Bipolar disorder

Bipolar disorder is not a single disorder, but a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood, clinically referred to as mania. Individuals who experience manic episodes also commonly experience depressive episodes or symptoms, or mixed episodes in which features of both mania and depression are present at the same time. These episodes are normally separated by periods of normal mood, but in some patients, depression and mania may rapidly alternate, known as rapid cycling. Extreme manic episodes can sometimes lead to psychotic symptoms such as delusions and hallucinations. The disorder has been subdivided into bipolar I, bipolar II, Bipolar NOS, and cyclothymia based on the type and severity of mood episodes experienced.

Also called bipolar affective mood disorder until recently, the current name is of fairly recent origin and refers to the cycling between high and low episodes; it has replaced the older term manic-depressive illness coined by Emil Kraepelin (1856–1926) in the late nineteenth century. The new term is designed to avoid the social stigma associated with the conflation of "manic" and "depression."

Introduction
The onset of symptoms generally occurs in young adulthood. Diagnosis is based on the person's self-reported experiences, as well as observed behavior. Episodes of abnormality are associated with distress and disruption, and a high risk of suicide, especially during depressive episodes. Studies suggest that genetics, early environment, neurobiology, and psychological and social processes are important contributory factors. Psychiatric research is focused on the role of neurobiology, but a clear organic cause has not been found. Bipolar disorder is usually treated with medications and/or counseling. The mainstay of medication are a number of drugs termed 'mood stabilizers', in particular lithium and sodium valproate; these are chemically unrelated medications used to prevent relapses of further episodes. Antipsychotic medications, sometimes called neuroleptics, in particular olanzapine, are used to treat and prevent manic episodes. The benefits of using antidepressants in depressive episodes is unclear. Depending on the jurisdiction, in serious cases in which there is a risk of harm to oneself or others involuntary commitment may be used; these cases generally involve severe manic episodes with dangerous behaviour or depressive episodes with suicidal ideation.

Some studies have suggested a significant correlation between creativity and bipolar disorder. Though studies consistently show a positive correlation between the two, the exact nature of the relationship between the disorder and creativity is still relatively unclear. One study indicated than an increased striving for and attainment of goals and achievements corresponded with the onset of manic symptoms. While the disorder affects people differently, individuals with bipolar disorder tend to be much more outgoing and daring than individuals without bipolar disorder. The disorder is also found in a large number of people involved in the arts. It is an ongoing question as to why many creative geniuses had bipolar disorder.

Course
Bipolar disorder is often a cyclic condition with which people periodically exhibit elevated (manic) and depressive episodes. Most people will experience a number of episodes, averaging 0.4 to 0.7 a year with each lasting three to six months, although some will experience only a single mood episode. Late adolescence and early adulthood are peak years for the onset of the disorder. These are critical periods in a young adult's social and vocational development, and they can be severely disrupted by disease onset.

Rapid cycling, defined as having four or more episodes per year, is found in a significant fraction of patients with bipolar disorder. It has been associated with greater disability or a worse prognosis, due to the confusing changeability and difficulty in establishing a stable state. Rapid cycling can be induced or made worse by antidepressants, unless there is adjunctive treatment with a mood stabilizer.

The definition of rapid cycling most frequently cited in the literature is that of Dunner and Fieve: at least four major depressive, manic, hypomanic or mixed episodes are required to have occurred during a 12-month period. There are references that describe very rapid (ultra-rapid) or extremely rapid (ultra-ultra or ultradian) cycling. One definition of ultra-ultra rapid cycling is defining distinct shifts in mood within a 24–48-hour period.

Major depressive episode
Signs and symptoms of the depressive phase of bipolar disorder include: persistent feelings of sadness, anxiety, guilt, anger, isolation and/or hopelessness, disturbances in sleep and appetite, fatigue and loss of interest in usually enjoyed activities, problems concentrating, loneliness, self-loathing, apathy or indifference, depersonalization, loss of interest in sexual activity, shyness or social anxiety, irritability, chronic pain (with or without a known cause), lack of motivation, and morbid/suicidal ideation. In severe cases, the individual may become psychotic, a condition also known as severe bipolar depression with psychotic features.

