Major depressive disorder (MDD), also known simply as depression, is a mental disorder characterized by at least two weeks of low mood that is present across most situations. It is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. People may also occasionally have false beliefs or see or hear things that others cannot. Some people have periods of depression separated by years in which they are normal, while others nearly always have symptoms present. Major depressive disorder can negatively affect a person's personal life, work life, or education, as well as sleeping, eating habits, and general health. Between 2–8% of adults with major depression die by suicide, and about 50% of people who die by suicide had depression or another mood disorder.
The cause is believed to be a combination of genetic, environmental, and psychological factors. Risk factors include a family history of the condition, major life changes, certain medications, chronic health problems, and substance abuse. About 40% of the risk appears to be related to genetics. The diagnosis of major depressive disorder is based on the person's reported experiences and a mental status examination. There is no laboratory test for major depression. Testing, however, may be done to rule out physical conditions that can cause similar symptoms. Major depression is more severe and lasts longer than sadness, which is a normal part of life. The United States Preventive Services Task Force (USPSTF) recommends screening for depression among those over the age 12, while a prior Cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment.
Typically, people are treated with counseling and antidepressant medication. Medication appears to be effective, but the effect may only be significant in the most severely depressed. It is unclear whether medications affect the risk of suicide. Types of counseling used include cognitive behavioral therapy (CBT) and interpersonal therapy. If other measures are not effective, electroconvulsive therapy (ECT) may be considered. Hospitalization may be necessary in cases with a risk of harm to self and may occasionally occur against a person's wishes.
Major depressive disorder affected approximately 216 million people (3% of the world's population) in 2015. The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. Lifetime rates are higher in the developed world (15%) compared to the developing world (11%). It causes the second-most years lived with disability, after lower back pain. The most common time of onset is in a person's 20s and 30s. Females are affected about twice as often as males. The American Psychiatric Association added "major depressive disorder" to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980. It was a split of the previous depressive neurosis in the DSM-II, which also encompassed the conditions now known as dysthymia and adjustment disorder with depressed mood. Those currently or previously affected may be stigmatized.
|Major depressive disorder|
|Other names||Clinical depression, major depression, unipolar depression, unipolar disorder, recurrent depression|
|Vincent van Gogh's 1890 painting|
Sorrowing old man ('At Eternity's Gate')
|Symptoms||Low mood, low self-esteem, loss of interest in normally enjoyable activities, low energy, pain without a clear cause|
|Duration||> 2 weeks|
|Causes||Genetic, environmental, and psychological factors|
|Risk factors||Family history, major life changes, certain medications, chronic health problems, substance abuse|
|Differential diagnosis||Bipolar disorder, ADHD, sadness|
|Treatment||Counseling, antidepressant medication, electroconvulsive therapy, exercise|
|Frequency||216 million (2015)|
Major depression significantly affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health. Its impact on functioning and well-being has been compared to that of other chronic medical conditions, such as diabetes.
A person having a major depressive episode usually exhibits a very low mood, which pervades all aspects of life, and an inability to experience pleasure in activities that were formerly enjoyed. Depressed people may be preoccupied with, or ruminate over, thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness, hopelessness, and self-hatred. In severe cases, depressed people may have symptoms of psychosis. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. Other symptoms of depression include poor concentration and memory (especially in those with melancholic or psychotic features), withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common among the depressed. In the typical pattern, a person wakes very early and cannot get back to sleep. Hypersomnia, or oversleeping, can also happen. Some antidepressants may also cause insomnia due to their stimulating effect.
A depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the World Health Organization's criteria for depression. Appetite often decreases, with resulting weight loss, although increased appetite and weight gain occasionally occur. Family and friends may notice that the person's behavior is either agitated or lethargic. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements. Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson's disease, and chronic obstructive pulmonary disease.
Depressed children may often display an irritable mood rather than a depressed one, and show varying symptoms depending on age and situation. Most lose interest in school and show a decline in academic performance. They may be described as clingy, demanding, dependent, or insecure. Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness."
Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reports that half of those with major depression also have lifetime anxiety and its associated disorders such as generalized anxiety disorder. 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. There are increased rates of alcohol and drug abuse and particularly dependence, and around a third of individuals diagnosed with ADHD develop comorbid depression. Post-traumatic stress disorder and depression often co-occur. Depression may also coexist with attention deficit hyperactivity disorder (ADHD), complicating the diagnosis and treatment of both. Depression is also frequently comorbid with alcohol abuse and personality disorders. Depression can also be exacerbated during particular months (usually winter) for those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, digital media may also be utilised in some situations to improve mood.
Depression and pain often co-occur. One or more pain symptoms are present in 65% of depressed patients, and anywhere from 5 to 85% of patients with pain will be suffering from depression, depending on the setting; there is a lower prevalence in general practice, and higher in specialty clinics. The diagnosis of depression is often delayed or missed, and the outcome can worsen if the depression is noticed but completely misunderstood.
Depression is also associated with a 1.5- to 2-fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. People with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, which further increases their risk of medical complications. In addition, cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care.
The cause of major depressive disorder is unknown. The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis–stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The preexisting vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.
Childhood abuse, either physical, sexual or psychological, are all risk factors for depression, among other psychiatric issues that co-occur such as anxiety and drug abuse. Childhood trauma also correlates with severity of depression, lack of response to treatment and length of illness. However, some are more susceptible to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.
Family and twin studies find that nearly 40% of individual differences in risk for major depressive disorder can be explained by genetic factors. Like most psychiatric disorders, major depressive disorder is likely to be influenced by many individual genetic changes. In 2018, a genome-wide association study discovered 44 variants in the genome linked to risk for major depression. This was followed by a 2019 study that found 102 variants in the genome linked to depression. These results have enabled scientists to calculate polygenic risk scores, which combine the estimated effects across the genome into a single score in order to estimate a person’s genetic liability for depression. Although these scores explain a small proportion (less than 2%) of individual differences in the risk for major depressive disorder.
