<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Neisseria meningitidis and can you explain it in depth? [/INST] Neisseria meningitidis, often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a coccus because it is round, and more specifically a diplococcus because of its tendency to form pairs.
About 10% of adults are carriers of the bacteria in their nasopharynx. As an exclusively human pathogen, it is the main cause of bacterial meningitis in children and young adults, causing developmental impairment and death in about 10% of cases. It causes the only form of bacterial meningitis known to occur epidemically, mainly in Africa and Asia. It occurs worldwide in both epidemic and endemic form.N. meningitidis is spread through saliva and respiratory secretions during coughing, sneezing, kissing, chewing on toys and through sharing a source of fresh water. It has also been reported to be transmitted through oral sex and cause urethritis in men. It infects its host cells by sticking to them with long thin extensions called pili and the surface-exposed proteins Opa and Opc and has several virulence factors.

Signs and symptoms
Meningococcus can cause meningitis and other forms of meningococcal disease. It initially produces general symptoms like fatigue, fever, and headache and can rapidly progress to neck stiffness, coma and death in 10% of cases. Petechiae occur in about 50% of cases. Chance of survival is highly correlated with blood cortisol levels, with lower levels prior to steroid administration corresponding with increased patient mortality. Symptoms of meningococcal meningitis are easily confused with those caused by other bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae. Suspicion of meningitis is a medical emergency and immediate medical assessment is recommended. Current guidance in the United Kingdom is that if a case of meningococcal meningitis or septicaemia (infection of the blood) is suspected, intravenous antibiotics should be given and the ill person admitted to the hospital. This means that laboratory tests may be less likely to confirm the presence of Neisseria meningitidis as the antibiotics will dramatically lower the number of bacteria in the body. The UK guidance is based on the idea that the reduced ability to identify the bacteria is outweighed by reduced chance of death.
Septicaemia caused by Neisseria meningitidis has received much less public attention than meningococcal meningitis even though septicaemia has been linked to infant deaths. Meningococcal septicaemia typically causes a purpuric rash, that does not lose its color when pressed with a glass slide ("non-blanching") and does not cause the classical symptoms of meningitis. This means the condition may be ignored by those not aware of the significance of the rash. Septicaemia carries an approximate 50% mortality rate over a few hours from initial onset.
Other severe complications include Waterhouse–Friderichsen syndrome, a massive, usually bilateral, hemorrhage into the adrenal glands caused by fulminant meningococcemia, adrenal insufficiency, and disseminated intravascular coagulation.Not all instances of a purpura-like rash are due to meningococcal septicaemia; other possible causes, such as idiopathic thrombocytopenic purpura (ITP; a platelet disorder) and Henoch–Schönlein purpura, also need prompt investigation.

Microbiology
N. meningitidis is a Gram-negative diplococcus since it has an outer and inner membranes with a thin layer of peptidoglycan in between. It is 0.6–1.0 micrometers in size. It tests positive for the enzyme cytochrome c oxidase.

Habitat
N. meningitidis is a part of the normal nonpathogenic flora in the nasopharynx of up to 8–25% of adults. It colonizes and infects only humans, and has never been isolated from other animals. This is thought to result from the bacteriums inability to get iron from sources other than human transferrin and lactoferrin.

Subtypes
Disease-causing strains are classified according to the antigenic structure of their polysaccharide capsule. Serotype distribution varies markedly around the world. Among the 13 identified capsular types of N. meningitidis, six (A, B, C, W135, X, and Y) account for most disease cases worldwide. Type A has been the most prevalent in Africa and Asia, but is rare/practically absent in North America. In the United States, serogroup B is the predominant cause of disease and mortality, followed by serogroup C. The multiple subtypes have hindered development of a universal vaccine for meningococcal disease.

Pathogenesis
Virulence
Lipooligosaccharide (LOS) is a component of the outer membrane of N. meningitidis. This acts as an endotoxin and is responsible for septic shock and hemorrhage due to the destruction of red blood cells. Other virulence factors include a polysaccharide capsule which prevents host phagocytosis and aids in evasion of the host immune response. Adhesion is another key virulence strategy to successfully invade host cell. There are several known proteins that are involved in adhesion and invasion, or mediate interactions with specific host cell receptors. These include the Type IV pilin adhesin which mediates attachment of the bacterium to the epithelial cells of the nasopharynx, surface-exposed Opa and Opc proteins which mediate interactions with specific host cell receptors, and NadA which is involved in adhesion.Pathogenic meningococci that have invaded into the bloodstream must be able to survive in the new niche, this is facilitated by acquisition and utilisation of iron (FetA and Hmbr), resisting intracellular oxidative killing by producing catalase and superoxide dismutase and ability to avoid complement mediated killing (fHbp). Meningococci produce an IgA protease, an enzyme that cleaves IgA class antibodies and thus allows the bacteria to evade a subclass of the humoral immune system.
A hypervirulent strain was discovered in China. Its impact is yet to be determined.

Complement inhibition
Factor H binding protein (fHbp) that is exhibited in N. meningitidis and some commensal species is the main inhibitor of the alternative complement pathway. fHbp protects meningococci from complement-mediated death in human serum experiments, but has also been shown to protect meningococci from antimicrobial peptides in vitro. Factor H binding protein is key to the pathogenesis of N. meningitidis, and is, therefore, important as a potential vaccine candidate. Porins are also an important factor for complement inhibition for both pathogenic and commensal species. Porins are important for nutrient acquisition. Porins are also recognized by TLR2, they bind complement factors (C3b, C4b, factor H, and C4bp (complement factor 4b-binding protein)). Cooperation with pili for CR3-mediated internalization is another function of porins. Ability to translocate into host cells and modulate reactive oxygen species production and apoptosis is made possible by porins, as well. Strains of the same species can express different porins.

