a view on high so to speak; and this may well break the chains of the ... depression." Humanistic psychologists argue that depression can result from an incongruity between society and the individual's innate drive to self-actualize, or to realize one's full potential. American humanistic psychologist Abraham Maslow theorized that depression is especially likely to arise when the world precludes a sense of "richness" or "totality" for the self-actualizer.

Social

Poverty and social isolation are associated with increased risk of psychiatric problems in general. Childhood emotional, physical, or sexual abuse, or neglect are also associated with increased risk of developing depressive disorders later in life. Disturbances in family functioning, such as parental (particularly maternal) depression, severe marital conflict or divorce, death of a parent, or other disturbances in parenting are additional risk factors. In adulthood, stressful life events are strongly associated with the onset of major depressive episodes; a first episode is more likely to be immediately preceded by stressful life events than are recurrent ones. The relationship between stressful life events and social support has been a matter of some debate. Perhaps the lack of social support only increases the likelihood that life stress will lead to depression. More likely, however, the absence of social support constitutes a form of strain that provokes depression directly. 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. Adverse conditions at work, particularly demanding jobs with little scope for decision-making, are associated with depression, although diversity and confounding factors make it difficult to confirm the relationship is causal.

Evolutionary hypothesis

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 depression are explained by the proposal that certain components of depression are adaptations such as the mechanisms underlying behaviors relating to attachment and social rank. Evolutionary theorists view the condition 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 counseling therapy.

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. The assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans. 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.

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 and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including ESR to rule out a systemic infection or chronic disease. Testosterone levels may be evaluated 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, additional tests such as cognitive testing and brain imaging, can help distinguish depression from dementia. 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 medical indication.

Rating scales

Depression screening measures are not used to diagnose the condition, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose. The Hamilton Depression Rating Scale and the Montgomery-Åsberg Depression Rating Scale are the two most commonly used among those completed by researchers assessing the effects of drug therapy. The Beck Depression Inventory is a scale completed by patients to identify the presence and severity of symptoms consistent with the DSM-IV diagnostic criteria. The Geriatric Depression Scale is a self-administered scale used in older populations that is also valid in patients with mild to moderate dementia. The Patient Health Questionnaire (PHQ-9) and the Primary Care Evaluation of Mental Disorders (PRIME-MD) are two self-administered questionnaires for use in primary care, although the lengthy administration time of the PRIME-MD has limited its clinical usefulness. The PHQ-9 is a slightly more detailed nine-question survey for assessing symptoms of major depressive disorder in greater detail. Screening programs have been advocated to improve detection of depression, but there is evidence that they do not improve detection rates, treatment, or outcome.

DSM-IV-TR and ICD-10 criteria

The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Association's revised fourth edition of the 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) which uses the name recurrent depressive disorder. The latter system is typically used in European countries, while the former is used in the US and many other non-European nations, and the authors of both have worked towards conforming one with the other.

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 very similar criteria for the diagnosis of a depressive episode (mild, moderate or severe); the term recurrent may be added if there have been multiple episodes without mania.

Major depressive episode

Main article: 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".

DSM-IV-TR excludes cases where the symptoms are a result of bereavement, although it is possible for normal bereavement to evolve into a depressive episode if the mood persists and the characteristic features of a major depressive episode develop. 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

The DSM-IV-TR recognizes 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.

Other types of depression, not categorized as Major depressive disorder, are recognized by the DSM-IV-TR:

• Postpartum depression (Mild mental and behavioral disorders associated with the puerperium, not elsewhere classified in ICD-10) 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 decide that major depressive disorder is the most likely diagnosis, the probability of several other potential diagnoses must be considered, 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.

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 is 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 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 by some to be a combination of medication and psychotherapy. In people under 18 years of age, medication should be offered only in conjunction with a psychological therapy, not as a first line treatment. Psychotherapy has been shown to be effective in older people. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional booster sessions, although the same degree of prevention can be achieved by continuing antidepressant 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 CBT was not as effective as antidepressant medication; however, research in 1996 suggests that it can perform as well as antidepressants in patients with moderate to severe depression. Overall, evidence shows CBT to be effective in depressed adolescents, although one systematic review noted there was insufficient evidence for severe episodes. Combining fluoxetine with CBT appeared to bring no additional benefit, or, at the most, only marginal benefit. Several variants have been used in depressed patients, most notably rational emotive behaviour therapy, and more recently mindfulness-based cognitive therapy.

