Hepatitis C

Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV).^[1] The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis) which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer.^[1]

The hepatitis C virus (HCV) is spread by blood-to-blood contact. Most people have few, if any symptoms after the initial infection, yet the virus persists in the liver in about 85% of those infected. Persistent infection can be treated with medication, peginterferon and ribavirin being the standard-of-care therapy. 51% are cured overall. Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after transplantation.

An estimated 270-300 million people worldwide are infected with hepatitis C. Hepatitis C is a strictly human disease. It cannot be contracted from or given to any animal. Chimpanzees can be infected with the virus in the laboratory, but do not develop the disease, which has made research more difficult. No vaccine against hepatitis C is available. The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proved conclusively in 1989. It is one of five known hepatitis viruses: A, B, C, D, and E.

Signs and symptoms

Acute

Acute hepatitis C refers to the first 6 months after infection with HCV. Between 60% to 70% of people infected develop no symptoms during the acute phase. In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C. Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms.

The hepatitis C virus is usually detectable in the blood within one to three weeks after infection by PCR, and antibodies to the virus are generally detectable within 3 to 15 weeks. Spontaneous viral clearance rates are highly variable and between 10–60%^[2] of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in liver enzymes (alanine transaminase (ALT) & aspartate transaminase (AST)), and plasma HCV-RNA clearance (this is known as spontaneous viral clearance). However, persistent infections are common^[3] and most patients develop chronic hepatitis C, i.e., infection lasting more than 6 months.^[4][5][6]

Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies have shown that treatment during the acute phase of genotype 1 infections has a greater than 90% success rate with half the treatment time required for chronic infections.^[7]

Chronic

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months. Clinically, it is often asymptomatic (without symptoms) and it is mostly discovered accidentally.

The natural course of chronic hepatitis C varies considerably from one person to another. Although almost all people infected with HCV have evidence of inflammation on liver biopsy the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Accurate estimates of the risk over time are difficult to establish because of the limited time that tests for this virus have been available.

Recent data suggest that among untreated patients, roughly one-third progress to liver cirrhosis in less than 20 years. Another third progress to cirrhosis within 30 years. The remainder of patients appear to progress so slowly that they are unlikely to develop cirrhosis within their lifetimes. In contrast the NIH consensus guidelines state that the risk of progression to cirrhosis over a 20-year period is 3-20 percent.^[8]

Factors that have been reported to influence the rate of HCV disease progression include age (increasing age associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV coinfection (associated with a markedly increased rate of disease progression), and fatty liver (the presence of fat in liver cells has been associated with an increased rate of disease progression).

Symptoms specifically suggestive of liver disease are typically absent until substantial scarring of the liver has occurred. However, hepatitis C is a systemic disease and patients may experience a wide spectrum of clinical manifestations ranging from an absence of symptoms to a more symptomatic illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include fatigue, flu-like symptoms, joint pains, itching, sleep disturbances, appetite changes, nausea, and depression.

Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms may appear that are generally caused by either decreased liver function or increased pressure in the liver circulation, a condition known as portal hypertension. Possible signs and symptoms of liver cirrhosis include ascites (accumulation of fluid in the abdomen), bruising and bleeding tendency, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. Hepatic encephalopathy is due to the accumulation of ammonia and other substances normally cleared by a healthy liver.

Liver enzyme tests show variable elevation of ALT and AST. Periodically they might show normal results. Usually prothrombin and albumin results are normal, but may become abnormal, once cirrhosis has developed. The level of elevation of liver tests do not correlate well with the amount of liver injury on biopsy. Viral genotype and viral load also do not correlate with the amount of liver injury. Liver biopsy is the best test to determine the amount of scarring and inflammation. Radiographic studies such as ultrasound or CT scan do not always show liver injury until it is fairly advanced. However, non-invasive tests (blood sample) are coming, with FibroTest^[9] and ActiTest, respectively estimating liver fibrosis and necrotico-inflammatory. These tests are validated^[10] and recommended in Europe (FDA procedures initiated in USA)

Chronic hepatitis C, more than other forms of hepatitis, can be associated with extrahepatic manifestations associated with the presence of HCV such as porphyria cutanea tarda, cryoglobulinemia (a form of small-vessel vasculitis)^[11] and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN).^[12] Hepatitis C is also rarely associated with sicca syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus and with B-cell lymphoproliferative disorders.^[13]

Virology

The Hepatitis C virus (HCV) is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. It is the only known member of the hepacivirus genus in the family Flaviviridae. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.).

The hepatitis C virus (HCV) is transmitted by blood-to-blood contact. In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or sexual exposure. In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products. There has not been a documented transfusion-related case of hepatitis C in the United States for over a decade as the blood supply is vigorously screened with both EIA and PCR technologies.

Although injection drug use is the most common routes of HCV infection, any practice, activity, or situation that involves blood-to-blood exposure can potentially be a source of HCV infection. The virus may be sexually transmitted, although this is rare, and usually only occurs when an STD that causes open sores and bleeding is also present and makes blood contact more likely.^[14].

Transmission

Sexual activities and practices were initially identified as potential sources of exposure to the hepatitis C virus. More recent studies question this route of transmission. Currently it is felt to be a means of rare transmission of hepatitis C infection. These are simply the current known modes of transmission and due to the nature of Hepatitis there may be more ways that it is transmitted than the current known methods.

Injection drug use

Those who currently use or have used drug injection as their delivery route for drugs are at increased risk for getting hepatitis C because they may be sharing needles or other drug paraphernalia (includes cookers, cotton, spoons, water, etc.), which may be contaminated with HCV-infected blood. An estimated 60% to 80% of intravenous recreational drug users in the United States have been infected with HCV.^[15] Harm reduction strategies are encouraged in many countries to reduce the spread of hepatitis C, through education, provision of clean needles and syringes, and safer injecting techniques. For reasons that are not clear transmission by this route currently appears to be declining in the USA.