Genome
At least 8 complete genomes of Neisseria meningitidis strains have been determined which encode about 2,100 to 2,500 proteins.The genome of strain MC58 (serogroup B) has 2,272,351-base pairs. When sequenced in 2000, it was found to contain 2158 open reading frames (ORFs). Of these, a biological function was predicted for 1158 (53.7%). There were three major islands of horizontal DNA transfer found. Two encode proteins involved in pathogenicity. The third island only codes for hypothetical proteins. They also found more genes that undergo phase variation than any pathogen then known. Phase variation is a mechanism that helps the pathogen to evade the immune system of the host.The genome size of strain H44/76 is 2.18 Mb, and encodes 2,480 open reading frames (ORFs), compared to 2.27 Mb and 2,465 ORFs for MC58. Both strains have a GC content of 51.5%. A comparison with MC58 showed that four genes are uniquely present in H44/76 and nine genes are only present in MC58. Of all ORFs in H44/76, 2,317 (93%) show more than 99% sequence identity.The complete genome sequence of strain NMA510612 (serogroup A) consists of one circular chromosome with a size of 2,188,020 bp, and the average GC content is 51.5%. The chromosome is predicted to possess 4 rRNA operons, 163 insertion elements (IS), 59 tRNAs, and 2,462 ORFs.There is a public database available for N. meningitidis core genome multilocus sequence typing (cMILST). Available at: https://pubmlst.org/bigsdb?db=pubmlst_neisseria_seqdef

Genetic transformation
Genetic transformation is the process by which a recipient bacterial cell takes up DNA from a neighboring cell and integrates this DNA into the recipients genome by recombination. In N. meningitidis, DNA transformation requires the presence of short DNA sequences (9–10 mers residing in coding regions) of the donor DNA. These sequences are called DNA uptake sequences (DUSs). Specific recognition of these sequences is mediated by a type IV pilin. In N. meningitidis DUSs occur at a significantly higher density in genes involved in DNA repair and recombination (as well as in restriction-modification and replication) than in other annotated gene groups. The over-representation of DUS in DNA repair and recombination genes may reflect the benefit of maintaining the integrity of the DNA repair and recombination machinery by preferentially taking up genome maintenance genes, that could replace their damaged counterparts in the recipient cell.N. meningititis colonizes the nasopharyngeal mucosa, which is rich in macrophages. Upon their activation, macrophages produce superoxide (O2−) and hydrogen peroxide (H2O2). Thus N. meningitidis is likely to encounter oxidative stress during its life cycle. Consequently, an important benefit of genetic transformation to N. meningitidis may be the maintenance of the recombination and repair machinery of the cell that removes oxidative DNA damages such as those caused by reactive oxygen. This is consistent with the more general idea that transformation benefits bacterial pathogens by facilitating repair of DNA damages produced by the oxidative defenses of the host during infection.Meningococci population is extensively diverse genetically, this is due to horizontal gene transfers while in the nasophanrynx. Gene transfer can occur within and between genomes of Neisseria species, and it is the main mechanism of acquiring new traits. This is facilitated by the natural competence of the meningococci to take up foreign DNA. The commensal species of Neisseria can act as a reservoir of genes that can be acquired, for example, this is how capsule switching can occur as a means of hiding from the immune system. An invasive N. meningitidis strain of serogroup C broke out in Nigeria in 2013 - the strain was a new sequence type, ST-10217 determined by multilocus sequence typing. It was determined that a commensal strain of N. meningitidis acquired an 8-kb prophage, the meningococcal disease-associated island (MDAΦ), previously associated with hyper-invasiveness; and the full serogroup C capsule operon, thus becoming a hypervirulent strain. This illustrates how hypervirulent strains can arise from non-pathgenic strains due to the high propensity of gene transfers and DNA uptake by N. meningitidis.

Diagnosis
A small amount of cerebrospinal fluid (CSF) is sent to the laboratory as soon as possible for analysis. The diagnosis is suspected, when Gram-negative diplococci are seen on Gram stain of a centrifuged sample of CSF; sometimes they are located inside white blood cells. The microscopic identification takes around 1–2 hours after specimen arrival in the laboratory.The gold standard of diagnosis is microbiological isolation of N. meningitidis by growth from a sterile body fluid, which could be CSF or blood. Diagnosis is confirmed when the organism has grown, most often on a chocolate agar plate, but also on Thayer-Martin agar. To differentiate any bacterial growth from other species a small amount of a bacterial colony is tested for oxidase, catalase for which all clinically relevant Neisseria show a positive reaction, and the carbohydrates maltose, sucrose, and glucose, in which N. meningitidis will ferment that is, utilize the glucose and maltose. Finally, serology determines the subgroup of the N. meningitidis, which is important for epidemiological surveillance purposes; this may often only be done in specialized laboratories.
The above tests take a minimum of 48–72 hours turnaround time for growing the organism, and up to a week more for serotyping. Growth can and often does fail, either because antibiotics have been given preemptively, or because specimens have been inappropriately transported, as the organism is extremely susceptible to antibiotics and fastidious in its temperature, CO2 and growth medium requirements.
Polymerase chain reaction (PCR) tests where available, mostly in industrialized countries, have been increasingly used; PCR can rapidly identify the organism, and works even after antibiotics have been given.