Manic episode
Mania is generally characterized by a distinct period of an elevated, expansive, or irritable mood state. People commonly experience an increase in energy and a decreased need for sleep. A person's speech may be pressured, with thoughts experienced as racing. Attention span is low and a person in a manic state may be easily distracted. Judgment may become impaired; sufferers may go on spending sprees or engage in behavior that is quite abnormal for them. They may indulge in substance abuse, particularly alcohol or other depressants, cocaine or other stimulants, or sleeping pills. Their behavior may become aggressive or intrusive. People may feel they have been "chosen", are "on a special mission", or other grandiose or delusional ideas. Sexual drive may increase. At more extreme phases, a person in a manic state can begin to experience psychosis, or a break with reality, where thinking is affected along with mood. Many people in a manic state experience severe anxiety and are very irritable (to the point of rage), while others are euphoric and grandiose.

In order to be diagnosed with mania according to DSM-IV a person must experience this state of elevated or irritable mood, as well as other symptoms, for at least one week, less if hospitalisation is required. According to the National Institute of Mental Health, "A manic episode is diagnosed if elevated mood occurs with three or more of the other symptoms most of the day, nearly every day, for 1 week or longer. If the mood is irritable, four additional symptoms must be present."

Hypomanic episode
Hypomania is generally a less extreme state than mania, and people in the hypomanic phase generally experience fewer symptoms of mania than those in a full-blown manic episode. During an episode, one might feel an uncontrollable impulse to laugh at things he or she does not normally find funny. The duration is usually also shorter than in mania. This is often a very "artistic" state of the disorder, in which a flight of ideas, extremely clever thinking, and an increase in energy can occur.

Mixed affective episode
In the context of bipolar disorder, a mixed state is a condition during which symptoms of mania and clinical depression occur simultaneously (for example, agitation, anxiety, aggressiveness or belligerence, confusion, fatigue, impulsiveness, insomnia, irritability, morbid and/or suicidal ideation, panic, paranoia, persecutory delusions, pressured speech, racing thoughts, restlessness, and rage).

Diagnosis
Diagnosis is based on the self-reported experiences of the patient as well as abnormalities in behavior reported by family members, friends or co-workers, followed by secondary signs observed by a psychiatrist, nurse, social worker, clinical psychologist or other clinician in a clinical assessment. There is a list of criteria that must be met for someone to be so diagnosed. These depend on both the presence and duration of certain signs and symptoms.

An initial assessment includes a comprehensive history and physical examination by a physician. Although there are no biological tests which confirm bipolar disorder, tests are carried out to exclude medical illnesses which may rarely present with psychiatric symptoms. These include blood tests measuring TSH to exclude hypo- or hyperthyroidism, basic electrolytes and serum calcium to rule out a metabolic disturbance, full blood count including ESR to rule out a systemic infection or chronic disease, and serology to exclude syphilis or HIV infection; two commonly ordered investigations are EEG to exclude epilepsy, and a CT scan of the head to exclude brain lesions.

There are several psychiatric illnesses which may present with similar symptoms; these include schizophrenia, schizoaffective disorder, drug intoxication, brief drug-induced psychosis, schizophreniform disorder and borderline personality disorder. Alternately, patients currently in a hypomanic or mixed affective episode may display symptoms resembling borderline personality disorder.

The last is important as both diagnoses involve symptoms commonly known as "mood swings". In bipolar disorder, the term refers to the cyclic episodes of elevated and depressed mood which generally last weeks or months (notwithstanding Rapid Cycling variant of greater than four episodes a year). The term in borderline personality refers to the marked lability and reactivity of mood, known as emotional dysregulation, due to response to external psychosocial and intrapsychic stressors; these may arise or subside suddenly and dramatically and last for seconds, minutes, hours or days. A bipolar depression is generally more pervasive with sleep, appetite disturbance and nonreactive mood, whereas the mood in dysthymia of borderline personality remains markedly reactive and sleep disturbance not acute.