Blood products

Blood transfusion, blood products, or organ transplantation prior to implementation of HCV screening (in the U.S., this would refer to procedures prior to 1992) is a decreasing risk factor for hepatitis C.

The virus was first isolated in 1989 and reliable tests to screen for the virus were not available until 1992. Therefore, those who received blood or blood products prior to the implementation of screening the blood supply for HCV may have been exposed to the virus. Blood products include clotting factors (taken by hemophiliacs), immunoglobulin, Rhogam, platelets, and plasma. In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.

Iatrogenic medical or dental exposure

People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc. Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.

Occupational exposure to blood

Medical and dental personnel, first responders (e.g., firefighters, paramedics, emergency medical technicians, law enforcement officers), and military combat personnel can be exposed to HCV through accidental exposure to blood through accidental needlesticks or blood spatter to the eyes or open wounds. Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.

Recreational exposure to blood

Contact sports and other activities, such as "slam dancing" that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV.^[16]

Sexual exposure

Sexual transmission of HCV is considered to be rare. Studies show the risk of sexual transmission in heterosexual, monogamous relationships is extremely rare or even null.^[17][18] The CDC does not recommend the use of condoms between long-term monogamous discordant couples (where one partner is positive and the other is negative).^[19] However, because of the high prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases transmitted by sexual routes. Vaginal penetrative sex is believed to have a lower risk of transmission than sexual practices that involve higher levels of trauma to anogenital mucosa (anal penetrative sex, fisting, use of sex toys).^[20]

Body piercings and tattoos

Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed. Tattoos or piercings performed before the mid 1980s, "underground," or non-professionally are of particular concern since sterile techniques in such settings may have been or be insufficient to prevent disease. Despite these risks, it is rare for tattoos to be directly associated with HCV infection and the U.S. Centers for Disease Control and Prevention's position on this subject states that, "no data exist in the United States indicating that persons with exposures to tattooing alone are at increased risk for HCV infection."^[21]

Shared personal care items

Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially lead to exposure to HCV. Appropriate caution should be taken regarding any medical condition which results in bleeding such as canker sores, cold sores, and immediately after flossing.

HCV is not spread through casual contact such as hugging, kissing, or sharing eating or cooking utensils.^[22]

Vertical transmission

Vertical transmission refers to the transmission of a communicable disease from an infected mother to her child during the birth process. Mother-to-child transmission of hepatitis C has been well described, but occurs relatively infrequently. Transmission occurs only among women who are HCV RNA positive at the time of delivery; the risk of transmission in this setting is approximately 6 out of 100. Among women who are both HCV and HIV positive at the time of delivery, the risk of transmitting HCV is increased to approximately 25 out of 100.

The risk of vertical transmission of HCV does not appear to be associated with method of delivery or breastfeeding.

Diagnosis

The diagnosis of "hepatitis C" is rarely made during the acute phase of the disease because the majority of people infected experience no symptoms during this phase of the disease. Those who do experience acute phase symptoms are rarely ill enough to seek medical attention. The diagnosis of chronic phase hepatitis C is also challenging due to the absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades into the disease.

Chronic hepatitis C may be suspected on the basis of the medical history (particularly if there is any history of IV drug abuse or inhaled substance usage such as cocaine), a history of piercings or tattoos, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing. Occasionally, hepatitis C is diagnosed as a result of targeted screening such as blood donation (blood donors are screened for numerous blood-borne diseases including hepatitis C) or contact tracing.

Hepatitis C testing begins with serological blood tests used to detect antibodies to HCV. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months after exposure, and in >97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus, but may miss patients who have not yet developed antibodies (seroconversion), or have an insufficient level of antibodies to detect. Rarely, people infected with HCV never develop antibodies to the virus and therefore, never test positive using HCV antibody screening. Because of this possibility, RNA testing (see nucleic acid testing methods below) should be considered when antibody testing is negative but suspicion of hepatitis C is high (e.g. because of elevated transaminases in someone with risk factors for hepatitis C).

Anti-HCV antibodies indicate exposure to the virus, but cannot determine if ongoing infection is present. All persons with positive anti-HCV antibody tests must undergo additional testing for the presence of the hepatitis C virus itself to determine whether current infection is present. The presence of the virus is tested for using molecular nucleic acid testing methods such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to detect not only whether the virus is present, but also to measure the amount of virus present in the blood (the HCV viral load). The HCV viral load is an important factor in determining the probability of response to interferon-based therapy, but does not indicate disease severity nor the likelihood of disease progression.

In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.

Treatment

There is a very small chance of clearing the virus spontaneously in chronic HCV carriers (0.5% to 0.74% per year).^[23][24] However, the majority of patients with chronic hepatitis C will not clear it without treatment.

Current treatment is a combination of Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on hepatitis C virus genotype. Treatment is generally recommended for patients with proven hepatitis C virus infection and persistently abnormal liver function tests. Sustained cure rates (sustained viral response) of 75% or better are seen in people with HCV genotypes 2 and 3 with 24 weeks of treatment.^[25] Sustained responses are rarer with other genotypes, at about 50% in patients with HCV genotype 1 given 48 weeks of treatment and 65% in those with genotype 4 given 48 weeks of treatment. Approximately 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is more common in the Middle East and Africa.

In patients with HCV genotype 1, if treatment with pegylated interferon + ribavirin does not produce a 2-log viral load reduction or complete clearance of RNA (termed "early virological response") after 12 weeks the chance of treatment success is less than 1%. Early virological response is typically not tested in non-genotype 1 patients, as the chances of attaining it are greater than 90%. The mechanism of cure is not entirely clear, because even patients who appear to have a sustained virological response still have actively replicating virus in their liver and peripheral blood mononuclear cells.^[26]

The evidence for treatment in genotype 6 disease is currently sparse, and the evidence that exists is for 48 weeks of treatment at the same doses as are used for genotype 1 disease.^[27] Physicians considering shorter durations of treatment (e.g., 24 weeks) should do so within the context of a clinical trial.