Prevention
All recent contacts of the infected patient over the 7 days before onset should receive medication to prevent them from contracting the infection. This especially includes young children and their child caregivers or nursery-school contacts, as well as anyone who had direct exposure to the patient through kissing, sharing utensils, or medical interventions such as mouth-to-mouth resuscitation. Anyone who frequently ate, slept or stayed at the patients home during the 7 days before the onset of symptom, or those who sat beside the patient on an airplane flight or classroom for 8 hours or longer, should also receive chemoprophylaxis. The agent of choice is usually oral rifampicin for a few days.Receiving a dose of the Meningococcal vaccine before traveling to a country in the "meningitis belt" or having a booster meningitis vaccine, normally five years apart could prevent someone from getting an infection from the pathogen.

Vaccination
United States
A number of vaccines are available in the U.S. to prevent meningococcal disease. Some of the vaccines cover serogroup B, while others cover A, C, W, and Y. The Centers for Disease Control and Prevention (CDC) recommends all teenagers receive MenACWY vaccine and booster, with optional MenB. MenACWY and MenB are also recommended for people of other ages with various medical conditions and social risk factors.A meningococcal polysaccharide vaccine (MPSV4) has been available since the 1970s and is the only meningococcal vaccine licensed for people older than 55. MPSV4 may be used in people 2–55 years old if the MCV4 vaccines are not available or contraindicated. Two meningococcal conjugate vaccines (MCV4) are licensed for use in the U.S. The first conjugate vaccine was licensed in 2005, the second in 2010. Conjugate vaccines are the preferred vaccine for people 2 through 55 years of age. It is indicated in those with impaired immunity, such as nephrotic syndrome or splenectomy.
In June 2012, the U.S. Food and Drug Administration (FDA) approved a combination vaccine against two types of meningococcal diseases and Hib disease for infants and children 6 weeks to 18 months old. The vaccine, Menhibrix, was designed to prevent disease caused by Neisseria meningitidis serogroups C and Y, and Haemophilus influenzae type b (Hib). It was the first meningococcal vaccine that could be given to infants as young as six weeks old.In October 2014 the FDA approved the first vaccine effective against serogroup B, named Trumenba, for use in 10- to 25-year-old individuals.

Africa
In 2010, the Meningitis Vaccine Project introduced a vaccine called MenAfriVac in the African meningitis belt. It was made by generic drug maker Serum Institute of India and cost 50 U.S. cents per injection. Beginning in Burkina Faso in 2010, it has been given to 215 million people across Benin, Cameroon, Chad, Ivory Coast, Ethiopia, Ghana, Mali, Niger, Mauritania, Nigeria, Senegal, Sudan, Togo and Gambia. The vaccination campaign has resulted in near-elimination of serogroup A meningitis from the participating countries.

Treatment
Persons with confirmed N. meningitidis infection should be hospitalized immediately for treatment with antibiotics. Because meningococcal disease can disseminate very rapidly, a single dose of intramuscular antibiotic is often given at the earliest possible opportunity, even before hospitalization, if disease symptoms look suspicious enough. Third-generation cephalosporin antibiotics (i.e. cefotaxime, ceftriaxone) should be used to treat a suspected or culture-proven meningococcal infection before antibiotic susceptibility results are available. Clinical practice guidelines endorse empirical treatment in the event a lumbar puncture to collect cerebrospinal fluid (CSF) for laboratory testing cannot first be performed. Antibiotic treatment may affect the results of microbiology tests, but a diagnosis may be made on the basis of blood-cultures and clinical examination.

Epidemiology
N. meningitidis is a major cause of illness, developmental impairment and death during childhood in industrialized countries and has been responsible for epidemics in Africa and in Asia. Every year, about 2,500 to 3,500 people become infected with N. meningitidis in the US, with a frequency of about 1 in 100,000. Children younger than 5 years are at greatest risk, followed by teenagers of high school age. Rates in the African meningitis belt were as high as 1 in 1,000 to 1 in 100 before introduction of a vaccine in 2010. The incidence of meningococcal disease is highest among infants (children younger than 1-year-old) whose immune system is relatively immature. In industrialized countries there is a second peak of incidence in young adults, who are congregating closely, living in dormitories or smoking. Vaccine development is ongoing.It is spread through saliva and other respiratory secretions during coughing, sneezing, kissing, and chewing on toys. Inhalation of respiratory droplets from a carrier which may be someone who is themselves in the early stages of disease can transmit the bacteria. Close contact with a carrier is the predominant risk factor. Other risk factors include a weakened general or local immune response, such as a recent upper respiratory infection, smoking, and complement deficiency </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Clonorchiasis and can you explain it in depth? [/INST] Clonorchiasis is an infectious disease caused by the Chinese liver fluke (Clonorchis sinensis) and two related species.
Clonorchiasis is a known risk factor for the development of cholangiocarcinoma, a neoplasm of the biliary system.Symptoms of opisthorchiasis caused by Opisthorchis viverrini and by O. felineus are indistinguishable from clonorchiasis caused by Clonorchis sinensis, leading some to argue that the disease by these three parasites should be referred to collectively as clonorchiasis.

Signs and symptoms
Cause
Clonorchiasis sinensis is a trematode (fluke) which is part of the phylum Platyhelminthes. The parasitic worm is as long as 10 to 25 mm and lives in the bile ducts of the liver. It is a hermaphroditic fluke that requires two intermediate hosts. The eggs of the worms are passed in fecal matter into a body of water and are then ingested by mollusks. The water snail is the first intermediate host, in which a miracidium (an embryonated egg discharged in stool) goes through its developmental stages (sporocyst, rediae and cercariae). Freshwater fish are a second intermediate host for the parasitic worm </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tuberculous meningitis and can you explain it in depth? [/INST] Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelop the central nervous system.

