Major depressive disorder
Specialty	Psychiatry

Clinical depression (also called major depressive disorder, severe depression disorder or unipolar depression) is a psychiatric disorder characterized by a pervasive low mood, loss of interest in a person's usual activities and diminished ability to experience pleasure. The course of clinical depression 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 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 the term "depression" is commonly used by laypersons to describe a temporary depressed mood, when a person may feel sad or "down", clinical depression is 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]Clinical depression may be isolated or be a secondary result of a primary condition such as bipolar disorder or chronic pain. When specific treatment is indicated, it usually consists of psychotherapy and antidepressants.

Clinical depression can present with a variety of symptoms, but almost all patients display a marked change in mood, a deep feeling of sadness, and a noticeable loss of interest or pleasure in favorite activities. Other symptoms include:

• Persistent sad, anxious or "empty" mood
• Loss of appetite and/or weight loss or conversely overeating and weight gain
• Insomnia, early morning awakening, or oversleeping
• Restlessness or irritability
• Psychomotor agitation or psychomotor retardation
• Feelings of worthlessness, inappropriate guilt, helplessness
• Feelings of hopelessness, pessimism
• Difficulty thinking, concentrating, remembering or making decisions
• Thoughts of death or suicide or attempts at suicide
• Loss of interest or pleasure in hobbies and activities that were once enjoyed
• Withdrawal from social situations, family and friends
• Decreased energy, fatigue, feeling "slowed down" or sluggish
• Persistent physical symptoms that do not respond to treatment, such as headaches, digestive problems, and chronic pain
• Decrease/Feeling in motor-speed (time seems to slow down)

Not all patients will suffer from every symptom. The severity of symptoms will vary widely among individuals. Symptoms must, however, persist for at least two weeks before being considered a potential sign of depression, with the exception of suicidal thoughts or attempts.^[3][1]

Diagnosis of clinical depression in children is more difficult than in adults and is often left undiagnosed, and thus untreated, because the symptoms in children are often written off as normal childhood moodiness. Diagnosis is also made difficult because 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 depression will suffer from 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 and/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]

Before a diagnosis of depression is made, a physician should perform a complete medical exam to rule out any possible physical cause for the suspected depression. If no such cause is found, a psychological evaluation should be done by the physician or by referral to a psychiatrist, social worker, or psychologist.^[1] The evaluation will include a complete history of symptoms, a discussion of alcohol and drug use, and 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]

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 defines the criteria used to diagnose various mental disorders, including depression.

The Beck Depression Inventory, originally created by Dr. 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.^[5] The Beck Inventory is one of the most widely used diagnostic tools for self-diagnosis of depression, although its primary purpose is not the diagnosis of depression, but determining the severity and presence of symptoms.^[6]

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.^[7] 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.^[8]

Clinical depression affects about 8–17 percent of the population on at least one occasion in their lives, before the age of 40. 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.^[9] An estimated 121 million people worldwide currently suffer from depression.^[10]

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 both as a personal and public health concern.^[11]

About twice as many females as males report or receive treatment for clinical depression, though this imbalance is shrinking over the course of recent history; This difference seems to completely disappear after 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.^[12]

A recent study suggested that the diagnostic criteria for depression may be too broad, resulting in diagnosis of clinical depression in people who are not truly suffering from the disorder and who have shown normal responses to negative events.^[13]

The diagnostic category major depressive disorder appears in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. The term is generally not used in countries which instead use the ICD-10 system, but the diagnosis of depressive episode is very similar to an episode of major depression. Clinical depression also usually refers to acute or chronic depression severe enough to need treatment. Minor depression is a less-used term for a subclinical depression that does not meet criteria for major depression but where there are at least two symptoms present for two weeks.

Major depression is 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 usually made instead. Depression without periods of elation or mania is therefore sometimes referred to as unipolar depression because the mood remains at one emotional state or "pole". The diagnosis usually excludes cases where the symptoms are a normal result of bereavement (though it is possible for normal bereavement to turn into a depressive episode).

Diagnosticians recognize several possible subtypes of major depression:

• Depression with melancholic features – 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.

• Depression with atypical features – atypical depression is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite ("comfort eating"),^[14] 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.^[15]

• Depression with Psychotic Features – Some people with major depressive episodes 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.

It is possible for a person to have a combination of these subtypes. For instance someone may experience loss of pleasure in activities as seen in melancholic depression in addition to over-eating and weight gain common.