Treatment during the acute infection phase has much higher success rates (greater than 90%) with a shorter duration of treatment; however, this must be balanced against the 15-40% chance of spontaneous clearance without treatment (see Acute Hepatitis C section above).

Those with low initial viral loads respond much better to treatment than those with higher viral loads (greater than 400,000 IU/mL). Current combination therapy is usually supervised by physicians in the fields of gastroenterology, hepatology or infectious disease.

The treatment may be physically demanding, particularly for those with a prior history of drug or alcohol abuse. It can qualify for temporary disability in some cases. A substantial proportion of patients will experience a panoply of side effects ranging from a 'flu-like' syndrome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation. The latter are exacerbated by the general physiological stress experienced by the patient.

Current guidelines strongly recommend that hepatitis C patients be vaccinated for hepatitis A and B if they have not yet been exposed to these viruses, as infection with a second virus could worsen their liver disease.

Alcoholic beverage consumption accelerates HCV associated fibrosis and cirrhosis, and makes liver cancer more likely; insulin resistance and metabolic syndrome may similarly worsen the hepatic prognosis. There is also evidence that smoking increases the fibrosis (scarring) rate.

Host genetic factors influencing treatment response

For genotype 1 hepatitis C treated with Pegylated_interferon-alpha-2a or Pegylated_interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature ^[28], showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained sustained virological response after the treatment than others. Later report from Nature ^[29] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

During pregnancy and breastfeeding

If a woman who is pregnant has risk factors for hepatitis C, she should be tested for antibodies against HCV. About 4% infants born to HCV infected women become infected. There is no treatment that can prevent this from happening. There is a high chance of the baby ridding the HCV in the first 12 months.

In a mother who also has HIV, the rate of transmission can be as high as 19%. There are currently no data to determine whether antiviral therapy reduces perinatal transmission. Ribavirin and interferons are contraindicated during pregnancy. However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant.

HCV antibodies from the mother may persist in infants until 15 months of age. If an early diagnosis is desired, testing for HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result. If a later diagnosis is preferred, an anti-HCV test can performed after 15 months of age. Most infants infected with HCV at the time of birth have no symptoms and do well during childhood. There is no evidence that breast-feeding spreads HCV. To be cautious, an infected mother should avoid breastfeeding if her nipples are cracked and bleeding.^[30]

Alternative therapies

Several alternative therapies aim to maintain liver functionality, rather than treat the virus itself, thereby slowing the course of the disease to retain quality of life. As an example, extract of Silybum marianum and Sho-saiko-to are sold for their HCV related effects; the first is said to provide some generic help to hepatic functions, and the second claims to aid in liver health and provide some antiviral effects.^[31]. There has never been any verifiable histologic or virologic benefit demonstrated with any of the alternative therapies.

Experimental treatments

The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C. It will be used in conjunction with interferons^{[disambiguation needed]}, in the same manner as ribavirin. However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.

There are new drugs under development like the protease inhibitors (including VX 950) and polymerase inhibitors (such as NM 283), but development of some of these is still in the early phase. VX 950, also known as Telaprevir^[32] is currently in Phase 3 Trials. ^[33][34] One protease inhibitor, BILN 2061, had to be discontinued due to safety problems early in the clinical testing. Some more modern new drugs that provide some support in treating HCV are Albuferon,^[35] Zadaxin,^[36] and DAPY.^{[citation needed]} Antisense phosphorothioate oligos have been targeted to hepatitis C.^[37] Antisense Morpholino oligos have shown promise in preclinical studies^[38] however, they were found to cause a limited viral load reduction.

Immunoglobulins against the hepatitis C virus exist and newer types are under development. Thus far, their roles have been unclear as they have not been shown to help in clearing chronic infection or in the prevention of infection with acute exposures (e.g. needlesticks). They do have a limited role in transplant patients.

In addition to the standard treatment with interferon and ribavirin, some studies have shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to the regimen. Sometimes called "triple therapy", it involves the addition of 100 mg of amantadine twice a day. Studies indicate that this may be especially helpful for "nonresponders" - patients who have not been successful in previous treatments using interferon and ribavirin only.^[39] Currently, amantadine is not approved for treatment of Hepatitis C, and studies are ongoing to determine when it is most likely to benefit the patient.

Among the more novel treatments under development is the Hemopurifier(R),^[40] a first-in-class medical device that selectively removes infectious viruses and immunosuppressive proteins from the bloodstream. In HCV care, the Hemopurifier(R) inhibits viral replication through selective adsorption of circulating HCV and augments the immune response by removing toxic proteins shed from HCV to kill-off immune cells. Recent clinical data validates the mechanical removal of HCV through blood filtration in combination with SOC therapy can increase HCV cure rates by greater than 50%. Studies are ongoing at the Fortis Hospital in New Dehli, India.

Epidemiology

It is estimated that Hepatitis C has infected nearly 200 million people worldwide, and infects 3-4 million more people per year.^[41][42] There are about 35,000 to 185,000 new cases a year in the United States. It is currently a leading cause of cirrhosis, a common cause of hepatocellular carcinoma, and as a result of these conditions it is the leading reason for liver transplantation in the United States. Co-infection with HIV is common and rates among HIV positive populations are higher. 10,000-20,000 deaths a year in the United States are from HCV; expectations are that this mortality rate will increase, as those who were infected by transfusion before HCV testing become apparent. A survey conducted in California showed prevalence of up to 34% among prison inmates;^[43] 82% of subjects diagnosed with hepatitis C have previously been in jail,^[44] and transmission while in prison is well described.^[45]

Prevalence is higher in some countries in Africa and Asia.^[46] Egypt has the highest seroprevalence for HCV, up to 20% in some areas. There is a hypothesis that the high prevalence is linked to a now-discontinued mass-treatment campaign for schistosomiasis, which is endemic in that country.^[47] Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.