The relationship between bipolar disorder and borderline personality disorder has been debated; some hold that the latter represents a subthreshold form of affective disorder, while others maintain the distinctness, though noting they often coexist.

Investigations are not generally repeated for relapse unless there is a specific medical indication. These may include serum BSL if olanzapine has previously been prescribed, lithium or valproate level to check compliance or toxicity with those medications, renal or thyroid function if lithium has been previously prescribed and taken regularly. Assessment and treatment are usually done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to oneself or others.

The most widely used criteria for diagnosing bipolar disorder are from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the current version being DSM-IV-TR, and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, currently the ICD-10. The latter criteria are typically used in European countries while the DSM criteria are used in the USA or the rest of the world, as well as prevailing in research studies.

Recent studies by John Kelsoe have linked bipolar disorder to genetic defects. “…[M]utations in the G protein receptorhinase (GRK3) gene—which regulates sensitivity to brain neurotransmitters such as dopamine…” Kelsoe’s genetic discovery seeks to provide alternative treatments for those with bipolar disease. In 1997 a genome survey was completed and Kelsoe and colleges reported that, “results support the presence of a susceptibility locus for bipolar disorder on chromosome 22…These molecular data raise the possibility that common susceptibility genes may be involved.”

Diagnostic criteria and classification
There is no clear consensus as to how many types of bipolar disorder exist. In DSM-IV-TR and ICD-10, bipolar disorder is conceptualized as a spectrum of disorders occurring on a continuum. The DSM-IV-TR lists four types of mood disorders which fit into the bipolar categories: Bipolar I, Bipolar II, Cyclothymia, and Bipolar Disorder NOS (Not Otherwise Specified).

Bipolar I
In Bipolar I disorder, an individual has experienced one or more manic episodes with or without major depressive episodes. For a diagnosis of Bipolar I disorder according to the DSM-IV-TR, there requires one or more manic or mixed episodes. A depressive episode is not required for the diagnosis of Bipolar I disorder but it frequently occurs.

Bipolar II
Bipolar II disorder is characterized by more hypomanic episodes rather than actual manic episodes, as well as at least one major depressive episode. Hypomanic episodes usually do not go to the full extremes of mania (i.e. do not usually cause severe social or occupational impairment, and without psychosis), and this can make Bipolar II more difficult to diagnose, since the hypomanic episodes may simply appear as a period of successful high productivity and is reported less frequently than a distressing depression. For both disorders, there are a number of specifiers that indicate the presentation and course of the disorder, including "chronic", "rapid cycling", "catatonic" and "melancholic".

Cyclothymia
Cyclothymia involves a presence or history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes. A diagnosis of Cyclothymic Disorder requires the presence of numerous hypomanic episodes, intermingled with depressive episodes that do not meet full criteria for major depressive episodes. The main idea here is that there is a low-grade cycling of mood which appears to the observer as a personality trait, but interferes with functioning.

Bipolar-NOS
Bipolar Disorder Not Otherwise Specified is a catch-all diagnosis that is used to indicate bipolar illness that does not fit into the other diagnostic categories. If an individual clearly seems to be suffering from some type of bipolar disorder but does not meet the criteria for one of the subtypes above, he or she receives a diagnosis of Bipolar Disorder NOS (Not Otherwise Specified).

Although a patient will most likely be depressed when they first seek help, it is important to find out from the patient or the patient's family or friends if a manic or hypomanic episode has ever occurred. This will prevent misdiagnosis of Depressive Disorder and avoids the use of an antidepressant which may trigger a "switch" to hypomania or mania or induce rapid cycling. Recent screening tools such as the Hypomanic Check List Questionnaire (HCL-32) have been developed to assist the quite often difficult detection of Bipolar II disorders.