• 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").^[16]

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

• Postnatal depression or postpartum depression is a form of clinical depression that occurs after childbirth. Postnatal depression primarily occurs in women, less commonly in men, with similar symptoms and treatment methods as clinical depression. Postnatal depression generally lasts only a few weeks with proper diagnosis and treatment.

• 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.^[17]

The different types of depression and anxiety are classified separately by the DSM-IV-TR. Despite the different categories, depression and anxiety can indeed be co-occurring (occurring together), independently (without mood congruence), or comorbid (occurring together, with overlapping symptoms, and with mood congruence). In an effort to bridge the gap between the DSM-IV-TR categories and what clinicians actually encounter, experts such as Herman Van Praag of Maastricht University have proposed ideas such as anxiety/aggression-driven depression.^[18] This idea refers to an anxiety/depression spectrum for these two disorders, which differs from the mainstream perspective of discrete diagnostic categories.

Although there is no specific diagnostic category for the comorbidity of depression and anxiety in the DSM or ICD, the National Comorbidity Survey (US) reports that 58 percent of those with major depression also suffer from lifetime anxiety. Supporting this finding, two widely accepted clinical colloquialisms include

• Agitated depression - a state of depression that presents as anxiety and includes akathisia (heightened restlessness), suicide, insomnia (not early morning wakefulness), nonclinical (meaning "doesn't meet the standard for formal diagnosis") and nonspecific panic, and a general sense of dread.

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.^[19] These patients also had higher levels of residual impairment, or the ability to get back into the swing of things. On a similar note, Robert Sapolsky of Stanford University argues that the relationship between stress, anxiety, and depression could be measured and demonstrated biologically.^[20] To that point, a^[21] study by Heim and Nemeroff et al., of Emory University, found that depressed and anxious women with a history of child abuse recorded higher heart rates and the stress hormone ACTH when subjected to stressful situations.

Current theories regarding the risk factors and causes of clinical depression can be broadly classified into two categories, Physiological and Sociopsychological:

The tendency to develop depression may be inherited: according to the National Institute of Mental Health^[22] there is some evidence that depression may run in families. Most experts believe that both biological and psychological factors play a role.

Many modern antidepressant drugs change levels of certain neurotransmitters, namely serotonin and norepinephrine (noradrenaline). However, the relationship between serotonin, SSRIs, and depression is typically greatly oversimplified when presented to the public, though this may be due to the lack of scientific knowledge regarding the mechanisms of action.^[23] Evidence has shown the involvement of neurogenesis in depression, though the role is not exactly known.^[24] Recent research has suggested that there may be a link between depression and neurogenesis of the hippocampus.^[25] This horseshoe-shaped structure is a center for both mood and memory. Loss of neurons in the hippocampus is found in depression and correlates with impaired memory and dysthymic mood. The most widely accepted explanation for this is that the drugs increase serotonin levels in the brain which in turn stimulate neurogenesis and therefore increase the total mass of the hippocampus and would in theory restore mood and memory, therefore assisting in the fight against the mood disorder.

About one-third of individuals diagnosed with attention-deficit hyperactivity disorder (ADHD), may develop comorbid depression.^[26] 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.^[27]

New evidence shows that individuals with clinical depression exhibit markedly higher levels of monoamine oxidase A (MAO-A) in the brain compared to people without depression.^[28] MAO-A is an enzyme which reacts with and decreases the concentration of monoamines such as serotonin, norephinephrine and dopamine.

Certain illnesses, including cardiovascular disease,^[29] hepatitis, mononucleosis, hypothyroidism, fructose malabsorption,^[30] sleep apnea, and organic brain damage caused by degenerative conditions such as Parkinson disease, Multiple Sclerosis or by traumatic blunt force injury may contribute to depression, as may certain prescription drugs such as hormonal contraception methods and steroids. Depression also occurs in patients with chronic pain, such as chronic back pain, much more frequently than in the general population. Fibromyalgia Syndrome sufferers also experience depression and anxiety.

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.^[31] About two new mothers out of 1000 experience Postnatal Psychosis, which includes hallucinations and/or delusions.