The 5-HTTLPR, or serotonin transporter promoter gene's short allele has been associated with increased risk of depression. However, since the 1990s, results have been inconsistent, with three recent reviews finding an effect and two finding none. Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. There is no conclusive effects of candidate gene on depression, either alone or in combination with life stress. Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings. There are also other efforts to examine interactions between life stress and polygenic risk for depression.
Depression may also come secondary to a chronic or terminal medical condition, such as HIV/AIDS or asthma, and may be labeled "secondary depression." It is unknown whether the underlying diseases induce depression through effect on quality of life, of through shared etiologies (such as degeneration of the basal ganglia in Parkinson's disease or immune dysregulation in asthma). Depression may also be iatrogenic (the result of healthcare), such as drug-induced depression. Therapies associated with depression include interferons, beta-blockers, isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin-releasing hormone agonist. Drug abuse in early age is also associated with increased risk of developing depression later in life. Depression that occurs as a result of pregnancy is called postpartum depression, and is thought to be the result of hormonal changes associated with pregnancy. Seasonal affective disorder, a type of depression associated with seasonal changes in sunlight, is thought to be the result of decreased sunlight.
The pathophysiology of depression is not yet understood, but the current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA axis dysfunction and structural or functional abnormalities of emotional circuits.
The monoamine theory, derived from the efficacy of monoaminergic drugs in treating depression, was the dominant theory until recently. The theory postulates that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. Firstly, acute depletion of tryptophan, a necessary precursor of serotonin, a monoamine, can cause depression in those in remission or relatives of depressed patients; this suggests that decreased serotonergic neurotransmission is important in depression. Secondly, the correlation between depression risk and polymorphisms in the 5-HTTLPR gene, which codes for serotonin receptors, suggests a link. Third, decreased size of the locus coeruleus, decreased activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression. Furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor D1 binding in the striatum, and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression. Lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression. However, this theory is inconsistent with the fact that serotonin depletion does not cause depression in healthy persons, the fact that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway. One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self-inhibition in raphe nuclei by the increased serotonin mediated by antidepressants. However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls, the finding of increased jugular 5-HIAA in depressed patients that normalized with SSRI treatment, and the preference for carbohydrates in depressed patients. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.
Immune system abnormalities have been observed, including increased levels of cytokines involved in generating sickness behavior (which shares overlap with depression). The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors in treating depression, and normalization of cytokine levels after successful treatment further suggest immune system abnormalities in depression.
HPA axis abnormalities have been suggested in depression given the association of CRHR1 with depression and the increased frequency of dexamethasone test non-suppression in depressed patients. However, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%. These stress-related abnormalities have been hypothesized to be the cause of hippocampal volume reductions seen in depressed patients. Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors. Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.
Theories unifying neuroimaging findings have been proposed. The first model proposed is the "Limbic Cortical Model", which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing. Another model, the "Corito-Striatal model", suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures results in depression. Another model proposes hyperactivity of salience structures in identifying negative stimuli, and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies.
A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist, who records the person's current circumstances, biographical history, current symptoms, and family history. The broad clinical aim is to formulate the relevant biological, psychological, and social factors that may be impacting on the individual's mood. The assessor may also discuss the person's current ways of regulating mood (healthy or otherwise) such as alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans. Specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary-care clinicians. This issue is even more marked in developing countries. The mental health examination may include the use of a rating scale such as the Hamilton Rating Scale for Depression, the Beck Depression Inventory or the Suicide Behaviors Questionnaire-Revised. The score on a rating scale alone is insufficient to diagnose depression to the satisfaction of the DSM or ICD, but it provides an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose.
Primary-care physicians and other non-psychiatrist physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatric physicians, in part because of the physical symptoms that often accompany depression, in addition to many potential patient, provider, and system barriers. A review found that non-psychiatrist physicians miss about two-thirds of cases, though this has improved somewhat in more recent studies.
Before diagnosing a major depressive disorder, in general a doctor 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. Adverse affective reactions to medications or alcohol misuse are often ruled out, as well. Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men. Vitamin D levels might be evaluated, as low levels of vitamin D have been associated with greater risk for depression.
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. Cognitive testing and brain imaging can help distinguish depression from dementia. A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms. In general, investigations are not repeated for a subsequent episode unless there is a medical indication.
No biological tests confirm major depression. Biomarkers of depression have been sought to provide an objective method of diagnosis. There are several potential biomarkers, including brain-derived neurotrophic factor and various functional MRI (fMRI) techniques. One study developed a decision tree model of interpreting a series of fMRI scans taken during various activities. In their subjects, the authors of that study were able to achieve a sensitivity of 80% and a specificity of 87%, corresponding to a negative predictive value of 98% and a positive predictive value of 32% (positive and negative likelihood ratios were 6.15, 0.23, respectively). However, much more research is needed before these tests can be used clinically.
The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems which uses the name depressive episode for a single episode and recurrent depressive disorder for repeated episodes. The latter system is typically used in European countries, while the former is used in the US and many other non-European nations, and the authors of both have worked towards conforming one with the other.
Both DSM-5 and ICD-10 mark out typical (main) depressive symptoms. ICD-10 defines three typical depressive symptoms (depressed mood, anhedonia, and reduced energy), two of which should be present to determine the depressive disorder diagnosis. According to DSM-5, there are two main depressive symptoms- a depressed mood and loss of interest/pleasure in activities (anhedonia). These symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis.
Major depressive disorder is classified as a mood disorder in DSM-5. The diagnosis hinges on the presence of single or recurrent major depressive episodes. Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Unspecified Depressive Disorder 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.
A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks. Episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features—commonly referred to as psychotic depression—is automatically rated as severe. If the patient has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".