Delay in diagnosis
The behavioral manifestations of bipolar disorder are often not understood by patients nor recognized by mental health professionals, so diagnosis may sometimes be delayed for 10 years or more. That treatment lag is apparently not decreasing, even though there is now increased public awareness of this mental health condition in popular magazines and health websites. Recent TV specials, for example the BBC's The Secret Life of the Manic Depressive, MTV's True Life: I'm Bipolar, talk shows, and public radio shows, and the greater willingness of public figures to discuss their own bipolar disorder, have focused on psychiatric conditions thereby further raising public awareness. Despite this increased focus, individuals are still commonly misdiagnosed.

Children
Children with bipolar disorder do not often meet the strict DSM-IV definition, tending to have rapid-cycling or mixed-cycling pattern. The incidence in this age group has been traditionally held to be very rare. In September 2007, experts (from New York, Maryland and Madrid) found that the number of American children and adolescents treated for bipolar disorder increased 40-fold from 1994 to 2003, and it was increasing ever since. They concluded that doctors had been more aggressively applying the diagnosis to children, and not that the incidence of the disorder had increased. The study calculated the number of visits which increased, from 20,000 in 1994 to 800,000 in 2003, or 1% of the population under age 20.

Often other psychiatric conditions are diagnosed in bipolar children. These other diagnoses may be concurrent problems, or they may be misdiagnosed as bipolar disorder. Depression, ADHD, ODD, schizophrenia, and Tourette syndrome are common comorbid conditions. Furthermore some children with histories of abuse or neglect may have Bipolar I Disorder.

Other theoretical models
Flux is the fundamental nature of bipolar disorder. Individuals with the illness have continual changes in energy, mood, thought, sleep, and activity. The diagnostic subtypes of bipolar disorder are thus static descriptions — snapshots, perhaps — of an illness in continual flux, with a great diversity of symptoms and varying degrees of severity. Individuals may stay in one subtype, or change into another, over the course of their illness (Goodwin &amp; Jamison, 1990). The DSM V, to be published in 2012, will likely include further and more accurate sub-typing (Akiskal and Ghaemi, 2006).

Associated features
Associated features are clinical phenomenon that often accompany the disorder, but are not part of the diagnostic criteria for the disorder.

Cognitive impairment
Recent studies have found that bipolar disorder involves certain cognitive deficits or impairments, even in states of remission.

It is not known whether specific cognitive deficits are mood state dependent or disorder-specific features of bipolar disorder. Few studies have examined impairments throughout all the different mood states, and many studies show conflicting data compared to other studies on account of methodological differences. Furthermore, the presence of mixed mood states complicates the identification of accurate cognitive models for this condition. Some use theories that conform to the cognitive models for unipolar depression and others on theories that focus solely on physiological or biological aspects of mania. However, Deborah Yurgelun-Todd of McLean Hospital in Belmont, Massachusetts has argued that some deficits should be included as a core feature of bipolar disorder. According to McIntyre et al. (2006),

Study results now press the point that neurocognitive deficits are a primary feature of BD; they are highly prevalent and persist in the absence of overt symptomatology. Although disparate neurocognitive abnormalities have been reported, disturbances in attention, visual memory, and executive function are most consistently reported.

However, in the April–June 2007 issue of the Journal of Psychiatric Research (41, 3–4, 265–272) Spanish researchers (Selva et al.) reported that people with bipolar I who have a history of psychotic symptoms do not necessarily experience an increase in cognitive impairment. Some individuals diagnosed with bipolar I may experience only mood-congruent psychotic symptoms which may suggest a less severe prognosis, but this is by no means conclusive.

Creativity
A number of recent studies have observed a correlation between creativity and bipolar disorder, although it is unclear in which direction the cause lies, or whether both conditions are caused by a third unknown factor. Temperament has been hypothesized to be one such factor.

Epidemiology
Clinical depression and bipolar disorder are classified as separate illnesses. Some researchers increasingly view them as part of an overlapping spectrum that also includes anxiety and psychosis.