Signs and symptoms
Fever and headache are the cardinal features; confusion is a late feature and coma bears a poor prognosis. Meningism is absent in a fifth of patients with TB meningitis.  Patients may also have focal neurological deficits.

Causes
Mycobacterium tuberculosis of the meninges is the cardinal feature and the inflammation is concentrated towards the base of the brain. When the inflammation is in the brain stem subarachnoid area, cranial nerve roots may be affected.  The symptoms will mimic those of space-occupying lesions.Blood-borne spread certainly occurs, presumably by crossing the blood–brain barrier; but a proportion of patients may get TB meningitis from rupture of a cortical focus in the brain; an even smaller proportion get it from rupture of a bony focus in the spine.

Pathophysiology
The pathophysiology of tuberculous meningitis involves bacterial invasion of the brain parenchyma meninges or cortex, causing the formation of small subpial foci. These foci, termed Rich foci, are necrotic and expand as the colonies within them multiply. Tubercle (focal) rupture in the subarachnoid space causes meningitis.

Diagnosis
Diagnosis of TB meningitis is made by analysing cerebrospinal fluid  collected by lumbar puncture.  When collecting CSF for suspected TB meningitis, a minimum of 1ml of fluid should be taken (preferably 5 to 10ml). The CSF usually has a high protein, low glucose and a raised number of lymphocytes. Acid-fast bacilli are sometimes seen on a CSF smear, but more commonly, M </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Major depressive disorder and can you explain it in depth? [/INST] Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introduced by a group of US clinicians in the mid-1970s, the term was adopted by the American Psychiatric Association for this symptom cluster under mood disorders in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and has become widely used since.
The diagnosis of major depressive disorder is based on the persons reported experiences, behavior reported by relatives or friends, and a mental status examination. There is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms. The most common time of onset is in a persons 20s, with females affected about twice as often as males. The course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent major depressive episodes.
Those with major depressive disorder are typically treated with psychotherapy and antidepressant medication. Medication appears to be effective, but the effect may be significant only in the most severely depressed. Hospitalization (which may be involuntary) may be necessary in cases with associated self-neglect or a significant risk of harm to self or others. Electroconvulsive therapy (ECT) may be considered if other measures are not effective.Major depressive disorder is believed to be caused by a combination of genetic, environmental, and psychological factors, with about 40% of the risk being genetic. Risk factors include a family history of the condition, major life changes, certain medications, chronic health problems, and substance use disorders. It can negatively affect a persons personal life, work life, or education, and cause issues with a persons sleeping habits, eating habits, and general health. Major depressive disorder affected approximately 163 million people (2% of the worlds population) in 2017. 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%). The disorder causes the second-most years lived with disability, after lower back pain.

Symptoms and signs
Major depression significantly affects a persons family and personal relationships, work or school life, sleeping and eating habits, and general health. A person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities. Depressed people may be preoccupied with—or ruminate over—thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness. Other symptoms of depression include poor concentration and memory, withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common; 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. In severe cases, depressed people may have psychotic symptoms. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. People who have had previous episodes with psychotic symptoms are more likely to have them with future episodes.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 Organizations criteria for depression. Appetite often decreases, resulting in weight loss, although increased appetite and weight gain occasionally occur. Family and friends may notice agitation or lethargy. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements.Depressed children may often display an irritable rather than a depressed mood; most lose interest in school and show a steep decline in academic performance. Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness." Elderly people may not 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.

Cause
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. American psychiatrist Aaron Beck suggested that a triad of automatic and spontaneous negative thoughts about the self, the world or environment, and the future may lead to other depressive signs and symptoms.Adverse childhood experiences (incorporating childhood abuse, neglect and family dysfunction) markedly increase the risk of major depression, especially if more than one type. Childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness. Some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.

Genetics
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 influenced by many individual genetic changes. In 2018, a genome-wide association study discovered 44 genetic variants linked to risk for major depression; a 2019 study found 102 variants in the genome linked to depression. 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.

Other health problems
Depression can also arise after 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, or through shared etiologies (such as degeneration of the basal ganglia in Parkinsons 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. Substance use in early age is associated with increased risk of developing depression later in life. Depression occurring after giving birth 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 triggered by decreased sunlight.
Vitamin B2, B6 and B12 deficiency may cause depression in females.

Pathophysiology
The pathophysiology of depression is not completely understood, but current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA-axis dysfunction and structural or functional abnormalities of emotional circuits.
Derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. First, acute depletion of tryptophan—a necessary precursor of serotonin and a monoamine—can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression. Second, 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, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, 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 people who are depressed that normalized with selective serotonin reuptake inhibitor (SSRI) treatment, and the preference for carbohydrates in people who are depressed. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. A 2022 review found no consistent evidence supporting the serotonin hypothesis, linking serotonin levels and depression.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 people who are depressed. However, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%. These stress-related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed. 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 cortico-striatal model, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures result 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.

Diagnosis
Clinical assessment
A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist, who records the persons current circumstances, biographical history, current symptoms, family history, and alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the persons 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. Rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose; these include the Hamilton Rating Scale for Depression, the Beck Depression Inventory or the Suicide Behaviors Questionnaire-Revised.Primary-care physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatrists. These cases may be missed because for some people with depression, physical symptoms often accompany depression. In addition, there may also be barriers related to the person, provider, and/or the medical system. Non-psychiatrist physicians have been shown to miss about two-thirds of cases, although there is some evidence of improvement in the number of missed cases.A doctor generally performs a medical examination and selected investigations to rule out other causes of depressive 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 may be 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 Alzheimers 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. No biological tests confirm major depression. In general, investigations are not repeated for a subsequent episode unless there is a medical indication.