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment. The therapy takes a structured course with a set number of weekly sessions (often 12), 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 of Short Psychodynamic Supportive Psychotherapy, this modification was found to be as effective as medication for mild to moderate depression.

Medication

Antidepressants in general are as effective as psychotherapy; their benefits increase with the severity of the depression, although more patients cease treatment than psychotherapy, likely because of the side effects of antidepressants. A large 2008 meta-analysis of past studies reported that the response to antidepressant treatment in moderate depression were not shown to exceed that of placebo; this interpretation was questioned in an editorial of the BMJ, and a positive but small effect was not ruled out. A black box warning has been introduced in the United States in 2007 on SSRI and other antidepressant medications due to increased risk of suicidality in patients younger than 24 years old.

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, escitalopram, fluoxetine, paroxetine, and citalopram are the primary medications considered owing to their effectiveness, relatively mild side effects, and because they are less toxic in overdose than other antidepressants. Those who do not respond to one SSRI can be switched to another, which results in improvement in almost 50% of cases. Another option is to switch to the atypical antidepressant bupropion. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating antidepressant mirtazapine can be used in such cases. Venlafaxine, 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 years.

Amitriptyline is a tricyclic antidepressant, so called because there are three rings in its molecular structure.

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 older different class of antidepressants, the monoamine oxidase inhibitors, have been plagued by potentially life-threatening dietary and drug interactions. They are still used only rarely, although newer and better tolerated agents of this class have been developed.

To find the most effective antidepressant medication with tolerable or fewest side effects, the dosages can be adjusted, and, if necessary, combinations of different classes of antidepressants can be tried. Response rates to the first antidepressant administered range from 50–75%, and it can take at least six to eight weeks from the start of medication to remission, when the patient is back to their normal self. Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimise the chance of recurrence. People with chronic depression may need to take medication indefinitely to avoid relapse. The terms refractory depression or treatment-resistant depression are used to describe cases that do not respond to adequate courses of least two antidepressants. Any antidepressant can cause low serum sodium levels (also called hyponatremia); nevertheless, it has been reported more often with SSRIs.

A doctor may add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance. Medication with lithium salts 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 offset by increased side effects.

Electroconvulsive therapy

Main article: Electroconvulsive therapy

Electroconvulsive therapy (ECT) is a procedure where pulses of electricity are sent through the brain via two electrodes, usually one on each temple, to induce a seizure while the patient is under a short general anaesthetic. Hospital psychiatrists may recommend ECT for cases of severe major depression which have not responded to antidepressant medication or, less often, psychotherapy or supportive interventions. ECT can have a quicker effect than antidepressant therapy and thus may be the treatment of choice in emergencies such as catatonic depression where the patient has stopped eating and drinking, or where a patient is severely suicidal. ECT is probably more effective than pharmacotherapy for depression in the immediate short-term, although a landmark community-based study found much lower remission rates in routine practice. Used on its own the relapse rate within the first six months is very high; early studies put the rate at around 50%, while a more recent controlled trial found rates of 84% even with placebos. The early relapse rate may be reduced by the use of psychiatric medications or further ECT (although the latter is not recommended by some authorities) but remains high. Common initial adverse effects from ECT include short and long-term memory loss, disorientation and headache. Although objective psychological testing shows memory disturbance after ECT has mostly returned to baseline by one month post treatment, ECT remains a controversial treatment, and debate on the extent of cognitive effects and safety continues.

Other

Bright light therapy is sometimes used to treat depression, especially in its seasonal form.

Two products, St John's wort and S-adenosylmethionine, are available as prescription antidepressants in several European countries, and are classified as herbal supplements and sold over-the-counter in the UK and US. 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, and the quantity of active ingredient varies between different preparations. St John's wort interacts with a number of prescribed medicines including other antidepressants, oestrogens and progesterones, and can reduce the effectiveness of oral contraceptive pills.