DSM-IV-TR excludes cases where the symptoms are a result of bereavement, although it is possible for normal bereavement to evolve into a depressive episode if the mood persists and the characteristic features of a major depressive episode develop. The criteria were criticized because they do not take into account any other aspects of the personal and social context in which depression can occur. In addition, some studies have found little empirical support for the DSM-IV cut-off criteria, indicating they are a diagnostic convention imposed on a continuum of depressive symptoms of varying severity and duration. Bereavement is no longer an exclusion criterion in DSM-5, and it is now up to the clinician to distinguish between normal reactions to a loss and MDD. Excluded are a range of related diagnoses, including dysthymia, which involves a chronic but milder mood disturbance; recurrent brief depression, consisting of briefer depressive episodes; minor depressive disorder, whereby only some symptoms of major depression are present; and adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor. Three new depressive disorders were added to the DSM-5: disruptive mood dysregulation disorder, classified by significant childhood irritability and tantrums, premenstrual dysphoric disorder (PMDD), causing periods of anxiety, depression, or irritability in the week or two before a woman's menstruation, and persistent depressive disorder.
The DSM-5 recognizes six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:
In 2016, the United States Preventive Services Task Force (USPSTF) recommended screening in the adult populations with evidence that it increases the detection of people with depression and with proper treatment improves outcomes. They recommend screening in those between the age of 12 to 18 as well.
To confirm major depressive disorder as the most likely diagnosis, other potential diagnoses must be considered, including dysthymia, adjustment disorder with depressed mood, or bipolar disorder. Dysthymia is a chronic, milder mood disturbance in which a person reports a low mood almost daily over a span of at least two years. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression). Adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode. Bipolar disorder, also known as manic–depressive disorder, is a condition in which depressive phases alternate with periods of mania or hypomania. Although depression is currently categorized as a separate disorder, there is ongoing debate because individuals diagnosed with major depression often experience some hypomanic symptoms, indicating a mood disorder continuum. Further differential diagnoses involve chronic fatigue syndrome.
Other disorders need to be ruled out before diagnosing major depressive disorder. They include depressions due to physical illness, medications, and substance abuse. Depression due to physical illness is diagnosed as a mood disorder due to a general medical condition. This condition is determined based on history, laboratory findings, or physical examination. When the depression is caused by a medication, drug of abuse, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance-induced mood disorder in the DSM-IV-TR).
Behavioral interventions, such as interpersonal therapy and cognitive-behavioral therapy, are effective at preventing new onset depression. Because such interventions appear to be most effective when delivered to individuals or small groups, it has been suggested that they may be able to reach their large target audience most efficiently through the Internet.
However, an earlier meta-analysis found preventive programs with a competence-enhancing component to be superior to behavior-oriented programs overall, and found behavioral programs to be particularly unhelpful for older people, for whom social support programs were uniquely beneficial. In addition, the programs that best prevented depression comprised more than eight sessions, each lasting between 60 and 90 minutes, were provided by a combination of lay and professional workers, had a high-quality research design, reported attrition rates, and had a well-defined intervention.
The Netherlands mental health care system provides preventive interventions, such as the "Coping with Depression" course (CWD) for people with sub-threshold depression. The course is claimed to be the most successful of psychoeducational interventions for the treatment and prevention of depression (both for its adaptability to various populations and its results), with a risk reduction of 38% in major depression and an efficacy as a treatment comparing favorably to other psychotherapies.
The three most common treatments for depression are psychotherapy, medication, and electroconvulsive therapy. Psychotherapy is the treatment of choice (over medication) for people under 18. The UK National Institute for Health and Care Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression, because the risk-benefit ratio is poor. The guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for:
The guidelines further note that antidepressant treatment should be continued for at least six months to reduce the risk of relapse, and that SSRIs are better tolerated than tricyclic antidepressants.
American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors including severity of symptoms, co-existing disorders, prior treatment experience, and patient preference. Options may include pharmacotherapy, psychotherapy, exercise, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all patients with severe depression unless ECT is planned. There is evidence that collaborative care by a team of health care practitioners produces better results than routine single-practitioner care.
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. A 2014 Cochrane review found insufficient evidence to determine the effectiveness of psychological versus medical therapy in children.
Physical exercise is recommended for management of mild depression, and has a moderate effect on symptoms. Exercise has also been found to be effective for (unipolar) major depression. It is equivalent to the use of medications or psychological therapies in most people. In older people it does appear to decrease depression. Exercise may be recommended to people who are willing, motivated, and physically healthy enough to participate in an exercise program as treatment.
There is a small amount of evidence that skipping a night's sleep may improve depressive symptoms, with the effects usually showing up within a day. This effect is usually temporary. Besides sleepiness, this method can cause a side effect of mania or hypomania.
Besides exercise, sleep and diet may play a role in depression, and interventions in these areas may be an effective add-on to conventional methods.
Psychotherapy can be delivered to individuals, groups, or families by mental health professionals. A 2015 review found that cognitive behavioral therapy appears to be similar to antidepressant medication in terms of effect. A 2012 review found psychotherapy to be better than no treatment but not other treatments. With more complex and chronic forms of depression, a combination of medication and psychotherapy may be used. A 2014 Cochrane review found that work-directed interventions combined with clinical interventions helped to reduce sick days taken by people with depression. There is moderate-quality evidence that psychological therapies are a useful addition to standard antidepressant treatment of treatment-resistant depression in the short term.
Psychotherapy has been shown to be effective in older people. Successful psychotherapy appears to reduce the recurrence of depression even after it has been terminated or replaced by occasional booster sessions.
Cognitive behavioral therapy (CBT) currently has the most research evidence for the treatment of depression in children and adolescents, and CBT and interpersonal psychotherapy (IPT) are preferred therapies for adolescent depression. In people under 18, according to the National Institute for Health and Clinical Excellence, medication should be offered only in conjunction with a psychological therapy, such as CBT, interpersonal therapy, or family therapy. Cognitive behavioral therapy has also been shown to reduce the number of sick days taken by people with depression, when used in conjunction with primary care.