DSM and ICD criteria
The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organizations International Statistical Classification of Diseases and Related Health Problems (ICD). 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 and ICD mark out typical (main) depressive symptoms. The most recent edition of the DSM is the Fifth Edition, Text Revision (DSM-5-TR), and the most recent edition of the ICD is the Eleventh Edition (ICD-11).Under mood disorders, ICD-11 classifies major depressive disorder as either single episode depressive disorder (where there is no history of depressive episodes, or of mania) or recurrent depressive disorder (where there is a history of prior episodes, with no history of mania). ICD-11 symptoms, present nearly every day for at least two weeks, are a depressed mood or anhedonia, accompanied by other symptoms such as "difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue." These symptoms must affect work, social, or domestic activities. The ICD-11 system allows further specifiers for the current depressive episode: the severity (mild, moderate, severe, unspecified); the presence of psychotic symptoms (with or without psychotic symptoms); and the degree of remission if relevant (currently in partial remission, currently in full remission). These two disorders are classified as "Depressive disorders", in the category of "Mood disorders".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 episodes manifestation does not meet the criteria for a major depressive episode.

Major depressive episode
A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks. Episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features—commonly referred to as psychotic depression—is automatically rated as severe. If the person 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".Bereavement is not an exclusion criterion in DSM-5, and it is 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.

Subtypes
The DSM-5 recognizes six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:

"Melancholic depression" is characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.
"Atypical depression" is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant long-term social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
"Catatonic depression" is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome.
"Depression with anxious distress" was added into the DSM-5 as a means to emphasize the common co-occurrence between depression or mania and anxiety, as well as the risk of suicide of depressed individuals with anxiety. Specifying in such a way can also help with the prognosis of those diagnosed with a depressive or bipolar disorder.
"Depression with peri-partum onset" refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth or while a woman is pregnant. DSM-IV-TR used the classification "postpartum depression," but this was changed to not exclude cases of depressed woman during pregnancy. Depression with peripartum onset has an incidence rate of 3–6% among new mothers. The DSM-V mandates that to qualify as depression with peripartum onset, onset occurs during pregnancy or within one month of delivery.
"Seasonal affective disorder" (SAD) is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer.

Differential diagnoses
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.Other disorders need to be ruled out before diagnosing major depressive disorder. They include depressions due to physical illness, medications, and substance use disorders. 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, non-medical use of a psychoactive substance, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance-induced mood disorder).

Screening and prevention
Preventive efforts may result in decreases in rates of the condition of between 22 and 38%. Since 2016, the United States Preventive Services Task Force (USPSTF) has recommended screening for depression among those over the age 12; though a 2005 Cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment. Screening the general population is not recommended by authorities in the UK or Canada.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.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.

Management
The most common and effective treatments for depression are psychotherapy, medication, and electroconvulsive therapy (ECT); a combination of treatments is the most effective approach when depression is resistant to treatment. 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 personal preference. Options may include pharmacotherapy, psychotherapy, exercise, 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 people 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.Psychotherapy is the treatment of choice (over medication) for people under 18, and cognitive behavioral therapy (CBT), third wave CBT and interpersonal therapy may help prevent depression. 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:
People with a history of moderate or severe depression
Those with mild depression that has been present for a long period
As a second line treatment for mild depression that persists after other interventions
As a first line treatment for moderate or severe depression.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.Treatment options are 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. There is insufficient evidence to determine the effectiveness of psychological versus medical therapy in children.

Lifestyle
Physical exercise has been found to be effective for major depression, and may be recommended to people who are willing, motivated, and healthy enough to participate in an exercise program as treatment. It is equivalent to the use of medications or psychological therapies in most people. In older people it does appear to decrease depression. Sleep and diet may also play a role in depression, and interventions in these areas may be an effective add-on to conventional methods. In observational studies, smoking cessation has benefits in depression as large as or larger than those of medications.

Talking therapies
Talking therapy (psychotherapy) can be delivered to individuals, groups, or families by mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. 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. 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 stopped or replaced by occasional booster sessions.
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. CBT can perform as well as antidepressants in people with major depression. CBT 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. 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. Problem solving therapy, cognitive behavioral therapy, and interpersonal therapy are effective interventions in the elderly.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 persons 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.

Antidepressants
Conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression. A review commissioned by the National Institute for Health and Care Excellence (UK) concluded that there is strong evidence that 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. Antidepressants work less well for the elderly than for younger individuals with depression.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 to 75%, and it can take at least six to eight weeks from the start of medication to improvement. 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 as it increases the risk of suicidal thoughts or attempts.For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy) but more research is needed to be certain. Sertraline, escitalopram, duloxetine might also help in reducing symptoms. Some 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.It is unclear whether antidepressants affect a persons risk of suicide. 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 people younger than 24 years old. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.

Other medications and supplements
The combined use of antidepressants plus benzodiazepines demonstrates improved effectiveness when compared to antidepressants alone, but these effects may not endure. The addition of a benzodiazepine is balanced against possible harms and other alternative treatment strategies when antidepressant mono-therapy is considered inadequate.Ketamine may have a rapid antidepressant effect lasting less than two weeks; there is limited evidence of any effect after that, common acute side effects, and longer-term studies of safety and adverse effects are needed. A nasal spray form of esketamine was approved by the FDA in March 2019 for use in treatment-resistant depression when combined with an oral antidepressant; risk of substance use disorder and concerns about its safety, serious adverse effects, tolerability, effect on suicidality, lack of information about dosage, whether the studies on it adequately represent broad populations, and escalating use of the product have been raised by an international panel of experts.There is insufficient high quality evidence to suggest omega-3 fatty acids are 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. 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
Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in a person with depression 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 person no longer has 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 people receive maintenance ECT.ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.

