Major depressive disorder
Specialty	Psychiatry

Major depressive disorder, also known as major depression, unipolar depression, clinical depression, or simply depression, is a mental disorder characterized by a pervasive low mood, loss of interest in usual activities and diminished ability to experience pleasure. The diagnosis is made if a person has suffered one or more major depressive episodes. The onset is usually in early- to mid-adulthood. Diagnosis is based on the patient's self-reported experiences and observed behavior. There is no laboratory test for major depression, although physicians often test for physical conditions that may cause similar symptoms before arriving at a diagnosis. The course varies widely: it can be a once-in-a-lifetime event or have multiple recurrences; it can appear either gradually or suddenly; and can either last for a few months or be a life-long disorder.

The term "depression" is commonly used in the vernacular to describe a temporary depressed mood, when a person may feel sad or "down." Ideas about what causes and constitutes depression have evolved over the centuries. Today, mental health professionals regard "major depression" as a serious and often disabling condition that can significantly affect a person's work, family and school life, sleeping and eating habits, general health and ability to enjoy life.^[1] Depression is a major risk factor for suicide; in addition, people with depression suffer from higher mortality from other causes.^[2] When specific treatment is indicated, it usually consists of psychotherapy and antidepressants.

A major depressive episode can manifest with a variety of symptoms, but almost all who experience such an episode display a marked change in mood, a deep feeling of sadness, and a noticeable loss of interest or pleasure in favorite activities. The psychological or mood change symptoms may include persistent sad, anxious or "empty" moods, and feelings of worthlessness, inappropriate guilt, helplessness, hopelessness, or pessimism, a sense of restlessness or irritability, and difficulty thinking, concentrating, remembering, or making decisions. Physical symptoms associated with depression include increased or decreased appetite or weight; insomnia, early morning awakening, or oversleeping; decreased energy, fatigue, feeling "slowed down" or sluggish; psychomotor agitation or psychomotor retardation; and persistent physical symptoms that do not respond to treatment, such as headaches, digestive problems, and chronic pain.

Other symptoms include withdrawal from social situations, family gatherings and activities with friends; and thoughts of death or suicide or attempts at suicide. Not all people will suffer from every symptom. The severity of symptoms will vary widely among individuals. According to one diagnostic standard, symptoms, with the exception of suicidal thoughts or attempts, must persist for at least two weeks before being considered a potential sign of depression.^[3][1]

Diagnosis of an episode in children is more difficult than in adults. Depression in children is often undiagnosed, and thus untreated, because the symptoms in children are often dismissed as normal childhood moodiness. Children are more likely than adults to show different symptoms depending on the situation.^[4] While some children still function reasonably well, most who are suffering from depression will exhibit a noticeable change in their social activities and life, a loss of interest in school and poor academic performance, and possibly drastic changes in appearance. They may also begin abusing drugs or alcohol, particularly past the age of 12. Although much more rarely than adults, children with major depression may attempt suicide or have suicidal thoughts even before the age of 12.^[4]

Depression and anxiety frequently co-occur; the National Comorbidity Survey (US) reports that 58 percent of those with major depression also suffer from lifetime anxiety. Even mild anxiety symptoms can have a major impact on the course of a depressive illness, and the commingling of any anxiety symptoms with the primary depression is important to consider. A pilot study by Ellen Frank et al., at the University of Pittsburgh, found that depressed or bipolar patients with lifetime panic symptoms experienced significant delays in their remission.^[5] These patients also had higher levels of residual impairment. On a similar note, Robert Sapolsky of Stanford University argues that the relationship between stress, anxiety, and depression could be measured and demonstrated biologically.^[6]

About one-third of individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) may develop comorbid depression.^[7] Dysthymia, a form of chronic, low-level depression, is particularly common in adults with undiagnosed ADHD who have encountered years of frustrating ADHD-related problems with education, employment, and interpersonal relationships.^[8]

Before a diagnosis of major depressive disorder is made, a physician may perform a medical examination to rule out a physical cause for the suspected depression. Although there are no biological tests which confirm major depression, tests are carried out to exclude medical illnesses. These include blood tests measuring TSH to exclude hypo- or hyperthyroidism, basic electrolytes and serum calcium to rule out a metabolic disturbance, full blood count including ESR to rule out a systemic infection or chronic disease, and serology to exclude syphilis or HIV infection. Two commonly ordered investigations are EEG to exclude epilepsy, and a CT scan of the head to exclude brain lesions. Early dementia may present with depressive symptoms in older patients.