A study published in the British Journal of Psychiatry in 2006, found that mental health problems were lower in rural areas. ^[32] This could be due to Mycobacterium vaccae, a ‘happy bug’ found in garden soil. In rural areas, the 'friendly' bacteria is breathed in through dust, & found on homegrown vegetables. Treatment of mice with a 'friendly' bacteria Mycobacterium vaccae, normally found in the soil, altered their behavior in a way similar to that produced by antidepressant drugs. Human cancer patients being treated with the bacteria Mycobacterium vaccae unexpectedly reported increases in their quality of life. The microbes are affecting the brain indirectly by causing immune cells to release chemicals called cytokines. The stimulated nerves cause certain neurons in the brain to release a chemical called serotonin into the prefrontal cortex, an area of the brain known to be involved in mood regulation. ^[33]

Low self-esteem and self-defeating or distorted thinking are connected with depression. However, it has been proposed that it is the result of depression and not necessarily the cause of it. This is still debated in the scientific community. Although it is not clear which is the cause and which is the effect, it is known that depressed persons who are able to make corrections in their thinking patterns can show improved mood and self-esteem (Cognitive Behavioral Therapy).^[34] 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.^[35]

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 also increase the likelihood of depression later in life. Post-traumatic stress disorder (PTSD) includes depression as one of its major locomotives symptoms.^[36]

The following experiences or circumstances may trigger a depressive episode:

• divorce or the end of a serious relationship
• financial difficulties or poverty
• ongoing major health problems
• gambling addiction
• eating disorders
• grief over the death of a child, spouse, other family member or friends.
• job loss or unemployment
• loss of religious faith^[37]
• Rape
• Abortions
• trauma
• sexual difficulties
• work-related stress

The treatment of depression is highly individualized to the patient, based on the patient's unique combination of biological, psychological and social health factors and the severity of their condition.^[38] The three most conventional treatments for depression include medication, psychotherapy, and Electroconvulsive therapy, however new treatments and less conventional options are also available, including self help, life style changes, and vagus nerve stimulation.^[38]

Patients are most commonly treated as outpatients, although may be admitted to hospital if there is a significant acute risk of suicide. The duration may be brief, enough to assess and minimize risk by either self-harm or poor oral intake, and people are often discharged to continue convalescing in their home environment. At-risk individuals may also be placed in a partial hospitalization therapy, in which the patient sleeps at home but spends most of the day in a psychiatric hospital setting. This intensive treatment usually involves group therapy, individual therapy, medication management, and may be used particularly with children and adolescents.

A wide range of antidepressant drugs have been prescribed to treat depression, beginning with imipramine and other tricyclics in the 1950s and 1960s. These were followed by MAOIs in the 1960s, though their use was hampered by inconvenient dietary restrictions and questions on their effectiveness. Treatment was revolutionised by the use of fluoxetine (Prozac) from 1988, and the class it belongs to, the SSRIs, remain the most widely prescribed drugs used to treat depression since 1990.

A widely-reported 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.^[39] This result is consistent with the earlier clinical studies where only patients with severe depression benefited from the treatment with a tricyclic antidepressant imipramine or from psychotherapy more than from the placebo treatment.^[40][41][42] Selective serotonin reuptake inhibitors, such as escitalopram oxalate (Lexapro), citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), are the primary medications considered for patients, having fewer side effects than the older monoamine oxidase inhibitors (MAOIs). MAOIs may be the best medication for a small number of patients, however those patients will have to avoid a variety of foods and decongestant medications to reduce the chances of a hypertensive crisis.^[1] Bupropion (Wellbutrin, Zyban), an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, is also considered to be effective in the treatment of depression,^[43] without sexual dysfunction or sexual side effects^[44] and without weight gain. Bupropion has also been shown to be more effective than SSRIs at improving symptoms such as hypersomnia and fatigue in depressed patients.^[45]

A patient's doctor may have to change the antidepressant taken, adjust the dosages of medications, or try different combinations of antidepressants before finding the most effective option for the patient; response rates to the first agent administered may be as low as 50 percent.^[46] 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 that have chronic depression, medication may need to be continued for the remainder of their life.^[1]

There are a number of psychotherapies for depression, which may be provided individually or in a group format. Psychotherapy can be delivered by a variety of mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, or psychiatric nurses.

The most studied form of psychotherapy for depression is cognitive therapy (also called Cognitive behavioral therapy). Several clinical trials have shown that CBT is as effective as anti-depressant medications, even among more severely depressed patients. While the precise mechanisms of change in CBT remain an active area of research, CBT is thought to work by teaching patients to learn a set of cognitive and behavioral skills, which they can employ on their own.

A number of other psychotherapies for depression exist. There is evidence that behavior therapy (called behavioral activation in the treatment of depression) and interpersonal therapy are effective treatments for depression. Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. Behavioral therapy is based on the assumption that behaviors are learned. Some behavior analytic models trace some depressions to childhood (see child development). This type of therapy attempts to teach people to learn healthier behaviors. 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. Narrative therapy gives attention to each person's "dominant story" by means of therapeutic conversations, which also may involve exploring unhelpful ideas and how they came to prominence. Possible social and cultural influences may be explored if the client deems it helpful. Supportive therapy encourages people to discuss their problems and provides them with emotional support. The focus is on sharing information, ideas, and strategies for coping with daily life.