Clinical trials of S-adenosylmethionine have shown that it is equivalent to tricyclic antidepressants in effectiveness, although the safety and efficacy of over-the-counter versions is unknown. Although good evidence is limited and long-term safety is unknown, available evidence suggests that tryptophan and 5-hydroxytryptophan are more effective than placebo. Available evidence for omega-3 fatty acids is too mixed and limited to make a strong conclusion, although the available evidence does not support their use.

Repetitive transcranial magnetic stimulation 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, Australia, and the US. It was inferior to ECT in a side-by-side randomized trial on a small sample.

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. Physical exercise has been proposed as an alternative form of treatment, and is recommended by U.K. health authorities, but systematic review has not been conclusive on its effectiveness in symptom reduction. Vagus nerve stimulation was approved by the FDA in the United States in 2005 for use in treatment-resistant depression, although it failed to show short-term benefit in the only large double-blind trial when used as an adjunct on treatment-resistant patients.

Prognosis

World map of suicide rates per 100,000.

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.

Depressed individuals have a shorter life expectancy than those without depression. Although depressed patients are at risk of dying by suicide, they are also more susceptible to medical conditions such as heart disease. 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 lifetime risk of suicide associated with a diagnosis of major depression in the US is estimated at 3.4%, which averages two highly disparate figures of almost 7% for men and 1% for women (although suicide attempts are more frequent in women). The estimate is substantially lower than a previously accepted figure of 15% which had been derived from older studies of hospitalized patients.

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 about twice as common in women than in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this. The relative increase in occurrence is related to pubertal development rather than chronological age and reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors.

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 with neurological conditions such as stroke, Parkinson's disease, or multiple sclerosis and during the first year after childbirth. It is also more common after cardiovascular illnesses, and is related to a worse outcome. Studies conflict on the prevalence of depression in the elderly, but most data suggests there is a reduction in this age group.

Depression is often associated with unemployment and poverty. 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. Delay or failure in seeking treatment after relapse, and the failure of health professionals to provide treatment are two barriers to reducing disability.

Comorbidity

Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reports that 51% of those with major depression also suffer from lifetime anxiety. Anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicide attempts. American neuroendocrinologist 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.

Depression and pain often co-occur; one or more pain symptoms is present in 65% of depressed patients, and anywhere from 5 to 85% of patients with pain will be suffering from depression, depending on setting. There is a lower prevalence in general practice, and higher in specialty clinics. The diagnosis of depression is often delayed or missed, and outcome worse.

History

See also: History of mental disorders and Classification of mental disorders

Prehistory to medieval periods

The four temperaments (clockwise from top left; sanguine; phlegmatic; melancholic; choleric) 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 world developed ideas about melancholia during the Islamic Golden Age. Ishaq ibn Imran (d. 908) combined the concepts of melancholia and phrenitis. The 11th century physician 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 the Christian environment of medieval Europe, a malaise called acedia (sloth or absence of caring) was identified, involving low spirits and lethargy typically linked to isolation.

17th to 19th centuries

Frontispiece of the 1638 edition of The Anatomy of Melancholy

The seminal scholarly work of the 17th century was English scholar Robert Burton's book, 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. 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 English author Richard Baker's Chronicle to refer to someone having "a great depression of spirit", and by English author 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 French psychiatrist 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; 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 and 21st centuries

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. German psychiatrist 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 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 Swiss psychiatrist Adolf Meyer and before him Sigmund Freud, the father of psychoanalysis.

Sigmund Freud argued that depression, or melancholia, could result from loss and is more severe than mourning.

Freud had likened the state of melancholia to mourning in his 1917 paper Mourning and Melancholia. 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 severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively, but the ego itself is compromised. The patient's decline of self-perception is revealed in his belief of his own blame, inferiority, and unworthiness. He also emphasized early life experiences as a predisposing factor. 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.

A half century ago, diagnosed depression was either endogenous (melancholic), considered a biological condition, or reactive (neurotic), a reaction to stressful events. 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.

Isoniazid, the first compound called antidepressant

In the mid-20th century, researchers theorized that depression was caused by a chemical imbalance in neurotransmitters 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 German psychiatrist Karl Kleist.