If no such cause is found, a psychological evaluation may be done by the physician or by referral to a psychiatrist or psychologist.^[1] The evaluation will include a complete history of symptoms, a discussion of alcohol and drug use, and a determination of whether the patient has had or is having suicidal thoughts or thinking about death. The evaluation will also include a family medical history to see if other family members suffer from any form of depression or similar mood disorder.^[1]

Investigations are not generally repeated for a recurrent episode unless there is a specific medical indication. These may include measuring serum sodium if the person presents with polyuria and is on a selective serotonin reuptake inhibitor (SSRI). Assessment and treatment are usually done on an outpatient basis; admission to an inpatient facility is considered for patients who pose a risk to themselves or to others.

There are several criteria lists and diagnostic tools that can also aid in the diagnosis of depression. Most are based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a book published by the American Psychiatric Association that stipulates the criteria used to diagnose various mental disorders, including depression. Many are used in research or as screening tools, but not in the absence of review by a medical practitioner or a psychologist.

The Beck Depression Inventory, originally designed by psychiatrist Aaron T. Beck in 1961, is a 21-question patient-completed survey that covers items related to the basic symptoms of depression, such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex.^[9] The Beck Inventory is one of the most widely used diagnostic tools for self-diagnosis of depression, although its main purpose is not the diagnosis of depression, but determining the severity and presence of symptoms.^[10]

There are also two Patient Health Questionnaires available that are also self-administered questionnaires. The PHQ-2 has only two questions that asks about the frequency of depressed mood and a loss of interest in doing things, with a positive to either question indicating the need for further testing.^[11] The PHQ-9 is a slightly more detailed nine question survey covering some of the major symptoms of depression and the frequency a person has experienced them. It is based directly on the diagnostic criteria listed in the DSM-IV and often used as a follow up to a positive PHQ-2 test.^[12]

Other scales commonly used include the Geriatric Depression Scale, in older populations, the widely-used Hamilton Depression Rating Scale designed by psychiatrist Max Hamilton in 1960,^[13] and the Montgomery-Åsberg Depression Rating Scale (MADRS).

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

The DSM IV-TR diagnosis hinges on the presence of a major depressive episode, which may be either single or recurrent. Further qualifiers are used to classify both the episode itself and the course of the disorder. The ICD-10 system does not use the term major depressive disorder, but the diagnosis of depressive episode is very similar. Minor depression is a less-used term for a subclinical depression that does not meet criteria for major depression but in which at least two symptoms are present for two weeks. It is not mentioned in DSM IV-TR.

A major depressive episode has been defined as a severely depressed mood that persists for at least two weeks. Episodes may be isolated or recurrent and categorized as mild, major or severe. If the patient has already had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without periods of elation or mania is sometimes referred to as unipolar depression because the mood remains at one emotional state or "pole". The DSM excludes cases in which the symptoms are a normal result of bereavement (though it is possible for normal bereavement to turn into a depressive episode). There is ongoing scientific debate about whether the exclusion criteria should cover other social or financial losses.^[14][15]

DSM diagnosticians recognize several possible subtypes:

• Melancholic depression – melancholia is characterized by a loss of pleasure (anhedonia) in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early morning waking, psychomotor retardation, excessive weight loss (not to be confused with Anorexia Nervosa), or excessive guilt.

• Atypical depression – atypical depression is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite ("comfort eating"),^[16] excessive sleep or somnolence (hypersomnia), leaden paralysis, or significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. Contrary to its name, atypical depression is the most common form of depression.^[17]

• Psychotic depression – Some people with a major depressive episode, particularly of melancholic nature, may experience psychotic features. They may be presented with hallucinations or delusions that are either mood-congruent (content coincident with depressive themes) or non-mood-congruent (content not coincident with depressive themes). It is clinically more common to encounter a delusional system as an adjunct to depression than to encounter hallucinations, whether visual or auditory.

• Postpartum depression refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression, which has incidence rate of 10-15%, typically sets in within three months of labor, and can last for as long as three months.^[18]

• Dysthymia is a chronic, mild depression in which a person suffers from a depressive mood almost daily over a span of at least two years without episodes of major depression. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to co-occurring episodes of major depression (sometimes referred to as "double depression").^[19]

• Bipolar disorder is an episodic condition characterized by alternating states of mania, hypomania and depression. In the United States, bipolar disorder has also been called "manic depression", but this term is no longer favored by the medical community.