Co-infection with HIV

Approximately 350,000, or 35% of patients in the USA infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and present in similar populations. In other countries co-infection is less common, and this is possibly related to differing drug policies.^{[citation needed]} HCV is the leading cause of chronic liver disease in the USA. It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure. This is not to say treatment is not an option for those living with co-infection.

Prevention

According to Centers for Disease Control, hepatitis C virus is spread by exposure to large quantities of blood, either through the skin or by injection:^[48]

• Injection drug use (currently the most common means of HCV transmission in the United States)
• Receipt of donated blood, blood products, and organs (once a common means of transmission but now rare in the United States since blood screening became available in 1992)
• Needlestick injuries in healthcare settings
• Birth to an HCV-infected mother

HCV can also be spread infrequently through

• Sex with an HCV-infected person (an inefficient means of transmission)
• Sharing personal items contaminated with infectious blood, such as razors or toothbrushes (also inefficient vectors of transmission)
• Other healthcare procedures that involve invasive procedures, such as injections (usually recognized in the context of outbreaks)

Proponents of harm reduction believe that strategies such as the provision of new needles and syringes, and education about safer drug injection procedures, greatly decreases the risk of hepatitis C spreading between injecting drug users.

No vaccine protects against contracting hepatitis C, or helps to treat it. Vaccines are under development and some have shown encouraging results.^[49]

History

In the mid 1970s, Harvey J. Alter, Chief of the Infectious Disease Section in the Department of Transfusion Medicine at the National Institutes of Health, and his research team demonstrated that most post-transfusion hepatitis cases were not due to hepatitis A or B viruses. Despite this discovery, international research efforts to identify the virus, initially called non-A, non-B hepatitis (NANBH), failed for the next decade. In 1987, Michael Houghton, Qui-Lim Choo, and George Kuo at Chiron Corporation, collaborating with Dr. D.W. Bradley from CDC, utilized a novel molecular cloning approach to identify the unknown organism.^[50] In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April of 1989, the discovery of the virus, re-named hepatitis C virus (HCV), was published in two articles in the journal Science. ^[51][52]

Chiron filed for several patents on the virus and its diagnosis.^[53] A competing patent application by the CDC was dropped in 1990 after Chiron paid $1.9 million to the CDC and $337,500 to Bradley. In 1994 Bradley sued Chiron, seeking to invalidate the patent, have himself included as a co-inventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.^{[54] [55]}

In 2000, Drs. Alter and Houghton were honored with the Lasker Award for Clinical Medical Research for "pioneering work leading to the discovery of the virus that causes hepatitis C and the development of screening methods that reduced the risk of blood transfusion-associated hepatitis in the U.S. from 30% in 1970 to virtually zero in 2000."^[56]

In 2004 Chiron held 100 patents in 20 countries related to hepatitis C and had successfully sued many companies for infringement. Scientists and competitors have complained that the company hinders the fight against hepatitis C by demanding too much money for its technology

Treatment for depression

Depression, for the purposes of this article, refers to the mental disorder known as major depressive disorder. This kind of depression is a recognised clinical condition and is becoming a common condition in developed countries, where up to 20% of the population is affected by this disorder at some stage of their lives.^[1] Patients are usually assessed and managed as outpatients, and only admitted to an inpatient mental health unit if they are considered to pose a risk to themselves or others.

The three most commonly indicated treatments for depression are psychotherapy, psychiatric medication, and electroconvulsive therapy. Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. Furthermore, pathology in the parents may need to be looked for and addressed in parallel.^[2]

Psychotherapy

There are a number of different psychotherapies for depression, which may be provided to individuals or groups. Psychotherapy can be delivered by a variety of mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. With more complex and chronic forms of depression the most effective treatment is often considered to be a combination of medication and psychotherapy.^[3] Psychotherapy is the treatment of choice in people under 18; medication is offered only in conjunction with the former and generally not as a first line agent. ^[2]

The most studied form of psychotherapy for depression is cognitive behavioral therapy (CBT), thought to work by teaching clients to learn a set of cognitive and behavioral skills, which they can employ on their own. Earlier research suggested that cognitive-behavioral therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression.^[4]

For the treatment of adolescent depression, CBT performed no better than placebo, and significantly worse than the antidepressant fluoxetine.^[5] Combining fluoxetine with CBT appeared to bring no additional benefit^[6][7] or, at the most, only marginal benefit.^[8]

A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects.^[9]

Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT, however the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.^[10]

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts,^[11] is used by its practitioners to treat clients presenting with major depression.^[12] A more widely practiced, eclectic technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus.^[13] In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.^[14]

Medication

Main article: Antidepressant

To find the most effective pharmaceutical treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressant changed. Response rates to the first agent administered may be as low as 50%.^[15] It may take anywhere from three to eight weeks after the start of medication before its therapeutic effects can be fully discovered. Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four months to prevent the chance of recurrence. People with chronic depression need to take the medication for the rest of their lives.^[16]

Isoniazid, the first compound called antidepressant

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine, and citalopram are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety. Those who do not respond to the first SSRI tried can be switched to another; such a switch results in improvement in almost 50% of cases.^[17] Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy;^[18] this strategy is possibly more effective.^[19][20] It is not uncommon for SSRIs to cause or worsen insomnia; the sedating antidepressant mirtazapine (Zispin, Remeron) can be used in such cases.^[21][22][23] Venlafaxine (Effexor) may be moderately more effective than SSRIs;^[24] however, it is not recommended as a first-line treatment because of the higher rate of side effects,^[25] and its use is specifically discouraged in children and adolescents.^[26] Fluoxetine is the only antidepressant recommended for people under the age of 18.^[26]

Tricyclic antidepressants have more side effects than SSRIs and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective.^[27][28] A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.^[29]

Augmentation

Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant.^[30] Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.^[31] Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.^[32] Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent side effects.^[33] There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.^[34]

Efficacy of medication and psychotherapy

Two recent meta-analyses of clinical trial results submitted to the FDA concluded that antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence criteria for a "clinically significant" effect. In particular, the effect size was very small for moderate depression but increased with severity reaching "clinical significance" for very severe depression.^[35][36] These result were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment.^[37][38][39] Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there "seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit."^[35] The other author agreed that "antidepressant 'glass' is far from full" but disagreed "that it is completely empty". He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.^[40]

Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD.^[41][42] In contrast, medication gives better results for dysthymia.^[41][42] The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants.^[41] Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional "booster" sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.^[42]

Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents)showed very similar results. TADS resulted in 71 percent of their teen subjects having a “much” or “very much” improvement in mood over the 60.6 with medication alone and the 43.2 with CBT alone ^[43]. Similarly, TORDIA showed a 54.8 percent improvement with CBT and drugs verses a 40.5 percent with drug therapy alone ^[44].