The most-studied form of psychotherapy for depression is CBT, which teaches clients to challenge self-defeating, but enduring ways of thinking (cognitions) and change counter-productive behaviors. Research beginning in the mid-1990s suggested that CBT could perform as well as or better than antidepressants in patients with moderate to severe depression. CBT may be effective in depressed adolescents, although its effects on severe episodes are not definitively known. Several variables predict success for cognitive behavioral therapy in adolescents: higher levels of rational thoughts, less hopelessness, fewer negative thoughts, and fewer cognitive distortions. CBT is particularly beneficial in preventing relapse.
Cognitive behavioral therapy and occupational programs (including modification of work activities and assistance) have been shown to be effective in reducing sick days taken by workers with depression.
Several variants of cognitive behavior therapy have been used in those with depression, the most notable being rational emotive behavior therapy, and mindfulness-based cognitive therapy. Mindfulness-based stress reduction programs may reduce depression symptoms. Mindfulness programs also appear to be a promising intervention in youth.
Psychoanalysis is a school of thought, founded by Sigmund Freud, which emphasizes the resolution of unconscious mental conflicts. Psychoanalytic techniques are used by some practitioners to treat clients presenting with major depression. A more widely practiced therapy, called psychodynamic psychotherapy, is in the tradition of psychoanalysis but less intensive, meeting once or twice a week. It also tends to focus more on the person's immediate problems, and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials of Short Psychodynamic Supportive Psychotherapy, this modification was found to be as effective as medication for mild to moderate depression.
Conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression. Stronger evidence supports the usefulness of antidepressants in the treatment of depression that is chronic (dysthymia) or severe.
While small benefits were found, researchers Irving Kirsch and Thomas Moore state they may be due to issues with the trials rather than a true effect of the medication. In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance. Similar results were obtained in a meta-analysis by Fornier.
A review commissioned by the National Institute for Health and Care Excellence (UK) concluded that there is strong evidence that selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, paroxetine, and sertraline, have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. Similarly, a Cochrane systematic review of clinical trials of the generic tricyclic antidepressant amitriptyline concluded that there is strong evidence that its efficacy is superior to placebo.
In 2014 the U.S. Food and Drug Administration published a systematic review of all antidepressant maintenance trials submitted to the agency between 1985 and 2012. The authors concluded that maintenance treatment reduced the risk of relapse by 52% compared to placebo, and that this effect was primarily due to recurrent depression in the placebo group rather than a drug withdrawal effect.
To find the most effective antidepressant medication with minimal 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. Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimize the chance of recurrence, and even up to one year of continuation is recommended. People with chronic depression may need to take medication indefinitely to avoid relapse.
SSRIs are the primary medications prescribed, owing to their relatively mild side-effects, and because they are less toxic in overdose than other antidepressants. People who do not respond to one SSRI can be switched to another antidepressant, and this results in improvement in almost 50% of cases. Another option is to switch to the atypical antidepressant bupropion. Venlafaxine, an antidepressant with a different mechanism of action, may be modestly more effective than SSRIs. However, venlafaxine is not recommended in the UK as a first-line treatment because of evidence suggesting its risks may outweigh benefits, and it is specifically discouraged in children and adolescents.
For children, some research has supported the use of the SSRI antidepressant fluoxetine. The benefit however appears to be slight in children, while other antidepressants have not been shown to be effective. Medications are not recommended in children with mild disease. There is also insufficient evidence to determine effectiveness in those with depression complicated by dementia. Any antidepressant can cause low blood sodium levels; nevertheless, it has been reported more often with SSRIs. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating atypical antidepressant mirtazapine can be used in such cases.
Irreversible monoamine oxidase inhibitors, an older class of antidepressants, have been plagued by potentially life-threatening dietary and drug interactions. They are still used only rarely, although newer and better-tolerated agents of this class have been developed. The safety profile is different with reversible monoamine oxidase inhibitors, such as moclobemide, where the risk of serious dietary interactions is negligible and dietary restrictions are less strict.
For children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behavior in those treated with SSRIs. For adults, it is unclear whether SSRIs affect the risk of suicidality. One review found no connection; another an increased risk; and a third no risk in those 25–65 years old and a decreased risk in those more than 65. A black box warning was introduced in the United States in 2007 on SSRIs and other antidepressant medications due to the increased risk of suicide in patients younger than 24 years old. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.
There is some evidence that omega-3 fatty acids fish oil supplements containing high levels of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) are effective in the treatment of, but not the prevention of major depression. However, a Cochrane review determined there was insufficient high quality evidence to suggest omega-3 fatty acids were effective in depression. There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D-deficient. There is some preliminary evidence that COX-2 inhibitors, such as celecoxib, have a beneficial effect on major depression. Lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression to nearly the same levels as the general population. There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed. Low-dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms in people who have tried multiple courses of medication. Limited evidence suggests stimulants, such as amphetamine and modafinil, may be effective in the short term, or as adjuvant therapy. Also, it is suggested that folate supplements may have a role in depression management. There is tentative evidence for benefit from testosterone in males.
Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses.:1880 ECT is used with informed consent as a last line of intervention for major depressive disorder.
A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond relapse within twelve months.
Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anesthesia.:259 Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.
A usual course of ECT involves multiple administrations, typically given two or three times per week, until the patient is no longer suffering symptoms. ECT is administered under anesthesia with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.
Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a noninvasive method used to stimulate small regions of the brain. TMS was approved by the FDA for treatment-resistant major depressive disorder (trMDD) in 2008 and as of 2014 evidence supports that it is probably effective. The American Psychiatric Association the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed TMS for trMDD.
Bright light therapy reduces depression symptom severity, with benefit for both seasonal affective disorder and for nonseasonal depression, and an effect similar to those for conventional antidepressants. For nonseasonal depression, adding light therapy to the standard antidepressant treatment was not effective. For nonseasonal depression, where light was used mostly in combination with antidepressants or wake therapy, a moderate effect was found, with response better than control treatment in high-quality studies, in studies that applied morning light treatment, and with people who respond to total or partial sleep deprivation. Both analyses noted poor quality, short duration, and small size of most of the reviewed studies. There is insufficient evidence for Reiki and dance movement therapy in depression.
