WikiPortallus: Clinical depression.html

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 coined by the American Psychiatric Association in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) classification for the symptom cluster, and has become widely used. 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.¹ 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. Both psychological 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;² its impact on functioning and well-being has been equated to that of chronic medical conditions such as diabetes.³

A person suffering a major depressive episode usually experiences a pervasive low mood, or loss of interest or pleasure in favored activities. Depressed people may be preoccupied with feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness.⁴ Other symptoms include poor concentration and memory, withdrawal from social situations and activities, reduced libido (sex drive), and thoughts of death or suicide. Insomnia is common: in the typical pattern, a person wakes very early and is unable to get back to sleep.⁵ Hypersomnia, or oversleeping, is less common.⁵ Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur.⁴ 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.⁶ Family and friends may perceive that the person is either agitated or slowed down.⁵ 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.⁷ In severe cases, depressed people may experience psychotic symptoms such as delusions or, less commonly, hallucinations, usually of an unpleasant nature.⁸⁹

Children may display an irritable rather than depressed mood,⁴ and show different symptoms depending on age and situation.¹⁰ 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.⁵ Diagnosis may be delayed or missed when symptoms are interpreted as normal moodiness.⁴

Causes

The etiology of mental disorders is best appreciated through a multidimensional integrative approach that disfavors reductionism and encourages models that consider a wide array of biological, psychological, and social forces.¹¹ Two such models are the biopsychosocial model and the diathesis-stress model. In the biopsychosocial model, biological, psychological, and social factors all play a role in causing depression.¹² There is overlap, and the precise causes vary depending on individual circumstances. The diathesis–stress model posits that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The predisposition can be either genetic,¹³¹⁴ implying an interaction of nature and nurture, or schematic,¹⁵ 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.¹³ 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.¹⁶

Biological

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.¹⁷ According to this "permissive hypothesis", depression can arise when low serotonin levels promote low levels of norepinephrine, another monoamine neurotransmitter.¹⁸ 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 theory of depression. In its contemporary formulation, the monoamine theory postulates that a deficiency of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life."¹⁹ 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.¹⁹

Major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across synapses to receptors on adjacent cells, and affect the likelihood that an electrical impulse will be triggered in the latter neurone.

In the past two decades, research has uncovered multiple limitations of the monoamine theory, and its inadequacy has been criticized within the psychiatric community.²⁰ 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.²¹ According to an essay published by the Public Library of Science, the monoamine theory, already limited, has been further oversimplified when presented to the general public.²²

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 hippocampal²³ volumes and increased numbers of hyperintensive lesions.²⁴ Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.²⁵

There may be a link between depression and neurogenesis of the hippocampus,²⁶ 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.²⁷²⁸ Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior.²⁹ 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.³⁰

Depression appears to be related to disruptions in the circadian rhythm, or human biological clock.

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 blunted circadian rhythm. Oversecretion of corticotropin-releasing hormone from the hypothalamus is thought to drive this, and is implicated in the cognitive and arousal symptoms.³¹ The REM stage of sleep, in which dreaming occurs, tends to be especially quick to arrive, and especially intense, in depressed people. Although the precise relationship between sleep and depression is mysterious, the relationship appears to be particularly strong among those whose depressive episodes are not precipitated by stress. In such cases, patients may be especially unaffected by therapeutic intervention.³²

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.³³ Conversely, the premenstrual and postpartum periods of low estrogen levels are also associated with increased risk.³³ The use of estrogen has been under-researched, and there although some small trials show promise in its use to prevent or treat depression, the evidence for its effectiveness is not strong.³³ 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.³³

Deficiencies in certain essential dietary nutrients, particularly Vitamin B12 and folic acid, have been associated with depression;³⁴ other agents such as the elements copper and magnesium,³⁵ and Vitamin A have been implicated.³⁶

Psychological

Various aspects of personality and its development are integral in the occurrence and persistence of depression.³⁷ Although episodes are strongly correlated with adverse events, how a person copes with stress also plays a role.³⁸ Low self-esteem and self-defeating or distorted thinking are related to depression. However, depression is less likely to occur among those who are religious.³⁹ It is not always clear which factors are causes or effects of depression, but in any case depressed persons who are able to make corrections in their thinking patterns often show improved mood and self-esteem.⁴⁰ Recent research emphasizes the importance of alterations in responses to stress in the etiology of depression.⁴¹