Other medications

There are numerous alternative treatments for depression, whether medications or other kinds of intervention.

Opiates

Various Opiates were commonly used as antidepressants until the mid-1950s, when they fell out of favor with medical orthodoxy due to their addictive nature, tolerance buildup issues and their side-effect profile. Today the use of opioids in treating depression is a large taboo in the medical field due to associations with drug abuse; hence, research has proceeded at a very slow rate. A small clinical trial conducted at Harvard Medical School in 1995,^[45] demonstrated that a majority of treatment-refractory, unipolar, non-psychotic, major depression patients could be successfully treated with an opioid medication called Buprenorphine, which is a partial mu agonist and potent kappa antagonist. The exact mechanism of its action in depression is not known, as kappa (κ) antagonists are antidepressants in their own right.

In 2006, The Journal of European Neuropsychopharmacology published a follow-up study to the 1995 Harvard experiment, with results consistent with the original Harvard findings. Eleven severely depressed patients, refractory to all the conventional depression treatments, were given small doses of buprenorphine. Most of these patients found the buprenorphine to be of significant benefit. The researchers theorized that "Possibly, the response to opiates describes a special subtype of depressive disorders e.g. corresponding to a dysregulation of the endogenous opioid system and not of the monaminergic system."^[46]

Another scientific paper was published in the American Journal of Psychiatry in 1999, detailing how researchers found Oxycodone/Oxymorphone to help 5 out of 6 'incurable' refractory severe depression patients.^[47]

While opioids have been proven to substantially relieve symptoms of depression for a large class of patients, re-acceptance of this fact has been severely hampered by governmental narcotic prohibition efforts^{[citation needed]}, and the (until buprenorphine) lack of alternatives with low risk of tolerance and addiction. Buprenorphine is generally preferred as the first-line opiate in depression treatment^{[citation needed]}, as managing the tolerance buildup of other opiates can be complicated.^{[citation needed]}

Opiorphin is a very recently discovered substance that increases the effectiveness of endorphins, meaning that it has effects similar to opioid agonists without the addiction and withdrawal effects. While it has been shown to be extremely effective for analgesia, any ability to treat depression or the presence of an abuse potential are largely informed guesswork at this stage.

Other treatments

• Gamma-Hydroxybutyric acid (GHB) has been used by some as an antidepressant. Claude Rifat, a French biologist, conducted some early research into GHB's antidepressant potential. Rifat noted that GHB did not cause the emotional blunting effects caused by conventional antidepressants, but instead intensified pleasurable and rewarding feelings in the user while powerfully suppressing depression.^[48] However, GHB has now been outlawed, except for use as a prescription treatment for narcolepsy.
• NMDA antagonists such as ketamine and dextromethorphan have recently gained some interest in this field as their apparent ability to reverse opioid tolerance, and can give fast-acting dramatic effects. However, their acute psychoactive effects have been a problem.^[49]
• Memantine, a moderate affinity NMDA antagonist, has been used to avoid tolerance buildup, and has seen use in opioid tolerance reversal. Proglumide is used to induce acute reversal of tolerance prior to this maintenance strategy; it does not work by itself in the long term, due to tolerance to its effects.
• Marijuana - The use of marijuana, in moderation, has shown to be of benefit in severely depressed patients. Many people that do not respond well to the use of traditional antidepressants, or who do not like the many unpleasant side effects, prove to do rather well using this plant in moderation.

Electroconvulsive therapy

Main article: Electroconvulsive therapy

Electroconvulsive therapy (ECT) is a treatment where seizures are electrically induced in anesthetized patients for therapeutic effect. ECT is most often used as a "last resort" (from the perspective of hospital psychiatrists) for severe major depression which has not responded to trials of antidepressant or, less often, psychotherapy or supportive interventions.^[50] It has a quicker effect than antidepressant therapy, and thus may be the treatment of choice in emergencies such as catatonic depression where the patient has ceased oral intake of fluid or nutrients, or where there is severe suicidality.^[50] Some evidence suggests it is the most effective treatment for depression in the short-term^[51] and one study, without a comparison group or assessment of additional treatments given, suggested that in the minority who remit it may be related to improved self-rated quality of life in both the short-term (which was correlated with the degree of amnesia) and after six months.^[52] However, the first systematic documentation of the effectiveness of ECT in community practice in the 65 years of its use found much lower remission rates than in prior research, and most of those relapsed.^[53] ECT on its own does not usually have a sustained benefit, as virtually all those who remit end up relapsing within 6 months following a course, even when given a placebo.^[54] The relapse rate in the first six months may be reduced by the use of psychatric medications or further ECT (though the latter is not recommended by some authorities, such as NICE), but remains high.^[55][56] Short-term memory loss, disorientation, headache and other adverse effects are common, as are long-term memory^[57] and other neurocognitive deficits, which may persist. The American Psychiatric Association and the National Institute for Health and Clinical Excellence have concluded that the evidence they had suggested that the procedure, when administered according to their standards and without complications, does not cause brain damage in adults.^[58][59]