Major depressive episodes often resolve over time whether or not they are treated. Outpatients on a waiting list show a 10–15% reduction in symptoms within a few months, with approximately 20% no longer meeting the full criteria for a depressive disorder. The median duration of an episode has been estimated to be 23 weeks, with the highest rate of recovery in the first three months.
Studies have shown that 80% of those suffering from their first major depressive episode will suffer from at least one more during their life, with a lifetime average of 4 episodes. Other general population studies indicate that around half those who have an episode recover (whether treated or not) and remain well, while the other half will have at least one more, and around 15% of those experience chronic recurrence. Studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence.
A high proportion of people who experience full symptomatic remission still have at least one not fully resolved symptom after treatment. Recurrence or chronicity 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 indicate 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.
People experiencing repeated episodes of depression require ongoing treatment in order to prevent more severe, long-term depression. In some cases, people must take medications for the rest of their lives.
Cases when outcome is poor are associated with inappropriate treatment, severe initial symptoms including psychosis, early age of onset, previous episodes, incomplete recovery after one year of treatment, pre-existing severe mental or medical disorder, and family dysfunction.
Depressed individuals have a shorter life expectancy than those without depression, in part because depressed patients are at risk of dying of suicide. However, they also have a higher rate of dying from other causes, being more susceptible to medical conditions such as heart disease. Up to 60% of people who die of 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. The lifetime risk of suicide associated with a diagnosis of major depression in the US is estimated at 3.4%, which averages two highly disparate figures of almost 7% for men and 1% for women (although suicide attempts are more frequent in women). The estimate is substantially lower than a previously accepted figure of 15%, which had been derived from older studies of hospitalized patients.
Depression is often associated with unemployment and poverty. Major depression is currently the leading cause of disease burden in North America and other high-income countries, and the fourth-leading cause worldwide. In the year 2030, it is predicted to be the second-leading cause of disease burden worldwide after HIV, according to the WHO. Delay or failure in seeking treatment after relapse and the failure of health professionals to provide treatment are two barriers to reducing disability.
Major depressive disorder affects approximately 216 million people in 2015 (3% of the global population). The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. In most countries the number of people who have depression during their lives falls within an 8–18% range. In North America, the probability of having a major depressive episode within a year-long period is 3–5% for males and 8–10% for females. Major depression is about twice as common in women as in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this. The relative increase in occurrence is related to pubertal development rather than chronological age, reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors. Depression is a major cause of disability worldwide.
People are most likely to develop their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60. The risk of major depression is increased with neurological conditions such as stroke, Parkinson's disease, or multiple sclerosis, and during the first year after childbirth. It is also more common after cardiovascular illnesses, and is related more to those with a poor cardiac disease outcome than to a better one. Studies conflict on the prevalence of depression in the elderly, but most data suggest there is a reduction in this age group. Depressive disorders are more common in urban populations than in rural ones and the prevalence is increased in groups with poorer socioeconomic factors, e.g., homelessness.
The Ancient Greek physician Hippocrates described a syndrome of melancholia as a distinct disease with particular mental and physical symptoms; he characterized all "fears and despondencies, if they last a long time" as being symptomatic of the ailment. It was a similar but 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.
The term depression itself was derived from the Latin verb deprimere, "to press down". From the 14th century, "to depress" meant to subjugate or to bring down in spirits. It was used in 1665 in English author Richard Baker's Chronicle to refer to someone having "a great depression of spirit", and by English author Samuel Johnson in a similar sense in 1753. The term also came into use in physiology and economics. An early usage referring to a psychiatric symptom was by French psychiatrist Louis Delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function. Since Aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. The newer concept abandoned these associations and through the 19th century, became more associated with women.
Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; German psychiatrist Emil Kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states.
Sigmund Freud likened the state of melancholia to mourning in his 1917 paper Mourning and Melancholia. He theorized that objective loss, such as the loss of a valued relationship through death or a romantic break-up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, narcissistic process called the libidinal cathexis of the ego. Such loss results in severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively but the ego itself is compromised. The patient's decline of self-perception is revealed in his belief of his own blame, inferiority, and unworthiness. He also emphasized early life experiences as a predisposing factor. Adolf Meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individual's life, and argued that the term depression should be used instead of melancholia. The first version of the DSM (DSM-I, 1952) contained depressive reaction and the DSM-II (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, and also included a depressive type of manic-depressive psychosis within Major affective disorders.
In the mid-20th century, researchers theorized that depression was caused by a chemical imbalance in neurotransmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms. The chemical imbalance theory has never been proven.
The term Major depressive disorder was introduced by a group of US clinicians in the mid-1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the "Research Diagnostic Criteria", building on earlier Feighner Criteria), and was incorporated into the DSM-III in 1980. To maintain consistency the ICD-10 used the same criteria, with only minor alterations, but using the DSM diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes. The ancient idea of melancholia still survives in the notion of a melancholic subtype.
The new definitions of depression were widely accepted, albeit with some conflicting findings and views. There have been some continued empirically based arguments for a return to the diagnosis of melancholia. There has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s.
The term "depression" is used in a number of different ways. It is often used to mean this syndrome but may refer to other mood disorders or simply to a low mood. People's conceptualizations of depression vary widely, both within and among cultures. "Because of the lack of scientific certainty," one commentator has observed, "the debate over depression turns on questions of language. What we call it—'disease,' 'disorder,' 'state of mind'—affects how we view, diagnose, and treat it." There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or is an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection of individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle.
The diagnosis is less common in some countries, such as China. It has been argued that the Chinese traditionally deny or somatize emotional depression (although since the early 1980s, the Chinese denial of depression may have modified). Alternatively, it may be that Western cultures reframe and elevate some expressions of human distress to disorder status. Australian professor Gordon Parker and others have argued that the Western concept of depression "medicalizes" sadness or misery. Similarly, Hungarian-American psychiatrist Thomas Szasz and others argue that depression is a metaphorical illness that is inappropriately regarded as an actual disease. There has also been concern that the DSM, as well as the field of descriptive psychiatry that employs it, tends to reify abstract phenomena such as depression, which may in fact be social constructs. American archetypal psychologist James Hillman writes that depression can be healthy for the soul, insofar as "it brings refuge, limitation, focus, gravity, weight, and humble powerlessness." Hillman argues that therapeutic attempts to eliminate depression echo the Christian theme of resurrection, but have the unfortunate effect of demonizing a soulful state of being.
Historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. Nevertheless, analysis or interpretation of letters, journals, artwork, writings, or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. People who may have had depression include English author Mary Shelley, American-British writer Henry James, and American president Abraham Lincoln. Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen and American playwright and novelist Tennessee Williams. Some pioneering psychologists, such as Americans William James and John B. Watson, dealt with their own depression.
There has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to Aristotelian times. British literature gives many examples of reflections on depression. English philosopher John Stuart Mill experienced a several-months-long period of what he called "a dull state of nerves", when one is "unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent". He quoted English poet Samuel Taylor Coleridge's "Dejection" as a perfect description of his case: "A grief without a pang, void, dark and drear, / A drowsy, stifled, unimpassioned grief, / Which finds no natural outlet or relief / In word, or sigh, or tear." English writer Samuel Johnson used the term "the black dog" in the 1780s to describe his own depression, and it was subsequently popularized by depression sufferer former British Prime Minister Sir Winston Churchill.
Social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. Public opinions on treatment differ markedly to those of health professionals; alternative treatments are held to be more helpful than pharmacological ones, which are viewed poorly. In the UK, the Royal College of Psychiatrists and the Royal College of General Practitioners conducted a joint Five-year Defeat Depression campaign to educate and reduce stigma from 1992 to 1996; a MORI study conducted afterwards showed a small positive change in public attitudes to depression and treatment.
Depression is especially common among those over 65 years of age and increases in frequency beyond this age. In addition, the risk of depression increases in relation to the frailty of the individual. Depression is one of the most important factors which negatively impact quality of life in adults, as well as the elderly. Both symptoms and treatment among the elderly differ from those of the rest of the population.
As with many other diseases, it is common among the elderly not to present with classical depressive symptoms. Diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases. Treatment differs in that studies of SSRIs have shown lesser and often inadequate effects among the elderly, while other drugs, such as duloxetine (a serotonin-norepinephrine reuptake inhibitor), with more clear effects have adverse effects, such as dizziness, dryness of the mouth, diarrhea and constipation, which can be especially difficult to handle among the elderly.
Problem solving therapy was, as of 2015, the only psychological therapy with proven effect, and can be likened to a simpler form of cognitive behavioral therapy. However, elderly with depression are seldom offered any psychological treatment, and the evidence proving other treatments effective is incomplete. ECT has been used in the elderly, and register-studies suggest it is effective, although less so as compared to the rest of the population. The risks involved with treatment of depression among the elderly as opposed to benefits are not entirely clear.
MRI scans of patients with depression have revealed a number of differences in brain structure compared to those who are not depressed. Meta-analyses of neuroimaging studies in major depression reported that, compared to controls, depressed patients had increased volume of the lateral ventricles and adrenal gland and smaller volumes of the basal ganglia, thalamus, hippocampus, and frontal lobe (including the orbitofrontal cortex and gyrus rectus). Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.
Trials are looking at the effects of botulinum toxins on depression. The idea is that the drug is used to make the person look less frowning and that this stops the negative facial feedback from the face. In 2015 results showed, however, that the partly positive effects that had been observed until then could have been due to placebo effects.
In 2018, the US Food and Drug Administration (FDA) approved a Phase 2 study on psilocybin in the treatment of treatment-resistant depression and granted Breakthrough Therapy Designation.
Models of depression in animals for the purpose of study include iatrogenic depression models (such as drug-induced), forced swim tests, tail suspension test, and learned helplessness models. Criteria frequently used to assess depression in animals include expression of despair, neurovegetative changes, and anhedonia, as many other criteria for depression are untestable in animals, such as guilt and suicidality.
Half of all completed suicides are related to depressive and other mood disorders
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Agomelatine is an atypical antidepressant used to treat major depressive disorder. One review found that it does not appear to be better than other antidepressants. Another review found it was similarly effective to many other antidepressants.Common side effects include weight gain, feeling tired, liver problems, nausea, headaches, and anxiety. Due to potential liver problems ongoing blood tests are recommended. Its use is not recommended in people with dementia or over the age of 75. There is tentative evidence that it may have less side effects than some other antidepressants. It works by stimulating melatonin receptors and blocking serotonin receptors.Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010. Its use is not approved in the United States and efforts to get approval were ended in 2011. It was developed by the pharmaceutical company Servier. In the United Kingdom a month of treatment costs the NHS about 30 pounds as of 2019.Amitifadine
Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience It was under development for the treatment of major depressive disorder, but in May 2013, it was reported that the drug failed to show superior efficacy to placebo in a phase IIb/IIIa clinical trial. It was suggested that this may have been due to the drug being underdosed. In September 2017, development of amitifadine for the treatment of major depressive disorder was finally officially discontinued. As of September 2017, it is still listed as being under development for the treatment of alcoholism and smoking withdrawal.Biology of depression
Scientific studies have found that numerous brain areas show altered activity in people with major depressive disorder, and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.Brexpiprazole
Brexpiprazole, sold under the brand name Rexulti, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug received FDA approval on July 13, 2015 for the treatment of schizophrenia, and as an adjunctive treatment for depression. It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).The drug was developed by Otsuka and Lundbeck, and is considered to be a successor of Otsuka's top-selling atypical antipsychotic aripiprazole (Abilify). Otsuka's U.S. patent on aripiprazole expired on October 20, 2014; and a generic was approved in April, 2015.Depression in childhood and adolescence