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.⁴² From these principles, he developed the structured technique of cognitive behavioral therapy.⁴³ 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.⁴⁴ Learned helplessness⁴⁵ and depression may be related to what American psychologist Julian Rotter, a social learning theorist, called an external locus of control, a tendency to attribute outcomes to events outside of personal control.⁴⁶

On the other hand, depressed individuals often blame themselves for negative events.⁴⁷ 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.⁴⁸ This tendency is characteristic of a depressive attributional, or pessimistic explanatory style.⁴⁷ 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 perceived lack a sense of self-efficacy; in other words they do not believe they can influence events or achieve personal goals.⁴⁹ Milder depression has been associated with what has been called depressive realism, or the "sadder-but-wiser" effect, a view of the world that is relatively undistorted by positive biases.⁵⁰

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.⁵¹ However, the validity of risk factors has been widely debated.⁵² 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.⁵³

Generally grouped together, existential and humanistic approaches represent a forceful affirmation of individualism.⁵⁴ Austrian existential psychiatrist Viktor Frankl connected depression to feelings of futility and meaninglessness.⁵⁵ Frankl's logotherapy is designed to help people fill the "existential vacuum" associated with such feelings, and may be particularly useful for depressed adolescents.⁵⁶ American existential psychologist Rollo May stated that "depression is the inability to construct a future".⁵⁷ In general, May wrote, "depression ... occur[s] more in the dimension of time than in space,"⁵⁸ 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."⁵⁹ 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.⁶⁰⁶¹ 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.⁶¹

Social

Poverty and social isolation are associated with increased risk of psychiatric problems in general.³⁷ Childhood emotional, physical, or sexual abuse, or neglect are also associated with increased risk of developing depressive disorders later in life.⁶²³⁷ 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.³⁷ In adulthood, stressful life events are strongly associated with the onset of major depressive episodes;⁶³ a first episode is more likely to be immediately preceded by stressful life events than are recurrent ones.⁶⁴ The relationship between stressful life events and social support has been a matter of some debate.⁶⁵ Perhaps the lack of social support only increases the likelihood that life stress will lead to depression.⁶⁵ More likely, however, the absence of social support constitutes a form of strain that provokes depression directly.⁶⁵ 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 workplace conditions, 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.⁶⁶

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 adaptations⁶⁷ such as the mechanisms underlying behaviors relating to attachment and social rank.⁶⁸ Evolutionary theorists view the condition as an adaptation to regulate relationships or resources, although it may be unwanted or disordered in modern environments.⁶⁹ 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".⁷⁰ 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.⁷¹ These insights may be helpful in counseling therapy.⁷⁰⁷²

Diagnosis

Clinical assessment

A diagnostic assessment may be conducted by a general practitioner or by a psychiatrist or psychologist,² who will record the person's current circumstances, biographical history and current symptoms, and a family medical history to see if other family members have suffered from a mood disorder, and discuss the person's alcohol and drug use. A mental state examination includes an assessment of the person's current mood and an exploration of thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans.² Specialist mental health services are rare in rural areas, and thus diagnosis and management is largely left to primary care clinicians.⁷³ This issue is even more marked in developing countries.⁷⁴

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.⁷⁵ Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men.⁷⁶ 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.⁷⁷ Depression is also a common initial symptom of dementia.⁷⁸ Conducted in older depressed people, additional tests such as cognitive testing and brain imaging, can help distinguish depression from dementia.⁷⁹ A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms.⁸⁰ No biological tests confirm major depression.⁸¹ Investigations are not generally repeated for a subsequent episode unless there is a medical indication. Serum sodium can rule out hyponatremia (low sodium) if the patient develops increased frequency of passing urine, a possible side-effect of selective serotonin reuptake inhibitor antidepressants.⁸²

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 a cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis.⁸³ Several rating scales are used for this purpose.⁸³ The Hamilton Depression Rating Scale⁸⁴ and the Montgomery-Åsberg Depression Rating Scale.⁸⁵ are the two most commonly used among those completed by researchers assessing the effects of drug therapy.⁸⁶ The Beck Depression Inventory is the most commonly used tool completed by patients, although scales completed by observers are more common.⁸⁷⁸⁸ The Geriatric Depression Scale is a self-administered scale used in older populations and also valid in patients with mild to moderate dementia.⁸⁹⁷⁸ The Patient Health Questionnaires (PHQ) 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.⁹⁰ 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.⁹¹ Screening programs have been advocated to improve detection of depression, but there is evidence that the use of screening instruments does little to improve detection rates, treatment, or outcome.⁹²⁹³