Other conventional methods of treatment

St John's wort

St John's wort extract is used extensively in Europe to treat mild and moderate depression. It is a prescription antidepressant in several European countries but is classified as an herbal supplement and sold over the counter in the U.S. Opinions on its efficacy for major depression differ. A systematic meta-analysis of 37 trials conducted by Cochrane Collaboration indicated statistically significant weak-to-moderate effect as compared to placebo. The same meta-analysis found that St John's wort efficacy for major depression is not different from prescription antidepressants.^[60] NCCAM and other NIH-affiliated organizations hold that St John's wort has minimal or no effects beyond placebo in the treatment of major depression, based primarily on one study with negative outcome conducted by NCCAM.^[61][62]

SAMe

S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the United States. Fairly strong evidence from 16 clinical trials suggests it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.^[63][64][65]

Repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) use in treatment-resistant depression is supported by multiple controlled studies, and it has been approved for this indication in Europe, Canada and Australia, but not in the U.S.^[66] A 2008 meta-analysis based on 32 trials found a robust effect of this method on depression, and it appeared similarly effective for both uncomplicated depression and depression resistant to medication.^[67] However, it was inferior to ECT in a side-by-side randomized trial.^[68]

Vagus nerve stimulation

Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit.^[66] The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favorable for the secondary outcome.^[69]

Alternative treatment methods

Bright light therapy

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

A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found it to be more effective than placebo—usually, dim light—for both seasonal affective disorder and for nonseasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective.^[70] A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly as an addition to medication or sleep deprivation. A moderate statistically significant effect of light therapy was found; however, it disappeared if a different statistical technique was used.^[71] Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1–2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

Acupuncture

A 2004 Cochrane Review concluded that based on the low quality of the evidence base there is "insufficient evidence to determine whether acupuncture is effective in the management of depression."^[72] Clinical trials have shown the effect of acupuncture to be comparable with amitriptyline; in addition, specifically Electroacupuncture has been found to be more effective in depressive patients with decreased excretion of 3-methyl-4-hydroxy-phenylglycol (the principal metabolite of the central neurotransmitter norepinephrine), while amitriptyline is more effective for those with inhibition in the dexamethasone suppression test.^[73] Acupuncture has also been proven to prompt the body to produce greater levels of endorphins.^[74]

Exercise

"A 2001 study by the Duke University in North Carolina found that exercise is a more effective treatment for depression than antidepressants, with fewer relapses and a higher recovery rate."^[75] An earlier Duke study likewise found patients who completed 30 minutes of brisk exercise at least three times a week had a significantly lower incidence of relapse; "Only 8 percent of patients in the exercise group had their depression return, while 38 percent of the drug-only group and 31 percent of the exercise-plus-drug group relapsed."^[76]

Vigorous exercise has significant physiological effects which help to reduce stress and counter depression. Also, by improving fitness and self-esteem, exercise may enable the sufferer to cope better with demanding events and situations and so reduce the likelihood of depressing failure.^[77]

Exercise in natural surroundings such as the countryside or parks is especially recommended because contact with nature and green spaces has a positive effect upon mental health.^[78] Gardening is an ideal activity of this sort, providing mental, practical and social benefits.^[79]

Deep Brain Stimulation

The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage.^[66]

Tryptophan

Although tryptophan and 5-hydroxytryptophan may be more effective than placebo in alleviating depression according to the Cochrane Collaboration meta-analysis, only 2 out of 108 trials were of sufficient quality to be included in this analysis. The reviewers concluded that they were unable to recommend the drugs for use in major depression.^[80]

Tryptophan is the precursor of the neurotransmitter serotonin. It has shown some promise as an antidepressant alone^[81] and as an augmenter of antidepressant drugs.^[81][82] Foods rich in tryptophan include chickpeas, milk products, eggs, pork, beef, chicken, fish, oats, dates, mangoes, seeds, nuts and spirulina.

Low fructose diet

Fructose malabsorption is poor absorption of fructose and fructans in the intestines. Subjects with this condition show a significantly higher score in the Beck Depression Inventory than normal fructose absorbers.^[83] Some minerals and amino acids (among others, tryptophan) are also poorly absorbed. Because of the inadequate supply of precursor molecules, some hormones and neurotransmitters (among others, serotonin) may not be synthesized in sufficient quantities.^[84] Treatment is a diet that is low in fructose, fructans and sorbitol. Depression scores were reduced by 65.2% after four weeks on this diet.^[85]

Omega-3 fatty acids

Omega-3 fatty acids have been studied in clinical trials for major depression primarily as an adjunctive to antidepressant therapy. A meta-analysis of eight such trials indicated a statistically significant superiority of combinations with omega-3 fatty acids over single antidepressants; however, the authors warned that, due to multiple problems with these trials, a reliable conclusion is difficult to achieve.^[86]

Omega-3 fatty acids have been shown to help many people with depression, the theory being that Omega-3 helps nourish brain cells that release serotonin into the brain. Omega-3 fatty acids are present, for example, in cold-water fish such as salmon, in flax seed, in fish oil capsules and in flax seed capsules.

"Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach." (American Journal of Psychiatry 163:969-978, June 2006)^[87]

DHEA

Dehydroepiandrosterone (DHEA), a metabolic precursor for several hormones including estrogen and testosterone, has been promoted as a remedy for many ailments. Sold in the 1970s and 1980s as a weight-loss aid, it was subsequently banned for over-the-counter sale, but then unbanned, and is currently available as a supplement in the US. It has been shown to be more effective than placebo in two small double-blind trials: in one as an adjunct to antidepressant treatment,^[88] and as monotherapy in another.^[89] However, a larger placebo-controlled randomized clinical trial reported in the New England Journal of Medicine in 2006 found that DHEA supplementation in elderly men and women had no beneficial effects on quality of life.^[90]

Chromium picolinate

Chromium picolinate was found to be equivalent to placebo for atypical depression overall but possibly efficacious in the sub-group of patients with severe carbohydrate craving.^[91]

Zinc

Zinc supplementation was found in a small study to augment the effect of antidepressants.^[92]

Serum levels of zinc are found to be low in depressed patients and supplementation with zinc has been demonstrated to be of benefit.^[93] Most of the zinc found in the human body are located in the brain, mainly in the hippocampus and cerebral cortex area. Lack of zinc influences zinc homeostasis and leads to a change in learning, behavior, mood swings, mental function and epilepsy. Zinc is found in beans, meat, nuts, oysters, whole grains and seeds.