• Adjustment disorder with depressed mood overlaps with what was previously known as Reactive depression.

• Recurrent brief depression (RBD) is distinguished from clinical depression primarily by differences in duration. Patients with RBD have depressive episodes about once per month, with individual episodes lasting less than two weeks and typically less than 2–3 days. Diagnosis of RBD requires that the episodes occur over the span of at least one year and, in female patients, independently of the menstrual cycle. People with clinical depression can develop RBD, and vice versa, with both illnesses having similar risks.^[20]

North American population studies have shown that 3-5% of males and 8-10% of females are suffering from a major depressive episode at any one time.^[21][22] The National Comorbidity Survey Replication (NCS-R) from 2001-02, a follow up of the original survey, found that 16.2% of people had suffered a major depressive episode in their lives.^[23]In some countries, such as Australia, one in four women and one in six men will suffer from depression. In Canada, major depression affects approximately 1.35 million people^{[citation needed]}, and in the United States approximately 14 million adults per year.^[24] An estimated 121 million people worldwide currently suffer from depression.^[25]

Major depressive disorder is a chronic condition in most cases, as up to 90% will have one or more subsequent episodes.^[26] People who have had one episode of depression may be more than normally likely to have more episodes in the future, so the first time a young person becomes depressed is important as both a personal and public health concern.^[27]

About twice as many females as males report or receive treatment for clinical depression, though this imbalance has recently shrunk, and the difference seems to disappear completely for those over the age of 50–55. Clinical depression is currently the leading cause of disability in North America, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization.^[28] The diagnostic criteria for depression may be too broad, resulting in diagnosis of major depression in people who are not truly suffering from the disorder, but who have shown normal responses to negative events.^[29]

Current theories regarding the risk factors and causes of clinical depression can be broadly classified into two categories: psychological and biological.

Events such as the death of a parent, issues with biological development, school related problems, abandonment or rejection, neglect, chronic illness, and physical, psychological, or sexual abuse can increase the likelihood of depression later in life. Post-traumatic stress disorder (PTSD) and depression often co-occur, and both can result from childhood trauma.^[30]

Stressful or traumatic life experiences or circumstances, including rape, assault, or the death of a relative or friend, may trigger a depressive episode. A depressive episode may also be triggered by other major changes such as unemployment, divorce, or a loss of religious faith.^[31] Ongoing issues, such as financial difficulties or poverty, ongoing major health problems (e.g., eating disorders), addictions (e.g., gambling addiction or drug addiction), sexual difficulties, or work-related stress can also contribute to depression. Low self-esteem and self-defeating or distorted thinking are connected with depression. The question of whether this is the result of depression or a cause of it is a matter of debate. In either case, it is known that depressed persons who are able to make corrections in their thinking patterns can show improved mood and self-esteem.^[32] Psychological factors related to depression include the complex development of one's personality and how one has learned to cope with external environmental factors, such as stress.^[33]

Existential psychologists argue that "depression is the inability to construct a future."^[34] In order to construct a future, people must become acutely aware of both their mortality and their freedom, and they must exercise the latter within the explicit framework of the former. This awareness and responsibility produce "normal anxiety,"^[35] whereas the lack of these things leads to "neurotic anxiety,"^[35] "self-alienation,"^[36] "inauthentic" living,^[37] and depression. Humanistic psychologists agree with many facets of existentialism, but argue that depression results from a specific incongruity between society on the one hand, and the individual's innate drive to self-actualize on the other.^[38]

Most experts believe that both biological and psychological factors play a role. The heritability of depression--the degree to which it is genetically determined--was estimated to be about 40% for women and about 30% for men.^[39]

Evolutionary psychologists have theorized that depression might be a useful adaptation in some situations.^[40] 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.^[41] These insights may be helpful in counselling therapy.^[42][43]

Many modern antidepressant drugs change synaptic levels of certain neurotransmitters, especially serotonin and norepinephrine. However, the precise relationships among serotonin, SSRIs, and depression are largely unknown and, typically, are greatly oversimplified when presented to the public.^[44]

There may be a link between depression and neurogenesis of the hippocampus,^[45] a center for both mood and memory. Loss of neurons in the hippocampus 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 thereby increasing the total mass of the hippocampus. This increase in mass may help to restore mood and memory.^[46][47]

Depression may also be caused in part by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.^[48]

Many individuals with clinical depression exhibit markedly higher levels of monoamine oxidase A (MAO-A) in the brain compared to people without depression.^[49] MAO-A is an enzyme which reacts with and decreases the concentration of monoamines such as serotonin, norepinephrine and dopamine.