Depression is a state of low mood and aversion to activity. It may be a normal reaction to occurring life events or circumstances, a symptom of a medical condition, a side effect of drugs or medical treatments, or a symptom of certain psychiatric syndromes, such as the mood disorders major depressive disorder and dysthymia. Depression in childhood and adolescence is similar to adult major depressive disorder, although young sufferers may exhibit increased irritability or aggressive and self-destructive behavior, rather than the all-encompassing sadness associated with adult forms of depression. Children who are under stress, experience loss, or have attention, learning, behavioral, or anxiety disorders are at a higher risk for depression. Childhood depression is often comorbid with mental disorders outside of other mood disorders; most commonly anxiety disorder and conduct disorder. Depression also tends to run in families. Psychologists have developed different treatments to assist children and adolescents suffering from depression, though the legitimacy of the diagnosis of childhood depression as a psychiatric disorder, as well as the efficacy of various methods of assessment and treatment, remains controversial.Desvenlafaxine
Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat major depressive disorder. Evidence supports a benefit up to eight weeks. It appears less effective than its parent compound venlafaxine. It is taken by mouth.Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure. A withdrawal syndrome may occur if the dose is rapidly decreased. It is unclear if use during pregnancy or breastfeeding is safe. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.Desvenlafaxine was approved for medical use in the United States in 2008. Use in Europe was declined in 2009. In the United States the wholesale cost is about 25.20 USD per month. In 2016, it was the 272nd most prescribed medication in the United States, with more than a million prescriptions.Duloxetine
Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, and neuropathic pain. It is taken by mouth.Common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating. Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. It is a serotonin–norepinephrine reuptake inhibitor. How it works is not entirely clear.Duloxetine was approved for medical use in the United States in 2004. It is available as a generic medication. In the United States the wholesale cost per dose is about 0.20 USD as of 2018. In 2016 it was the 48th most prescribed medication in the United States with more than 15 million prescriptions.Dysthymia
Persistent depressive disorder (PDD), formerly known as dysthymia, is a mood disorder consisting of the same cognitive and physical problems as depression, with less severe but longer-lasting symptoms. The concept was coined by Robert Spitzer as a replacement for the term "depressive personality" in the late 1970s.According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, published in 1994 (DSM-IV), dysthymia is a serious state of chronic depression, which persists for at least two years (one year for children and adolescents). Dysthymia is less acute and severe than major depressive disorder. As dysthymia is a chronic disorder, sufferers may experience symptoms for many years before it is diagnosed, if diagnosis occurs at all. As a result, they may believe that depression is a part of their character, so they may not even discuss their symptoms with doctors, family members or friends.
Dysthymia often co-occurs with other mental disorders. A "double depression" is the occurrence of episodes of major depression in addition to dysthymia. Switching between periods of dysthymic moods and periods of hypomanic moods is indicative of cyclothymia, which is a mild variant of bipolar disorder.
In the DSM-5, dysthymia is replaced by persistent depressive disorder. This new condition includes both chronic major depressive disorder and the previous dysthymic disorder. The reason for this change is that there was no evidence for meaningful differences between these two conditions.The term is from Ancient Greek δυσθυμία, meaning bad state of mind.Levomilnacipran
Levomilnacipran (brand name Fetzima) is an antidepressant which was approved in the United States in 2013 for the treatment of major depressive disorder (MDD) in adults. It is the levorotatory enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin–norepinephrine reuptake inhibitor (SNRI).Melancholic depression
Melancholic depression, or depression with melancholic features, is a DSM-IV subtype of clinical depression requiring at least one of the following symptoms:
Anhedonia (the inability to find pleasure in positive things)
Lack of mood reactivity (i.e. mood does not improve in response to positive events)And at least three of the following:
Depression that is subjectively different from grief or loss
Severe weight loss or loss of appetite
Psychomotor agitation or retardation
Early morning awakening
Guilt that is excessive
Worse mood in the morningMelancholic features apply to an episode of depression that occurs as part of either major depressive disorder or bipolar disorder I or II.Melancholic depression is often considered to be a biologically based and particularly severe form of depression. Treatment involves antidepressants, electroconvulsive therapy, or other empirically supported treatments such as cognitive behavioral therapy and interpersonal therapy for depression. A 2008 analysis of a large study of patients with unipolar major depression found a rate of 23.5% for melancholic features. It was the first form of depression extensively studied, and many of the early symptom checklists for depression reflect this.
The incidence of melancholic depression has been found to increase when the temperature and/or sunlight are low.
According to the DSM-IV, the "melancholic features" specifier may be applied to the following only:
Major depressive episode, single episode
Major depressive episode, recurrent episode
Bipolar I disorder, most recent episode depressed
Bipolar II disorder, most recent episode depressedMelancholy
Melancholy may refer to:
Melancholia, one of the four temperaments in pre-modern medicine and proto-psychology, representing a state of low mood
Depression (mood), a state of low mood, also known as melancholy
Major depressive disorder, a mood disorder historically called melancholyMinor depressive disorder
Minor depressive disorder, also known as minor depression, is a mood disorder that does not meet the full criteria for major depressive disorder but at least two depressive symptoms are present for two weeks. These symptoms can be seen in many different psychiatric and mental disorders, which can lead to more specific diagnoses of an individual's condition. However, some of the situations might not fall under specific categories listed in the Diagnostic and Statistical Manual of Mental Disorders. Minor depressive disorder is an example of one of these nonspecific diagnoses, as it is a disorder classified in the DSM-IV-TR under the category Depressive Disorder Not Otherwise Specified (DD-NOS). The classification of NOS depressive disorders is up for debate. Minor depressive disorder as a term was never an officially accepted term, but was listed in Appendix B of the DSM-IV-TR. This is the only version of the DSM that contains the term, as the prior versions and the most recent edition, DSM-5, does not mention it.A person is considered to have minor depressive disorder if they experience 2 to 4 depressive symptoms, with one of them being either depressed mood or loss of interest or pleasure, during a 2-week period. The person must not have experienced the symptoms for 2 years and there must not have been one specific event that caused the symptoms to arise. Although not all cases of minor depressive disorder are deemed in need of treatment, some cases are treated similarly to major depressive disorder. This treatment includes cognitive behavioral therapy (CBT), anti-depressant medication, and combination therapy. A lot of research supports the notion that minor depressive disorder is an early stage of major depressive disorder, or that it is simply highly predictive of subsequent major depressive disorder.Mixed affective state
A mixed affective state, formerly known as a mixed-manic or mixed episode, has been defined as a state wherein features unique to both depression and mania—such as despair, fatigue, morbid or suicidal ideation, racing thoughts, pressure of activity, and heightened irritability—occur either simultaneously or in very short succession.