Lithium

In the late 1800s there was a vogue for consumption of lithia water which contained a significant quantity of lithium. Some claimed that this cured depression, but its effectiveness is not clear.^[94]

In May 2009, the BBC reported that a Japanese study of lithium in drinking water in the Japan prefecture of Oita, which has a population of more than one million, revealed that the suicide rate was significantly lower in those areas with the highest levels of lithium.^[95]

Lithium is also used as the standard drug to treat different mood disorders including depression. See Lithium_pharmacology.

Magnesium

Magnesium deficiency is common and may cause depression. Supplementation or changes in diet may therefore be helpful.^[96] Foodstuffs rich in magnesium include whole grains, beans and seeds, halibut and spinach.

Cranial electrotherapy stimulation

Cranial electrotherapy stimulation (CES, electrosleep) devices currently on the market have been granted marketing authorization by the FDA based on the legacy waver, that is because a sufficiently similar device had been marketed before 1976, when the new regulations requiring controlled testing were introduced.^[97] The FDA considers them to be the class III devices—"devices for which insufficient information exists to ... provide reasonable assurance of safety and effectiveness"^[98] The effects of CES on depression were inconclusive or negative in multiple double-blind studies of psychiatric patients.^{[99][100][100][101][102][103]} In one of them, four out of six clinically depressed patients dropped out of the study because of the massive worsening of depressive symptoms, with two of them becoming actively suicidal.^[103] One of the authors of the latter study cautioned that CES “should not be used as a treatment of choice” for the patients with the primary diagnosis of depression, “and should be used with caution if this diagnosis is suspected.”^[104] Nevertheless, the CES practitioners continue to employ it as a treatment of choice for depression.^[105][106]

Eleuthero

Eleutherococcus senticosus is used in Traditional Chinese Medicine and is now used in the West as Eleuthero or Siberian Ginseng. The plant is an adaptogen or tonic and has been shown to have significant antidepressant effects in rats.^[107][108]

Saffron

Saffron, the flowers of Crocus sativus have been shown to have antidepressant properties.^[109] Two of the active ingredients are crocin and safranal.^[109]

Inositol (Vitamin B₈)

Inositol or vitamin B₈ has been shown to be an effective treatment for depression, bipolar disorder and obsessive-compulsive disorder^{[110][111][112]} and panic attacks. The therapeutic dosage of inositol seems to be between 6-20 g/day, with 12-18 g/day being more likely an effective dosage.^[113]

Kanna

Kanna (Sceletium tortuosum) is a succulent herb commonly found in South Africa. In doses as low as 50 mg, users have reported improvements in mood, decreased anxiety, relaxation and a sense of well-being. It contains about 1-1.5% alkaloids and those which are believed to be psychoactive include mesembrine, mesembrenone, mesembrenol and tortuosamine.^[114]

There is about 0.3% mesembrine in the leaves and 0.86% in the stems of the plant.^[115] This has been shown to be a potent serotonin reuptake inhibitor.^[116]

Flower remedies

Bach flower remedies and Australian bush flower essences are prepared from various flowers. Current clinical evidence does not support any hypothesized action or efficacy beyond placebo effects.^[117]

Four Bach flower remedies are described in connection with depression: gentian for very mild depression or pessimism; gorse for more serious depression; sweet chestnut for severe depression; and mustard for depression that comes from within and is not related to external circumstances.^{[118][119][120]} Two Australian bush flower essences are described in connection with depression: waratah for depression; and Sunshine Wattle for pessimism and defeatism, especially after a long run of bad luck.^[121]

Potassium phosphate

The homeopathic dilution of potassium phosphate is claimed to bring some short-term relief to depressed patients.^[122]

Meditation

Mindfulness Meditation has been shown to be of medical benefit in a number of ways, including lowering blood pressure and stress levels. The most helpful and gentle form of meditation for a clinically depressed person may be the repetition—silently or aloud—of a mantra.^[123][124]

Neurofeedback

Neurofeedback is a form of biofeedback therapy in which brain activity is monitored using an EEG. The output is presented to the patient who is then able to see any variation in the brain waves associated with depression and may then develop some ability to reduce them, so improving their mood. The resulting direct control of mental state is thought to be similar to that achieved by the mental exercises of yoga.^[125][126]

Reiki

Reiki is a form of energy medicine originated in 1922 by Mikao Usui. In the UK, it has been recommended as a complementary medicine for pain management, anxiety and depression by NHS Trusts and Princess of Wales's Foundation of Integrative Medicine, but there is no evidence of its efficacy in the treatment of any disorder^[127].

Religion

Numerous studies and clinical trials have looked at the relationship between religion and depression. These have looked at the matter from Buddhist, Christian and Muslim perspectives. These indicate that religious faith helps to prevent the onset of depression and assists recovery if depression should still occur.^[128]

Sleep

Depression is commonly associated with poor sleep - difficulty going to sleep, early waking and general lassitude during the day. The two interact to worsen the condition of each other. Good sleep hygiene is therefore important to help break this vicious circle.^[129] This would include measures such as regular bed times, avoidance of stimulants such as caffeine and management of disturbances such as sleep apnea. Ironically, sleep deprivation is also a temporary treatment for depression.