The three most commonly indicated treatments for depression are medication, psychotherapy, and electroconvulsive therapy.

A patient's doctor may change the antidepressant taken, adjust the dosages of medications, or try different combinations of antidepressants before finding the most effective option; response rates to the first agent administered may be as low as 50 percent.^[50] It may take anywhere from three to eight weeks after the start of medication before its therapeutic effects can be fully discovered. Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four months to prevent the chance of recurrence. For patients who have chronic depression, medication may be continued for the remainder of their lives.^[1]

A wide range of antidepressant drugs can be prescribed to treat depression. These drugs have historically been divided into four major groups: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other antidepressants.

Selective serotonin reuptake inhibitors, such as sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil) and citalopram (Celexa) are the primary medications considered for patients, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety. Those who do not respond to the first SSRI tried, can be switched to another SSRI antidepressant. Such a switch results in improvement in almost 50% of cases.^[51] Another popular option is to switch the patient to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy^[52] with the latter strategy possibly more effective.^[53][54] Venlafaxine (Effexor) may be moderately more effective than SSRIs;^[55] however, it is not recommended as a first line treatment because of the high rate of the side effects.^[56]

Tricyclic antidepressants are less well tolerated than SSRIs and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective.^[57][58] Their adverse side effect profile and toxicity in overdose limit their use.^{[citation needed]} The causing or worsening of insomnia is not uncommon with SSRIs; a sedating antidepressant mirtazapine (Zispin, Remeron) can be used in such cases.^[59][60][61] Monoamine oxidase inhibitors have historically been plagued by questionable efficacy and life-threatening adverse effects. They are still used only rarely, although newer agents of this class, with a better side effect profile, have been developed.^[62]

A meta-analysis combined 35 clinical trials submitted to the FDA before licensing of four newer antidepressants. The authors found that although the antidepressants were statistically superior to placebo they often did not exceed the NICE criteria for a 'clinically significant' effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression.^[63] This result is consistent with the earlier clinical studies in which only patients with severe depression benefited from the treatment with a tricyclic antidepressant, imipramine, or from psychotherapy more than from the placebo treatment.^[64][65][66]

There are a number of different psychotherapies for depression, which may be provided to individuals or groups. Psychotherapy can be delivered by a variety of mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, and psychiatric nurses. The most studied form of psychotherapy for depression is Cognitive behavioral therapy. Several clinical trials have shown that CBT is as effective as antidepressant medications, even among more severely depressed clients. CBT is thought to work by teaching clients to learn a set of cognitive and behavioral skills, which they can employ on their own. This type of therapy attempts to teach people to learn healthier behaviors. Earlier research suggested that psychotherapy, specifically cognitive-behavioral therapy, was not as effective as medication in the treatment of depression; however, recent research suggests that CBT can perform as well as anti-depressant medication in the treatment of moderate to severe depression treated on an outpatient basis.^[67] With more complex and chronic forms of depression the most effective treatment is often considered to be a combination of medication and psychotherapy.^[68]

Two randomized, controlled trials of mindfulness-based cognitive therapy (MBCT), which includes elements of meditation, have been reviewed. MBCT was significantly more effective than "usual care" for the prevention of recurrent depression in patients who had had three or more depressive episodes. According to the review, the "usual care" did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected the non-specific or placebo effects.^[69]

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT, however the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.^[70]

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts,^[71] is used by its practitioners to treat clients presenting with major depression.^[72] A more widely practiced, eclectic technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus.^[73] In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.^[74]

Electroconvulsive therapy (ECT), also known as electroshock, is a treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Today, ECT is a last resort, and is most often used as a treatment for severe major depression which has not responded to other treatment. An estimated 1 million people worldwide receive ECT every year^[75] usually in a course of 6-12 treatments administered 2 or 3 times a week. In a study, ECT was shown clinically to be the most effective treatment for severe depression, and to result in improved quality of life in both short- and long-term.^[76] After treatment, drug therapy can be continued, and some patients receive continuation/maintenance ECT. Short-term memory loss, disorientation, and headache are very common side effects. Detailed neuropsychological testing in clinical studies has not been able to prove permanent effects on memory.