Previously, the diagnostic criteria for both a manic and depressive episode had to be met in a consistent and sustained fashion, with symptoms enduring for at least a week (or any duration if psychiatric hospitalization was required), thereby restricting the official acknowledgement of mixed affective states to only a minority of patients with bipolar I disorder. In current DSM-5 nomenclature, however, a "mixed episode" no longer stands as an episode of illness unto itself; rather, the symptomology specifier "with mixed features" can be applied to any major affective episode (manic, hypomanic, or depressive), meaning that they are now officially recognized in patients with, in addition to bipolar I disorder, bipolar II disorder and, by convention, major depressive disorder. A depressive mixed state in a patient, however, even in the absence of discrete periods of mania or hypomania, effectively rules out unipolar depression.
Although convention dictates diagnosing such patients with major depressive disorder, it is more appropriate to classify such a patient as having an "Other Specified Bipolar or Related Disorder" and following up such patients in the long-term, to ascertain the eventual appearance of an episode of mania or hypomania (with or without mixed features), which would prompt diagnostic revision. As of now the diagnosis is only made as depression initially and later modified to agitated depression. In those uncommon cases wherein the diagnostic criteria for both a manic and depressive episode are met, constituting what were heretofore classified as "mixed episodes", such a patient would be diagnosed as having a "manic episode with mixed features", because of the substantial social and occupational dysfunction inherent in such a state.ORG-26576
ORG-26576 is an ampakine originally developed by Cortex Pharmaceuticals and then licensed to Organon International for development. In animal studies it has been shown to effectively potentiate AMPA receptor function, leading to increased BDNF release and enhanced neuronal differentiation and survival, as well as producing nootropic effects in standardised assays. Development as an antidepressant has been halted due to a failed Phase II trial for major depressive disorder.Psychomotor agitation
Psychomotor agitation is a spectrum of disorders characterized by unintentional and purposeless motions and restlessness, often accompanied by emotional distress, but not always. Typical manifestations include pacing around a room, wringing the hands, uncontrolled tongue movement, pulling off clothing and putting it back on, and other similar actions. In more severe cases, the motions may become harmful to the individual, such as ripping, tearing, or chewing at the skin around one's fingernails, lips, or other body parts to the point of bleeding. Psychomotor agitation is typically found in major depressive disorder or obsessive-compulsive disorder, and sometimes the manic phase in bipolar disorder, though it can also be a result of an excess intake of stimulants. It can also be caused by severe hyponatremia. The middle-aged and the elderly are more at risk to express it.Psychotic depression
Psychotic depression, also known as depressive psychosis, is a major depressive episode that is accompanied by psychotic symptoms. It can occur in the context of bipolar disorder or major depressive disorder. It can be difficult to distinguish from schizoaffective disorder, a diagnosis that requires the presence of psychotic symptoms for at least two weeks without any mood symptoms present. Unipolar psychotic depression requires that the psychotic features occur only during episodes of major depression. Diagnosis using the DSM-5 involves meeting the criteria for a major depressive episode, along with the criteria for "mood-congruent or mood-incongruent psychotic features" specifier.Rapastinel
Rapastinel (INN) (former developmental code names GLYX-13, BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder. It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%). The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder. As of 2015, the drug had completed phase II clinical development for this indication. On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.
Rapastinel belongs to a group of compounds, referred to as glyxins (hence the original developmental code name of rapastinel, GLYX-13), that were derived via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor. The glyxins were invented by Joseph Moskal, the co-founder of Naurex. Glyxins and B6B21 do not bind to the glycine site of the NMDA receptor but rather to a different regulatory site on the NMDA receptor complex that serves to allosterically modulate the glycine site. As such, rapastinel is technically an allosteric modulator of the glycine site of the NMDA receptor, and hence is more accurately described as a functional glycine site weak partial agonist.In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models. It has been shown to increase Schaffer collateral-CA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats. Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions. Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at non-ataxic doses.Apimostinel (NRX-1074), an analogue of rapastinel with the same mechanism of action but dramatically improved potency, is being developed by the same company as a follow-on compound to rapastinel.
On March 6, 2019, Allergan announced rapastinel failed to differentiate from placebo during phase III trial.Serotonin–norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD) and can also treat anxiety disorders, obsessive–compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms.
SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.
The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms.SNRIs, along with SSRIs and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have gradually replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as the drugs of choice for the treatment of MDD due to their improved tolerability and safety profile.A closely related type of drug is a serotonin–norepinephrine releasing agent (SNRA), for instance the withdrawn appetite suppressant fenfluramine/phentermine (Fen-Phen). SNRAs primarily induce the release rather than inhibit the reuptake of serotonin and norepinephrine.Zuranolone
Zuranolone (INN; developmental code SAGE-217) is an investigational medication which is under development by SAGE Therapeutics for the treatment of major depressive disorder, postpartum depression, essential tremor, Parkinson's disease, insomnia, and seizures. It is a synthetic, orally active, inhibitory pregnane neurosteroid, and acts as a positive allosteric modulator of the GABAA receptor. The drug was developed as an improvement of allopregnanolone (brexanolone) with high oral bioavailability and a biological half-life suitable for once-daily administration. As of February 2018, SAGE-217 is in phase II clinical trials for major depressive disorder, postpartum depression, essential tremor, and Parkinson's disease and is in phase I clinical studies for insomnia and seizures. It is also in the preclinical stage of development for dyskinesias.
Mood disorder (F30–F39, 296)