Chi Kung

The traditional Chinese exercise of Chi Kung and related martial arts such as Tai Chi can help to prevent and relieve depression.^[130]

Cold Shower

Taking cold showers according to a study led by Nikolai Shevchuk may be an effective way to help treat depression. Shevchuck believes the biological explanation as to why cold showers help with depression involves the stimulation of locus ceruleus oe blue spot which is the brain's primary source of norepinephrine. Also affected are beta-endorphin levels. Adapted cold shower as a potential treatment for depression☆ Medical Hypotheses , Volume 70 , Issue 5 , Pages 995 - 1001 N . Shevchuk Med Hypotheses. 2008;70(5):995-1001. Epub 2007 Nov 13 http://www.ncbi.nlm.nih.gov/pubmed/17993252

Music Therapy

Studies have demonstrated that music can bring about different moods, conditioned by different emotional states. Music has the property of facilitating self-expression and in this way giving vent to disturbing emotional upheavals and dissipating them. Music has been proven that it can reach the sub-cortical centers of the brain and thereby helps to integrate the personality that is being disrupted by unhealthy emotions. Researchers have shown that music therapy is effective in patients. It has been shown that clinically depressed patients who were made to listen to soft, dissonant-free, melodic music gradually became more emotional and rhythmical. ^[131]

Wake therapy

Wake therapy is a form of sleep deprivation used as a treatment for depression

Brain hemorrhage

Cerebral hemorrhage

A cerebral hemorrhage (or intracerebral hemorrhage, ICH), is a subtype of intracranial hemorrhage that occurs within the brain tissue itself. Intracerebral hemorrhage can be caused by brain trauma, or it can occur spontaneously in hemorrhagic stroke. Non-traumatic intracerebral hemorrhage is a spontaneous bleeding into the brain tissue.^[1]

A cerebral hemorrhage is an intra-axial hemorrhage; that is, it occurs within the brain tissue rather than outside of it. The other category of intracranial hemorrhage is extra-axial hemorrhage, such as epidural, subdural, and subarachnoid hematomas, which all occur within the skull but outside of the brain tissue. There are two main kinds of intra-axial hemorrhages: intraparenchymal hemorrhage and intraventricular hemorrhages. As with other types of hemorrhages within the skull, intraparenchymal bleeds are a serious medical emergency because they can increase intracranial pressure. The mortality rate for intraparenchymal bleeds is over 40%

Prevalence

It accounts for 20% of all cases of cerebrovascular disease in the US, behind cerebral thrombosis (40%) and cerebral embolism (30%).^[3]

It is two or more times more prevalent in African-American patients.^[4]

Causes

Intracerebral bleeds are the second most common cause of stroke, accounting for 30–60% of hospital admissions for stroke.^[1] High blood pressure raises the risk of spontaneous intracerebral hemorrhage by two to six times.^[1] More common in adults than in children, intraparenchymal bleeds due to trauma are usually due to penetrating head trauma, but can also be due to depressed skull fractures, acceleration-deceleration trauma,^[5][6][7] rupture of an aneurysm or arteriovenous malformation (AVM), and bleeding within a tumor. A very small proportion is due to cerebral venous sinus thrombosis.

Risk factors

Risk factors for ICH include:^[8]

• Hypertension
• Diabetes
• Menopause
• Current cigarette smoking
• Alcoholic drinks (≥2/day)
• Caffeine

Symptoms

Patients with intraparenchymal bleeds have symptoms that correspond to the functions controlled by the area of the brain that is damaged by the bleed.^[9] Other symptoms include those that indicate a rise in intracranial pressure due to a large mass putting pressure on the brain.^[9] Intracerebral hemorrhages are often misdiagnosed as Subarachnoid hemorrhages due to the similarity in symptoms and signs.

Diagnosis

Intraparenchymal hemorrhage can be recognized on CT scans because blood appears brighter than other tissue and is separated from the inner table of the skull by brain tissue. The tissue surrounding a bleed is often less dense than the rest of the brain due to edema, and therefore shows up lighter on the CT scan.

Treatment

Treatment depends substantially of the type of ICH. Rapid CT scan and other diagnostic measures are used to choose proper treatment, which may include both medication and surgery.

Medication

• Giving Factor VIIa within 4 hours limits the bleeding and formation of an hematoma However, it also increases the risk of thromboembolism. ^[10]
• Antihypertensives are given to stabilize the mean arterial pressure at below 130 mmHg, but without causing excessive hypotension. ^[10]
  • Mannitol is effective in acutely reducing raised intracranial pressure.
• Acetaminophen may be needed to avoid hyperthermia, and to relieve headache.^[10]
• Frozen plasma, vitamin K, protamine, or platelet transfusions are given in case of a coagulopathy.^[10]
• Fosphenytoin or other anticonvulsant is given in case of seizures or lobar hemorrhage.^[10]
• Antacids are given to prevent gastric ulcers, a condition somehow linked with ICH.^[10]
• Corticosteroids, in concert with antihypertensives, reduces swelling. ^[11]

Surgery

Surgery is required if the hematoma is greater than 3 cm, if there is a structural vascular lesion or lobar hemorrhage in a young patient.^[10]

• A catheter may be passed into the brain vasculature to close off or dilate blood vessels, avoiding rather invasive surgical procedures.^[12]
• Aspiration by stereotactic surgery or endoscopic drainage may be used in basal ganglia hemorrhages, although successful reports are limited.^[10]

Other treatment

• Tracheal intubation is indicated in patients with decreased level of consciousness or other risk of airway obstruction.^[10]
• IV fluids are given to maintain fluid balance, using normotonic rather than hypotonic fluids.^[10]

Prognosis

The risk of death from an intraparenchymal bleed in traumatic brain injury is especially high when the injury occurs in the brain stem.^[2] Intraparenchymal bleeds within the medulla oblongata are almost always fatal, because they cause damage to cranial nerve X, the vagus nerve, which plays an important role in blood circulation and breathing.^[5] This kind of hemorrhage can also occur in the cortex or subcortical areas, usually in the frontal or temporal lobes when due to head injury, and sometimes in the cerebellum.^[5][13]

For spontaneous ICH seen on CT scan, the death rate (mortality) is 34–50% by 30 days after the insult.