ECT produces a very fast response in the client; however, this response has been shown not always to last unless maintenance electroshock or maintenance medication is used. Whereas antidepressants usually take around a month to take effect, the results of ECT have been shown to be much faster. For this reason, it is the treatment of choice in emergencies (e.g., in catatonic depression in which the patient has ceased oral intake of fluid or nutrients). The American Psychiatric Association and the National Institute for Health and Clinical Excellence have concluded that the procedure does not cause brain damage.^[77][78] Like all forms of psychiatric treatment, ECT can be given without a patient's consent,^{[citation needed]} but this is subject to legal conditions dependent on the jurisdiction. In Oregon, patient consent is necessary by statute.^[79]

• St John's wort extract is used extensively in Europe to treat mild and moderate depression. It is a prescription antidepressant in several European countries but is classified as herbal supplement and sold over the counter in the U.S. The opinions on its efficacy for major depression differ. The systematic meta-analysis of 37 trials conducted by Cochrane Collaboration indicated statistically significant weak-to-moderate effect as compared to placebo. The same meta-analysis found that St John's wort efficacy for major depression is not different from prescription antidepressants.^[80] NCCAM and other NIH-affiliated organizations hold that St John's wort has minimal or no effects beyond placebo in the treatment of major depression, based primarily on one study with negative outcome conducted by NCCAM.^[81][82]

• S-Adenosyl methionine (SAM-e) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the United States. A fairly strong evidence, based on 16 clinical trials, suggests it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.^[83][84]

• Repetitive transcranial magnetic stimulation (rTMS) use in treatment-resistant depression is supported by multiple controlled studies, and it has been approved for this indication in Europe, Canada and Australia, but not in the U.S.^[85] A 2008 meta-analysis based on 32 trials found a robust effect of this method on depression, and it appeared similarly effective for both uncomplicated depression and depression resistant to medication.^[86] However, in a side-by-side randomized trial rTMS was inferior to electroconvulsive therapy.^[87]

• Vagus nerve stimulation (VNS) is an approved therapy for treatment-resistant depression and is used as an adjunctive to existing antidepressant treatment. The support for this method comes primarily from open-label trials, which indicate that a several month period may be necessary for the therapy to become effective.^[85] The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results. VNS failed to show superiority over a sham treatment on the primary efficacy outcome but the result were more favorable for the secondary outcome.^[88]

• A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found it to be more effective than placebo—usually, dim light—for both seasonal affective disorder and for nonseasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective.^[89] A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly as an addition to medication or sleep deprivation. A moderate statistically significant effect of light therapy was found; however, it disappeared if a different statistical technique was used.^[90] Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1-2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

• A 2004 Cochrane Review concluded that there was insufficient evidence to judge the efficacy of acupuncture in the management of depression. Although acupuncture showed no difference in the improvement of depression compared with conventional medication, the methodological quality of the evidence base was found to be poor.^[91]

• Exercise, when used in conjunction with medication with non-suicidal patients can have beneficial effects in preventing the return of depression. Patients that completed 30 minutes of brisk exercise at least three times a week were found to have a significantly lower incidence of relapse.^[92]

• The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage.^[85]

• Insulin shock therapy is an old and largely abandoned treatment for severe depression, psychosis, catatonia, and other mental disorders. It consists of induction of hypoglycemic coma by intravenous infusion of insulin.

• Tryptophan and 5-hydroxytryptophan may be more effective than placebo in alleviating depression according to the Cochrane Collaboration meta-analysis. However, only two out of 108 trials were of sufficient quality to be included in this analysis.^[93]

• Omega-3 fatty acids have been studied in clinical trials for major depression primarily as an adjunctive to antidepressant therapy. A meta-analysis of eight such trials indicated a statistically significant superiority of combinations with omega-3 fatty acids over single antidepressants; however, the authors warned that, due to multiple problems with these trials, a reliable conclusion is difficult to achieve.^[94]

• Dehydroepiandrosterone (DHEA), available as a supplement in the U.S., has been shown to be more effective than placebo for major depression in two small double-blind trials: in one—as an adjunctive to antidepressant treatment^[95], in another—as monotherapy.^[96]