Earlier research initially 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.^[47]With more complex and chronic forms of depression the most effective treatment is often a combination of medication and psychotherapy.^[48]

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 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^[49] 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.^[50] 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 offers the benefit of a very fast response; however, this response has been shown not 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.^[51][52] 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.^[53]

• 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.^[54] 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.^[55][56]

• 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.^[57][58]

• 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.^[59] 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.^[60] However, in a side-by-side randomized trial rTMS was inferior to electroconvulsive therapy.^[61]

• 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.^[59] 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.^[62]

• 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.^[63] 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.^[64] 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.

• 2004 Cochrane Review found indications that acupuncture improved depression to a degree similar to conventional medication. However, the authors concluded that there was insufficient evidence to judge the efficacy of acupuncture in the management of depression. The methodological quality of the evidence base was found to be poor, with both improved study design and larger studies required before a determination could be made.^[65]

• 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.^[66]

• Two randomized controlled trials of mindfulness-based cognitive therapy (MBCT), which includes the 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.^[67]

• The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies and it is still in a very early investigational stage.^[59]

• 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.^[68]

• 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.^[69]

• 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^[70], in another—as monotherapy.^[71]

• 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.^[72]

• Zinc supplementation was found in a single small study to augment the effect of antidepressants.^[73]

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Cranial electrotherapy stimulation devices (CES devices) use electrodes placed on or just behind the ear to generate a very small electrical current. In normal healthy males this microcurrent has been shown to affect alpha wave and beta wave brain activity, which according to the authors,"suggest beneficial changes in mental state".^[74] Unlike transcranial magnetic stimulation and vagus nerve stimulation, CES devices are small, relatively inexpensive, and are designed for home use. Unlike vagus nerve stimulation, no surgery is required.

Several double-blind studies of mixed groups of psychiatric patients have been conducted in the 1970s. The results were inconclusive and negative in one of these trials.^[75] In another trial, no difference between the placebo and treatment groups were found on any of the five measures employed.^[76] A third trial reported overall inconclusive results; however, 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.^[77] One of the authors of the third 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.”^[78] Many preliminary, small-scale studies have been conducted which show the effectiveness of CES therapy^{[79][80][81][82]}; however, to date there exists no consensus or even prospective clinical trials to support its use.

All of the CES 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.^[83] Such approval is sometimes misunderstood as evidence of efficacy, it should only be taken as lack of evidence of harm. The FDA considers them to be the class III devices—"devices for which insufficient information exists to assure that general controls and special controls provide reasonable assurance of safety and effectiveness"^[84]

Recurrence is more likely if treatment has not resulted in full remission of symptoms.⁴ In fact, 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 substantially reduces (halves) the chances of relapse. This preventive effect probably lasts for at least the first 36 months of use.^[85]

Anecdotal evidence suggests that chronic disease is accompanied by recurrence after prolonged treatment with antidepressants (tachyphylaxis). Psychiatric texts suggest that physicians respond to recurrence by increasing dosage, complementing the medication with a different class, or changing the medication class entirely. The reason for recurrence in these cases is as poorly understood as the change in brain physiology induced by the medications themselves. Possible reasons may include aging of the brain or worsening of the condition. Most SSRI psychiatric medications were developed for short-term use (a year or less) but are widely prescribed for indefinite periods.^[86]

The modern idea of depression appears similar to the much older concept of melancholia. The name melancholia derives from "black bile", one of the "four humours" postulated by Galen.

Clinical depression was originally considered to be 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.^[87] Since these suggestions, many other causes for clinical depression have been proposed.^[24]

Some medical professionals and anthropologists have formed several theories as to how depression may have evolutionary advantages, i.e., how it might have increased genetic fitness in ancestral populations. For example, psychic pain may have evolved in an analogous way to physical pain so that organisms avoid behaviour which hinders reproduction. This insight may be helpful in counselling therapy.^[88][89] Proponents of the psychic pain theory tend to view clinical depression as a dysfunctional extreme of low mood or mild depression.

• Emotion and memory
• Geriatric Depression Scale
• Hamilton Depression Rating Scale
• Montgomery-Åsberg Depression Rating Scale
• Journeys with the Black Dog
• List of people who have suffered from depression
• Depression and natural therapies

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• 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
• Stanford Depression Research Clinic
• Substance Abuse and Mental Health Services (SAMHSA) – United States Department of Health and Human Services (HHS)

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