DSM-IV-TR and ICD-10 criteria

Major depressive disorder is classified as a mood disorder in DSM-IV-TR.⁹⁷ The diagnosis hinges on the presence of a single or recurrent major depressive episode.⁴ 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.⁹⁸

Major depressive episode

A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks.⁴ 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.⁹⁶ Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".⁹⁹

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.¹⁰⁰ 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.¹⁰¹ 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:¹⁰² excluded are a range of related diagnoses, including dysthymia which involves a chronic but milder mood disturbance,¹⁰³ Recurrent brief depression which involves briefer depressive episodes,¹⁰⁴¹⁰⁵ Minor depressive disorder which involves only some of the symptoms of major depression,¹⁰⁶ and Adjustment disorder with depressed mood which involves low mood resulting from a psychological response to an identifiable event or stressor.¹⁰⁷

Subtypes

The DSM-IV-TR recognizes several subtypes, which are sometimes called "course specifiers":

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

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:

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.¹¹⁶

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 to be a combination of medication and psychotherapy.¹¹⁷ In people under 18, medication is usually offered only in conjunction with psychotherapy, not as a first line treatment.¹¹⁸ Psychotherapy has been shown to be effective in older people. ¹¹⁹¹²⁰ 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.¹²¹

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.¹²² Overall, systematic review reveals CBT to be an effective treatment in depressed adolescents,¹²³ although possibly not for severe episodes.¹²⁴ Combining fluoxetine with CBT appeared to bring no additional benefit¹²⁵¹²⁶ or, at the most, only marginal benefit.¹²⁷

A review of studies on the effectiveness of Mindfulness-based Cognitive Therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects.¹²⁸

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT, however the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.¹²⁹

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts,¹³⁰ is used by its practitioners to treat clients presenting with major depression.¹³¹ A more widely practiced, eclectic technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus.¹³² 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.¹³³

Medication

Antidepressants in general are as effective as psychotherapy; their benefits increase with the severity of the depression,¹³⁴¹²¹ although more patients cease treatment than psychotherapy, likely because of the side effects of antidepressants.¹³⁴ 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;¹³⁴ this interpretation was questioned in an editorial of the British Medical Journal, and a positive but small effect was not ruled out.¹³⁵ 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 24.¹³⁶

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.¹³⁷ Those who do not respond to one SSRI can be switched to another, which results in improvement in almost 50% of cases.¹³⁸ Another option is to switch to the atypical antidepressant bupropion.¹³⁹¹⁴⁰¹⁴¹ It is not uncommon for SSRIs to cause or worsen insomnia; the sedating antidepressant mirtazapine can be used in such cases.¹⁴²¹⁴³¹⁴⁴ Venlafaxine, and other serotonin-norepinephrine reuptake inhibitors, may be modestly more effective than SSRIs;¹⁴⁵ however, venlafaxine is not recommended as a first-line treatment because of evidence suggesting its risks may outweigh benefits.¹⁴⁶¹⁴⁷ Its use is specifically discouraged in children and adolescents.¹⁴⁸ Fluoxetine is the only antidepressant recommended for people under the age of 18 years.¹⁴⁸

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.¹⁴⁹¹⁵⁰ A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by life-threatening adverse effects. They are still used only rarely, although newer and better tolerated agents of this class have been developed.¹⁵¹

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.¹⁵² Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimise the chance of recurrence.¹⁵² People with chronic depression usually need to take medication for the rest of their lives.² The terms refractory depression or treatment-resistant depression are used to describe cases that do not respond to adequate courses of least two antidepressants.¹⁵³

A doctor may add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance.¹⁵⁴ Medication with lithium salts has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.¹⁵⁵ Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.¹⁵⁶ Addition of a thyroid hormone, triiodothyronine may work as well as lithium, even in patients with normal thyroid function.¹⁵⁷ 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.¹⁵⁸

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.¹⁵⁹ 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.¹⁵⁹ ECT is probably more effective than pharmacotherapy for depression in the immediate short-term,¹⁶⁰ although a landmark community-based study found much lower remission rates in routine practice.¹⁶¹ Used on its own the relapse rate within the first six months is very high; early studies put the rate at around 50%,¹⁶² while a more recent controlled trial found rates of 84% even with placebos.¹⁶³ The early relapse rate may be reduced by the use of psychiatric medications or further ECT¹⁶⁴¹⁶⁵ (although the latter is not recommended by some authorities¹⁶⁶) but remains high.¹⁶⁷ Common initial adverse effects from ECT include short and long-term memory loss, disorientation and headache.¹⁶⁸ Although objective psychological testing shows anterograde memory 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.¹⁶⁹¹⁷⁰