• Chromium picolinate was found to be equivalent to placebo for atypical depression overall but possibly efficacious in the sub-group of patients with severe carbohydrate craving.^[97]

• Zinc supplementation was found in a single small study to augment the effect of antidepressants.^[98]

• Cranial electrotherapy stimulation (CES, electrosleep) devices currently on the market have been granted marketing authorization by the FDA based on the legacy waver, that is because a sufficiently similar device had been marketed before 1976, when the new regulations requiring controlled testing were introduced.^[99] The FDA considers them to be the class III devices—"devices for which insufficient information exists to ... provide reasonable assurance of safety and effectiveness"^[100] The effects of CES on depression were inconclusive or negative in multiple double-blind studies of psychiatric patients.^{[101][102][103][104][102][105]} In one of them, four out of six clinically depressed patients dropped out of the study because of the massive worsening of depressive symptoms, with two of them becoming actively suicidal.^[105] One of the authors of the latter study cautioned that CES “should not be used as a treatment of choice” for the patients with the primary diagnosis of depression, “and should be used with caution if this diagnosis is suspected.”^[106] Nevertheless, the CES practitioners continue to employ it as a treatment of choice for depression.^[107][108]

Recurrence is more likely if treatment has not resulted in full remission of symptoms.⁴ Current guidelines for antidepressant use recommend 4 to 6 months of continuing treatment after symptom resolution to prevent relapse. Combined evidence from many randomized controlled trials indicates that continuing antidepressant medications after recovery can reduce the odds of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use. Thus, in a significant minority of patients depression recurs despite the prolonged treatment with antidepressants.^[109] The reason for recurrence in these cases is as poorly understood and could be a "true pharmacologic failure or a worsening of the disease, a relapse that overrides medication." Because of the difficulties of carrying out controlled clinical trials of longer duration, the approval of most antidepressants for the prevention of recurrence is based on up to a year-long trials.^[110]

Archaeologists have found human skulls from prehistoric eras, with large holes cut into them through a process called trepanation. Cave paintings suggest that people believed the practice would cure a range of ailments including mental disorders.^[111] Out of 120 prehistoric skulls found at one burial site in France dated to 6500 BC, 40 had trepanation holes.^[112]

The Greek scholar Empedocles (490-430 BC), who proposed disease was caused by an imbalance of the four humours, influenced Hippocrates (460-377 BC), who is credited with being the first physician to reject superstitions and beliefs that credited supernatural or divine forces with causing illness. He believed that disease was the product of environmental factors, diet and living habits, not a punishment inflicted by the gods. Hippocrates believed that the appropriate treatment for a mental disorder depended on which humor had caused the problem, and he argued that "mental disorder must be explained on the basis of natural causes" such as the "sudden flow of bile to the brain". ^{[113][unreliable source?]} Plato (427-347 BC) argued that there were two types of mental illness: "divinely inspired" mental illness that gave the person prophetic powers, and a second type that was caused by a physical disease.^{[114][unreliable source?]} Aristotle (384-322 BC), who studied under Plato, abandoned the divinely-caused mental illness theory, and proposed instead that all mental illness was caused by physical problems.

Through long contact with Greek culture, and their eventual conquest of Greece, the Romans absorbed many of the Greek ideas on medicine.^[115] The Greek physician Asclepiades (c. 124 – 40 BC), who practiced in Rome, discarded the humoral doctrine of Hippocrates. He advocated humane treatment of mental disorders, and had insane persons freed from confinement and treated them with natural therapy, such as diet and massages. While Arateus (ca AD 30-90) argued that it is hard to pinpoint where a mental illness comes from, Galen (AD 129 –ca. 200) revived the Greek theories of the "four humours" and proposed that melancholy is caused by "animal spirits". In the Old Testament, which was composed and compiled between the 12th and the 2nd century BC, the description of King Saul includes symptoms that resemble some elements in the modern diagnosis of depression; eventually the King commits suicide.