Other
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. Transcranial direct current stimulation (tDCS) is another noninvasive method used to stimulate small regions of the brain with a weak electric current. Several meta-analyses have concluded that active tDCS was useful for treating depression.There is a small amount of evidence that sleep deprivation may improve depressive symptoms in some individuals, 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. There is insufficient evidence for Reiki and dance movement therapy in depression. Cannabis is specifically not recommended as a treatment.

Prognosis
Studies have shown that 80% of those with a first major depressive episode will have at least one more during their life, with a lifetime average of four 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. 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.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 indicates continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use.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. According to a 2013 review, 23% of untreated adults with mild to moderate depression will remit within 3 months, 32% within 6 months and 53% within 12 months.

Ability to work
Depression may affect peoples ability to work. The combination of usual clinical care and support with return to work (like working less hours or changing tasks) probably reduces sick leave by 15%, and leads to fewer depressive symptoms and improved work capacity, reducing sick leave by an annual average of 25 days per year. Helping depressed people return to work without a connection to clinical care has not been shown to have an effect on sick leave days. Additional psychological interventions (such as online cognitive behavioral therapy) lead to fewer sick days compared to standard management only. Streamlining care or adding specific providers for depression care may help to reduce sick leave.

Life expectancy and the risk of suicide
Depressed individuals have a shorter life expectancy than those without depression, in part because people who are depressed are at risk of dying of suicide. About 50% 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. About 2–8% of adults with major depression die by suicide. In the US, the lifetime risk of suicide associated with a diagnosis of major depression is estimated at 7% for men and 1% for women, even though suicide attempts are more frequent in women.Depressed people have a higher rate of dying from other causes. There is 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, further increasing their risk of medical complications. Cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care.

Epidemiology
Major depressive disorder affected approximately 163 million people in 2017 (2% 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 the United States, 8.4% of adults (21 million individuals) have at least one episode within a year-long period; the probability of having a major depressive episode is higher for females than males (10.5% to 6.2%), and highest for those aged 18 to 25 (17%). Among adolescents between the ages of 12 and 17, 17% of the U.S. population (4.1 million individuals) had a major depressive episode in 2020 (females 25.2%, males 9.2%). Among individuals reporting two or more races, the US prevalence is highest.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. In 2019, major depressive disorder was identified (using either the DSM-IV-TR or ICD-10) in the Global Burden of Disease Study as the fifth most common cause of years lived with disability and the 18th most common for disability-adjusted life years.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, Parkinsons 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. 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. Depression is common among those over 65 years of age and increases in frequency beyond this age. 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.Major depression was the leading cause of disease burden in North America and other high-income countries, and the fourth-leading cause worldwide as of 2006. 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.

Comorbidity
Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reported 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 suicidal behavior. Depressed people have increased rates of alcohol and substance use, particularly dependence, and around a third of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) develop comorbid depression. Post-traumatic stress disorder and depression often co-occur. Depression may also coexist with ADHD, complicating the diagnosis and treatment of both. Depression is also frequently comorbid with alcohol use disorder and personality disorders. Depression can also be exacerbated during particular months (usually winter) in those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, using digital media may also improve mood in some situations.Depression and pain often co-occur. One or more pain symptoms are present in 65% of people who have depression, and anywhere from 5 to 85% of people who are experiencing pain will also have depression, depending on the setting—a lower prevalence in general practice, and higher in specialty clinics. Depression is often underrecognized, and therefore undertreated, in patients presenting with pain. Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinsons disease, and chronic obstructive pulmonary disease.

History
The Ancient Greek physician Hippocrates described a syndrome of melancholia (μελαγχολία, melankholía) 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 todays 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, meaning "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 Bakers 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. 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 persons 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 individuals 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.The term unipolar (along with the related term bipolar) was coined by the neurologist and psychiatrist Karl Kleist, and subsequently used by his disciples Edda Neele and Karl Leonhard.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. The American Psychiatric Association added "major depressive disorder" to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), as 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. 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.

Society and culture
Terminology
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. Peoples 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 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.

Stigma
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 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is MERRF syndrome and can you explain it in depth? [/INST] MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the diseases name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

Symptoms and signs
An individual displaying MERRFs syndrome will manifest not only a single symptom, but patients regularly display more than one affected body part at a time. It has been observed that patients with MERRF syndrome will primarily display myoclonus as a first symptom. There may also be seizures, cerebellar ataxia and myopathy. Secondary features can include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, multiple lipomata, and/or cardiomyopathy with Wolff Parkinson-White syndrome. Most patients will not exhibit all of these symptoms, but more than one of these symptoms will be present in a patient who has been diagnosed with MERRF disease. Mitochondrial disorders, including MERRF, may present at any age. Due to the multiple symptoms presented by the individual, the severity of the syndrome is very difficult to evaluate.

Causes
The cause of MERRF disorder is due to mutations in the mitochondrial genome. This means that it is a pathological variant in mtDNA (mitochondrial DNA) and is transmitted by maternal inheritance. Four point mutations in the genome can be identified that are associated with MERRF: m.A8344G, m.T8356C, m.G8361A, and m.G8363A. The point mutation m.A8344G is most commonly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation. This point mutation disrupts the mitochondrial gene for tRNA-Lys. This disrupts the synthesis of proteins. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.Many genes are involved. These genes include:

MT-TK
MT-TL1
MT-TH
MT-TS1
MT-TS2
MT-TFIt involves the following characteristics:

progressive myoclonic epilepsy
"Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain.There is currently no cure for MERRF.