The term Major depressive disorder was introduced by a group of US clinicians 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

See also: List of people with depression

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 of 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. Australian professor Gordon Parker and others have argued that the Western concept of depression "medicalizes" sadness or misery. Similarly, Hungarian-American psychiatrist Thomas Szasz and others argue that depression is a metaphorical illness that is inappropriately regarded as an actual disease. There has also been concern that the DSM, as well as the field of descriptive psychiatry that employs it, tends to reify abstract phenomena such as depression, which may in fact be social constructs. American archetypal psychologist James Hillman writes that depression can be healthy for the soul, insofar as "it brings refuge, limitation, focus, gravity, weight, and humble powerlessness." Hillman argues that therapeutic attempts to eliminate depression echo the Christian theme of resurrection, but have the unfortunate effect of demonizing a soulful state of being.

There has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to Aristotelian times. 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 English poet 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 writer Samuel Johnson used the term "the black dog" in the 1780s to describe his own depression, and it was subsequently popularized by depression sufferer former British Prime Minister Sir Winston Churchill.

American president Abraham Lincoln appears to have had at least two major depressive episodes.

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 English author Mary Shelley, American-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. Some pioneering psychologists, such as Americans 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 [was] the most manly form to put [his] 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."

Social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. Public opinions on treatment differ markedly to those of health professionals; alternative treatments are held to be more helpful than pharmacological ones, which are viewed poorly. The Royal College of Psychiatrists and the Royal College of General Practitioners conducted a joint Five-year Defeat Depression campaign to educate and reduce stigma from 1992 to 1996; a MORI study conducted afterwards showed a small positive change in public attitudes to depression and treatment.

References

Cited texts

• American Psychiatric Association (2000a). Diagnostic and statistical manual of mental disorders, Fourth Edition, Text Revision: DSM-IV-TR. Washington, DC: American Psychiatric Publishing, Inc. ISBN 0890420254.{{cite book}}: CS1 maint: ref duplicates default (link)
• Barlow DH (2005). Abnormal psychology: An integrative approach (5th ed.). Belmont, CA, USA: Thomson Wadsworth. ISBN 0534633560. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
• Beck, Aaron T. (1987) [1979]. Cognitive Therapy of depression. New York, NY, USA: Guilford Press. ISBN 0898629195. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: ref duplicates default (link)
• Freeman, Arthur (1987). Depression in the Family. Haworth Press. ISBN 0866566244. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
• Kent, Deborah (2003). Snake Pits, Talking Cures & Magic Bullets: A History of Mental Illness. Twenty-First Century Books. ISBN 0761327045.{{cite book}}: CS1 maint: ref duplicates default (link)
• Hergenhahn BR (2005). An Introduction to the History of Psychology (5th edition ed.). Belmont, CA, USA: Thomson Wadsworth. ISBN 0534554016. {{cite book}}: |edition= has extra text (help)
• May R (1994). The discovery of being: Writings in existential psychology. New York, NY, USA: W. W. Norton & Company. ISBN 0393312402.
• Parker, Gordon (1996). Melancholia: A disorder of movement and mood: A phenomenological and neurobiological review. Cambridge: Cambridge University Press. ISBN 052147275X. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: ref duplicates default (link)
• Royal Pharmaceutical Society of Great Britain (2008). [[British National Formulary]] (BNF 56). UK: BMJ Group and RPS Publishing. ISBN 9780853697787. {{cite book}}: URL–wikilink conflict (help); Unknown parameter |month= ignored (help)CS1 maint: ref duplicates default (link)
• Sadock, Benjamin J. (2002). Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (9th ed.). Lippincott Williams & Wilkins. ISBN 0781731836. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: ref duplicates default (link)

External links

• DSM-IV diagnostic criteria for major depressive disorder – DSM-IV-TR text from mindsite.com
• Depression at Curlie
• National Alliance on Mental Illness – National Alliance on Mental Illness
• Depression and Bipolar Support Alliance – Depression and Bipolar Support Alliance
• Black Dog Institute – Depression and bipolar disorder information from Australia
• Depression, out of the shadows – Public Broadcasting Service, a USA television program broadcast in May 2008