Galen's ideas on medicine dominated Western medical thinking from the medieval era until the Renaissance, in part because the Catholic church supported them. In addition to viewing mental illness through the lens of Galen's "four humours", medieval Europeans viewed mental illness as the entry of demons or evil spirits into the body. ^[116] Indeed, Arnaldus de Villanova (1235-1313) even combined the "evil spirit" and Galen-oriented "four humours" theories. Despite his familiarity with Arabic treatises (he translated a number of medical texts from Arabic, including works by Ibn Sina (Avicenna) and Galen), he suggested that people with mental illness could be cured by trepanning a cross-shaped hole in their head to let the demons and excess humours excape. In the 13th and 14th centuries, the treatment of people with mental illness varied. While some people with mental illnesses were treated at hospitals such as Bethlem Royal Hospital (better known by its nickname, “Bedlam”), which was founded in 1329^[117] , others were persecuted as witches. ^[118] For people deemed to be witches, the treatment was exorcism, often in the form of physical punishments that aimed to drive out the devil and save the person’s soul. The witch-hunting attitude was not held in all quarters. ^[119]The Franciscan monk Bartholomeus Anglicus (ca. 1203 - 1272) described a condition which resembles depression in his encyclopedia, De Proprietatibis Rerum, and he suggested that music would help people with this condition.

The modern idea of depression appears similar to the much older concept of melancholia, which derives its name from the theory of the four humours: disease being caused by an imbalance in one or other of the four basic bodily fluids, or humours. Personality types were similarly determined by the dominant humour in a particular person. Melancholia was caused by an excess of black bile; hence the name, which means 'black bile' (Ancient Greek μέλας, melas, "black", + χολή, kholé, "bile"); a person whose constitution tended to have a preponderance of black bile had a melancholic disposition. Melancholia was described as a distinct disease with particular mental and physical symptoms in the fifth and fourth centuries BC. Hippocrates, in his Aphorisms, characterized all "fears and despondencies, if they last a long time" as being symptomatic of melancholia.^[120]

In the medieval Islamic world, the Muslim psychologist Ishaq ibn Imran (d. 908), known as "Isaac" in the West, wrote an essay entitled Maqala fi-l-Malikhuliya, in which discovered a type of melancholia: the "cerebral type" or "phrenitis". In Arabic, he referred to this mood disorder as "malikhuliya", which Constantine the African translated into Latin as "melancolia", from which the English term "melancholia" is derived.^[121] In the The Canon of Medicine (1020s), Avicenna dealt with neuropsychiatry and described a number of neuropsychiatric conditions, including melancholia.^[122] He described melancholia as a depressive type of mood disorder in which the person may become suspicious and develop certain types of phobias.^[123] The Canon of Medicine was also translated into Latin in the 12th century.

In Larry Merkel's lectures on the history of Western psychiatry, he argues that "medieval concepts of mental illness stressed that individuals had free will and were responsible for their actions, but that illness (including mental illness) came from sin and resulting punishment from God or possession by the devil." ^[124]As a result, "[m]ental illness was seen as either the result of sin or as a test of faith". ^[125]"[M]elancholia was seen as a trial of faith", and one of the "seven deadly sins...sloth (acedia) had a clinical profile, presenting with boredom, depression, obsessions, anxiety, and a variety of psychosomatic symptoms." ^[126] In Robert Daly's article Before Depression: The Medieval Vice of Acedia, he argues that in medieval Europe, "phenomena akin to the symptoms and signs of modern depression", were interpreted as "acedia", a "spiritual disease", vice, or "undesirable trait of character." He also claims that "acedia was a vice that could be distinguished from melancholia" and notes that while acedia is similar to the modern concept of depression, it "should not be identified with depression." ^[127]

From the 11th century onwards, as medieval Europeans had increasing contact with Islamic culture, the "classical Greek and other Hellenistic ideas...of Hippocrates, Galen, and the philosophy of Aristotle were combined to create an advanced level of science and medicine." ^[128]In Islamic countries, physicians treated the mentally ill with "... a calm and relaxed environment, with fountains, gardens, and the use of soothing baths, perfumes, music and special diets." ^[129]

In the 16th century, the physician and alchemist Paracelsus (1493-1541) argued that sickness and health in the body relied on the harmony of man, the microcosm, and nature. Since he believed that illnesses could be cured by chemical remedies, he rejected the witch-hunt and demonology approach to mental illness. ^[130] In the 16th century, the physician Johann Weyer (1515-1588) also argued against the witchcraft and demon-possession theories, proposing instead that mental illnesses had natural causes^[131]. However, the Catholic church banned Weyer’s book, De Praestigiis Daemonum, and he was accused of being a sorcerer. ^[132] Juan Luis Vives (1492-1540) exemplifies the more humane approach to dealing with the mentally ill; he founded hospitals where mentally ill people could be treated.