Mechanism
The mechanism by which MERRFs syndrome occur is not yet well understood. The human mitochondrial tRNA mutations are associated with a variety of diseases including mitochondrial myopathies. However, it is understood that defects in the mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects.  One of these defects has to do with the decreased energy available for cell processes. As muscles are stained with Gömöri trichrome, characteristic ragged red fibers are visible under the microscope. This appearance is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber. These may extend throughout the muscle fiber as the disease severity increases. The mitochondrial aggregates cause the contour of the muscle fiber to become irregular, leading to the "ragged" appearance.

Diagnosis
The diagnosis varies from individual to individual. Each is evaluated and diagnosed according to age, clinical phenotype, and pressed inheritance pattern. If the individual has been experiencing myoclonus, the doctor will run a series of genetic studies to determine if it is a mitochondrial disorder.The molecular genetic studies are run to identify the reason of for the mutations underlying the mitochondrial dysfunction. This approach will avoid the need for a muscle biopsy or an exhaustive metabolic evaluation. After sequencing the mitochondrial genomes, four points mutations in the genome can be identified which are associated with MERRF: A8344G, T8356C, G8361A, and G8363A. The point mutation A8344G is mostly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation.  The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.If a patient does not exhibit mitochondrial DNA mutations, there are other ways that they can be diagnosed with MERRF. They can go through computed tomography (CT) or magnetic resonance imaging (MRI).The classification for the severity of MERRF syndrome is difficult to distinguish since most individuals will exhibit multi-symptoms. This is often necessary for children with complex neurologic or multi-system involvement, as described below.

History and physical examination of the patient
A detailed family history should be obtained from at least three generations, particularly if there have been any neonatal and childhood deaths. A family history may also indicate if any family members exhibit features of the multi-system disease, specifically if there has been maternal inheritance. This would show transmission of the disease only to females, or if there is a family member who experienced a multi-system involvement such as: brain condition that a family member has been record to have such as seizures, dystonia, ataxia, or stroke-like episodes. There may also be optic atrophy, skeletal muscle with a history of myalgia, weakness, or ptosis. Family history may also include neuropathy and dysautonomia, or heart conditions such as cardiomyopathy. The patients history might also exhibit kidney problems, such as proximal nephron dysfunction. There may also be endocrine conditions, such as diabetes or hypoparathyroidism. The patient might have also had a gastrointestinal condition which could have been due to liver disease, as well as episodes of nausea or vomiting </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acute pericarditis and can you explain it in depth? [/INST] Acute pericarditis is a type of pericarditis (inflammation of the sac surrounding the heart, the pericardium) usually lasting less than 6 weeks. It is the most common condition affecting the pericardium.

Signs and symptoms
Chest pain is one of the common symptoms of acute pericarditis. It is usually of sudden onset, occurring in the anterior chest and often has a sharp quality that worsens with breathing in or coughing, due to inflammation of the pleural surface at the same time. The pain may be reduced with sitting up and leaning forward while worsened with lying down, and also may radiate to the back, to one or both trapezius ridges. However, the pain can also be dull and steady, resembling the chest pain in an acute myocardial infarction. As with any chest pain, other causes must also be ruled out, such as GERD, pulmonary embolism, muscular pain, etc.
A pericardial friction rub is a very specific sign of acute pericarditis, meaning the presence of this sign invariably indicates presence of disease. However, absence of this sign does not rule out disease. This rub can be best heard by the diaphragm of the stethoscope at the left sternal border arising as a squeaky or scratching sound, resembling the sound of leather rubbing against each other. This sound should be distinguished from the sound of a murmur, which is similar but sounds more like a "swish" sound than a scratching sound. The pericardial rub is said to be generated from the friction generated by the two inflamed layers of the pericardium; however, even a large pericardial effusion does not necessarily present a rub. The rub is best heard during the maximal movement of the heart within the pericardial sac, namely, during atrial systole, ventricular systole, and the filling phase of early ventricular diastole.
Fever may be present since this is an inflammatory process.

Causes
There are several causes of acute pericarditis. In developed nations, the cause of most (80–90%) cases of acute pericarditis is unknown but a viral cause is suspected in the majority of such cases. The other 10–20% of acute pericarditis cases have various causes including connective tissue diseases (e.g., systemic lupus erythematosus), cancer, or involve an inflammatory reaction of the pericardium following trauma to the heart such as after a heart attack such as Dresslers syndrome. Familial mediterranean fever and TNF receptor associated periodic syndrome are rare inherited autoimmune diseases capable of causing recurring episodes of acute pericarditis.

Pathophysiology
Clinical presentation of diseases of pericardium may vary between:
Acute and recurrent pericarditis
Pericardial effusion without major hemodynamic compromise
Cardiac tamponade
Constrictive pericarditis
Effusive-constrictive pericarditis