Other

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

Two products, St John's wort and S-Adenosyl methionine, are available as prescription antidepressants in several European countries, and are classified as herbal supplements and sold over-the-counter in the UK¹³⁷ 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,¹⁷¹¹⁷² and the quantity of active ingredient varies between different preparations.¹³⁷ 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.¹⁷³

Clinical trials of S-Adenosyl methionine have shown that it is equivalent to tricyclic antidepressants in effectiveness, although the safety and efficacy of over-the-counter versions is unknown.¹⁷⁴¹⁷⁵ Other supplements such as omega-3 fatty acids,¹⁷⁶ tryptophan, and 5-hydroxytryptophan,¹⁷⁷ have shown no effect beyond those of placebo.

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.¹⁷⁸¹⁷⁹¹⁸⁰ It was inferior to ECT in a side-by-side randomized trial on a small sample.¹⁸¹

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.¹⁸²¹⁸³ Physical exercise has been proposed as an alternative form of treatment, and is recommended by U.K. health authorities,¹⁸⁴ but systematic review has not been conclusive on its effectiveness in symptom reduction.¹⁸⁵ Vagus nerve stimulation was approved by the FDA in the United States in 2005 for use in treatment-resistant depression,¹⁸⁶ although it failed to show short-term benefit in the only large double-blind trial when used as an adjunct on treatment-resistant patients.¹⁸⁷

Prognosis

World map of suicide rates per 100,000.¹⁸⁸

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.¹⁸⁹ The median duration of an episode has been estimated at least 23 weeks, with the highest rate of recovery in the first three months.¹⁹⁰

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.¹⁹¹ 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.¹⁹²¹⁹³

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. ¹⁹⁴

Depressed individuals have a shorter life expectancy than those without depression. Although depressed patients are at risk of dying by suicide,¹ they are also more susceptible to medical conditions such as heart disease.¹⁹⁵ 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.¹⁹⁶ Depressed people also have a higher rate of dying from other causes.¹⁹⁷ 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 women¹⁹⁸ (although suicide attempts are more frequent in women).¹⁹⁹ The estimate is substantially lower than a previously accepted figure of 15% which had been derived from older studies of hospitalized patients.²⁰⁰

Epidemiology

Depression is a major cause of morbidity worldwide.²⁰¹ 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.²⁰²²⁰³ 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.²⁰⁴²⁰⁵ 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.²⁰⁶ 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.²⁰⁶

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 60.²⁰⁷ 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.¹¹³²⁰⁸ It is also more common after cardiovascular illnesses, and is related to a worse outcome.²⁰⁹¹⁹⁵ Studies conflict on the prevalence of depression in the elderly, but most data suggests there is a reduction in this age group.²¹⁰

Depression is often associated with unemployment and poverty.²¹¹ 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.²¹² Delay or failure in seeking treatment after relapse, and the failure of health professionals to provide treatment are two barriers to reducing disability.²¹³

Comorbidity

Major depression frequently co-occurs with other psychiatric problems. The National Comorbidity Survey (US) reports that 51% of those with major depression also suffer from lifetime anxiety.²¹⁴ 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.²¹⁵ American neuroendocrinologist Robert Sapolsky similarly argues that the relationship between stress, anxiety, and depression could be measured and demonstrated biologically.²¹⁶ There are increased rates of alcohol and drug abuse and particularly dependence,²¹⁷ and around a third of individuals diagnosed with attention-deficit hyperactivity disorder develop comorbid depression.²¹⁸ Post-traumatic stress disorder and depression often co-occur.²

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.²¹⁹

History

Prehistory to medieval periods

The four temperaments (clockwise from top right; choleric; melancholic; sanguine; phlegmatic), according to an ancient theory of mental states

Notes in the Ancient Egyptian document known as the Ebers papyrus appear to refer to emotional distress of the heart or mind, which has been interpreted as sadness or depression.²²⁰ 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.²²¹

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",²²² 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.²²³ 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.²²⁴²²⁴

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.²²⁵ 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.²²⁶ His work, the Canon of Medicine, became the standard of medical thinking in Europe alongside those of Hippocrates and Galen.²²⁷ 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.²²⁸²²⁹

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