During the 17th century, science gained increasing prestige, and the relationship between emotions and anatomy were studied more closely. The philosopher Spinoza (1632-1677) argued that the mind and body are closely connected and literary figures such as William Shakespeare (1564-1616) and Miguel de Cervantes (1547-1616) described mental illness in an insightful way in their works. Shakespeare described characters with deep melancholy in plays such as Hamlet and King Lear. In the early 17th century, Robert Burton, the dean of divinity at Oxford University, wrote Anatomy of Melancholy, which described his experience with the disorder. Burton suggested that depression could be combated with a healthy diet, sufficient sleep, music, and "meaningful work", along with talking about the problem with a friend^[133]. In particular, Burton called music "...a sovereign remedy against despair and melancholy" which "will drive away the devil himself." [3] In the late 17th century, several “madhouses” were established in London for the care of patients with mental illnesses. ^[134]

French physician Phillipe Pinel (1745 - 1826), who has been called the father of modern psychiatry, argued that insanity was caused by factors in the environment or in a person's background. In the early 19th century, Franz Joseph Gall proposed the theory of phrenology, which claimed that the personality traits of a person could be determined by "reading" bumps and fissures in the skull. While now a defunct approach, phrenology was influential in 19th-century psychiatry. The German physician Johann Christian Heinroth (1773 - 1843) revived the notion that mental illness was caused by moral sins of the patient. He argued that mental sickness and many somatic illnesses are caused by the soul. His 1818 textbook Störungen des Seelenlebens classified mental disorders into different categories: exaltations, the "depressions" and the "mixed states" (Mischung) of exaltation and weakness. By the mid-19th century, scholars began to believe that mental illness was caused by physical and organic conditions. The German psychiatrist Wilhelm Griesinger (1817-1868) argued that mental illnesses were caused by the brain, and he promoted reforms such as the integration of the mentally ill into society.

German psychiatrist Emil Kraepelin (1855-1926) argued that psychiatric diseases were mainly caused by biological and genetic disorders. He opposed the approach of Sigmund Freud, who regarded and treated mental disorders as problems caused by psychological factors. Kraepelin classified the previously unitary concept of psychosis into two distinct forms: Manic Depression (now seen as comprising a range of mood disorders such as Major Depression and Bipolar disorder), and Dementia praecox. Sigmund Freud, on the other hand, argued that each patient's unique life history and experiences caused their mental problems. Freud is best known for his theories of the unconscious mind and the defense mechanism of repression, and for creating the clinical practice of psychoanalysis, which uses a form of dialogue between a patient and a psychoanalyst to treat mental illness or distress.

In the mid-20th century, researchers theorized that clinical depression was a chemical imbalance in transmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms.^[135] Subsequently, many other causes for clinical depression have been proposed.^[136] Psychiatrist David Healy wrote about the growth of the diagnosis, along with perspectives on the development and promotion of antidepressants and the biological model since the late 1950s.^[137] After the 1970s, scholars proposed a range of "genetic, biochemical and neuropathological causes of mental disorder."^{[138][unreliable source?]}

English essayist and wit Samuel Johnson (1709 – 1784) coined the term "the black dog" to describe his own battles with depression ^[139], a phrase which was subsequently popularised by former British Prime Minister Sir Winston Churchill, who also faced depression^[140]. While depression was often stigmatized until recent decades, since then, society has begun discussing depression more openly. Earlier 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.

Historical figures that may have had depression include the Dutch painter Vincent Van Gogh ^[141]; British writer Henry James^[142]; Abraham Lincoln, the 16th President of the United States ^[143]; German composer Robert Schumann ^[144] and German philosopher Friedrich Nietzsche.^[145]. Some well-known people with depression from the contemporary era include American film director Woody Allen ^{[146] [147]}; Canadian songwriter Leonard Cohen ^[148]; British musician Nick Drake, ^[149]; American poet T. S. Eliot ^[150] , American writer Ernest Hemingway^[151]; and American playwright and novelist Tennessee Williams ^[152].

• Black Dog Institute – Depression and Bipolar Disorder Information Australia
• Template:Dmoz
• Depression Research News - ScienceDaily's Depression Research News
• National Alliance on Mental Illness – Depression support, advocacy, and education
• National Depressive and Manic Depressive Association - National Depressive and Manic Depressive Association

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