Diagnosis
For acute pericarditis to formally be diagnosed, two or more of the following criteria must be present: chest pain consistent with a diagnosis of acute pericarditis (sharp chest pain worsened by breathing in or a cough), a pericardial friction rub, a pericardial effusion, and changes on electrocardiogram (ECG) consistent with acute pericarditis.A complete blood count may show an elevated white count and a serum C-reactive protein may be elevated. Acute pericarditis is associated with a modest increase in serum creatine kinase MB (CK-MB). and cardiac troponin I (cTnI), both of which are also markers for injury to the muscular layer of the heart. Therefore, it is imperative to also rule out acute myocardial infarction in the face of these biomarkers. The elevation of these substances may occur when inflammation of the hearts muscular layer in addition to acute pericarditis. Also, ST elevation on EKG (see below) is more common in those patients with a cTnI > 1.5 µg/L. Coronary angiography in those patients should indicate normal vascular perfusion. Troponin levels increase in 35-50% of people with pericarditis.Electrocardiogram (ECG) changes in acute pericarditis mainly indicates inflammation of the epicardium (the layer directly surrounding the heart), since the fibrous pericardium is electrically inert. For example, in uremia, there is no inflammation in the epicardium, only fibrin deposition, and therefore the EKG in uremic pericarditis will be normal. Typical EKG changes in acute pericarditis includes
stage 1 -- diffuse, positive, ST elevations with reciprocal ST depression in aVR and V1. Elevation of PR segment in aVR and depression of PR in other leads especially left heart V5, V6 leads indicates atrial injury.
stage 2 -- normalization of ST and PR deviations
stage 3 -- diffuse T wave inversions (may not be present in all patients)
stage 4 -- EKG becomes normal OR T waves may be indefinitely invertedThe two most common clinical conditions where ECG findings may mimic pericarditis are acute myocardial infarction (AMI) and generalized early repolarization. As opposed to pericarditis, AMI usually causes localized convex ST-elevation usually associated with reciprocal ST-depression which may also be frequently accompanied by Q-waves, T-wave inversions (while ST is still elevated unlike pericarditis), arrhythmias and conduction abnormalities. In AMI, PR-depressions are rarely present. Early repolarization usually occurs in young males (age <40 years) and ECG changes are characterized by terminal R-S slurring, temporal stability of ST-deviations and J-height/ T-amplitude ratio in V5 and V6 of <25% as opposed to pericarditis where terminal R-S slurring is very uncommon and J-height/ T-amplitude ratio is ≥ 25%. Very rarely, ECG changes in hypothermia may mimic pericarditis, however differentiation can be helpful by a detailed history and presence of an Osborne wave in hypothermia.Another important diagnostic electrocardiographic sign in acute pericarditis is the Spodick sign. It signifies to the PR-depressions in a usual (but not always) association with downsloping TP segment in patients with acute pericarditis and is present in up to 80% of the patients affected with acute pericarditis. The sign is often best visualized in lead II and lateral precordial leads. In addition, Spodicks sign may also serve as an important distinguishing electrocardiographic tool between the acute pericarditis and acute coronary syndrome. The presence of a classical Spodicks sign is often a giveaway to the diagnosis.Rarely, electrical alternans may be seen, depending on the size of the effusion.A chest x-ray is usually normal in acute pericarditis but can reveal the presence of an enlarged heart if a pericardial effusion is present and is greater than 200 mL in volume. Conversely, patients with unexplained new onset cardiomegaly should always be worked up for acute pericarditis.An echocardiogram is typically normal in acute pericarditis but can reveal pericardial effusion, the presence of which supports the diagnosis, although its absence does not exclude the diagnosis.

Treatment
Patients with uncomplicated acute pericarditis can generally be treated and followed up in an outpatient clinic. However, those with high risk factors for developing complications (see above) will need to be admitted to an inpatient service, most likely an ICU setting. High risk patients include the following:
subacute onset
high fever (> 100.4 F/38 C) and leukocytosis
development of cardiac tamponade
large pericardial effusion (echo-free space > 20 mm) resistant to NSAID treatment
immunocompromised
history of oral anticoagulation therapy
acute trauma
failure to respond to seven days of NSAID treatmentPericardiocentesis is a procedure whereby the fluid in a pericardial effusion is removed through a needle. It is performed under the following conditions:
presence of moderate or severe cardiac tamponade
diagnostic purpose for suspected purulent, tuberculosis, or neoplastic pericarditis
persistent symptomatic pericardial effusionNSAIDs in viral or idiopathic pericarditis. In patients with underlying causes other than viral, the specific etiology should be treated. With idiopathic or viral pericarditis, NSAID is the mainstay treatment. Goal of therapy is to reduce pain and inflammation. The course of the disease may not be affected. The preferred NSAID is ibuprofen because of rare side effects, better effect on coronary flow, and larger dose range. Depending on severity, dosing is between 300 and 800 mg every 6–8 hours for days or weeks as needed. An alternative protocol is aspirin 800 mg every 6–8 hours. Dose tapering of NSAIDs may be needed. In pericarditis following acute myocardial infarction, NSAIDs other than aspirin should be avoided since they can impair scar formation. As with all NSAID use, GI protection should be engaged. Failure to respond to NSAIDs within one week (indicated by persistence of fever, worsening of condition, new pericardial effusion, or continuing chest pain) likely indicates that a cause other than viral or idiopathic is in process.Colchicine, which has been essential to treat recurrent pericarditis, has been supported for routine use in acute pericarditis by recent prospective studies. Colchicine can be given 0.6 mg twice a day (0.6 mg daily for patients <70 kg) for 3 months following an acute attack. It should be considered in all patients with acute pericarditis, preferably in combination with a short-course of NSAIDs. For patients with a first episode of acute idiopathic or viral pericarditis, they should be treated with an NSAID plus colchicine 1–2 mg on first day followed by 0.5 daily or twice daily for three months. It should be avoided or used with caution in patients with severe chronic kidney disease, hepatobiliary dysfunction, blood dyscrasias, and gastrointestinal motility disorders.Corticosteroids are usually used in those cases that are clearly refractory to NSAIDs and colchicine and a specific cause has not been found. Systemic corticosteroids are usually reserved for those with autoimmune disease.

Prognosis
One of the most feared complications of acute pericarditis is cardiac tamponade </s>