According to Hagop Akiskal, M.D., at the one end of the spectrum is bipolar type schizoaffective disorder, and at the other end is unipolar depression (recurrent or not recurrent), with the anxiety disorders present across the spectrum. Also included in this view is premenstrual dysphoric disorder, postpartum depression, and postpartum psychosis. This view helps to explain why many people who have the illness do not have first-degree relatives with clear-cut "bipolar disorder", but who have family members with a history of these other disorders.

In a 2003 study, Hagop Akiskal M.D. and Lew Judd M.D. re-examined data from the landmark Epidemiologic Catchment Area study from two decades before. The original study found that 0.8 percent of the population surveyed had experienced a manic episode at least once (the diagnostic threshold for bipolar I) and 0.5 a hypomanic episode (the diagnostic threshold for bipolar II).

By tabulating survey responses to include sub-threshold diagnostic criteria, such as one or two symptoms over a short time-period, the authors arrived at an additional 5.1 percent of the population, adding up to a total of 6.4 percent of the entire population who can be thought of as having a bipolar spectrum disorder. This and similar recent studies have been interpreted by some prominent bipolar disorders researchers as evidence for a much higher prevalence of bipolar conditions in the general population than previously thought.

However these re-analyses should be interpreted cautiously because of substantive as well as methodological study limitations. Indeed, prevalence studies of bipolar disorder are carried out by lay interviewers (that is, not by expert clinicians/psychiatrists who are more costly to employ) who follow fully structured/fixed interview schemes; responses to single items from such interviews may suffer limited validity.

Furthermore, a well-known statistical problem arises when ascertaining disorders and conditions with a relatively low population prevalence or base-rate, such as bipolar disorder: even assuming that lay interviews diagnoses are highly accurate in terms of sensitivity and specificity and their corresponding area under the ROC curve (that is, AUC, or area under the receiver operating characteristic curve), a condition with a relatively low prevalence or base-rate is bound to yield high false positive rates, which exceed false negative rates; in such a circumstance a limited positive predictive value, PPV, yields high false positive rates even in presence of a specificity which is very close to 100%. To simplify, it can be said that a very small error applied over a very large number of individuals (that is, those who are *not affected* by the condition in the general population during their lifetime; for example, over 95%) produces a relevant, non-negligible number of subjects who are incorrectly classified as having the condition or any other condition which is the object of a survey study: these subjects are the so-called false positives; such reasoning applies to the 'false positive' but not the 'false negative' problem where we have an error applied over a relatively very small number of individuals to begin with (that is, those who are *affected* by the condition in the general population; for example, less than 5%). Hence, a very high percentage of subjects who seem to have a history of bipolar disorder at the interview are false positives for such a medical condition and apparently never suffered a fully clinical syndrome (that is, bipolar disorder type I): the population prevalence of bipolar disorder type I, which includes at least a lifetime manic episode, continues to be estimated at 1%. "Mild-to-severe versions of bipolar disorder afflict nearly 4 percent of adults at some time in their lives."

A different but related problem in evaluating the public health significance of psychiatric conditions has been highlighted by Robert Spitzer of Columbia University: fulfillment of diagnostic criteria and the resulting diagnosis do not necessarily imply need for treatment. As a consequence, subjects who experience bipolar symptoms but not a full-blown, impairing bipolar syndrome should not be automatically considered as patients in need of treatment.

Recent studies have indicated that at least 50% of adult sufferers report manifestation of symptoms before the age of 17. Moreover, there is a growing consensus that bipolar disorder originates in childhood. In young children the illness is now referred to as pediatric bipolar disorder. Today about 0.5% of children under 18 are believed to have the condition. For children, the main concern is that bipolar disorder needs to be diagnosed correctly and treated properly because it can look like unipolar depression, ADHD, or conduct disorder. Young children, adolescents and adults each express the condition differently according to child and adolescent bipolar disorders expert Demitri Papolos M.D. and the Child and Adolescent Bipolar Foundation. There is, however, controversy about this last point.

Bipolar disorder manifests in late life as well. Some individuals with "hyperthymic" temperament (or "hypomanic" personality style) who experience depression in later life appear to have a form of bipolar disorder. Much more needs to be elucidated about late-life bipolar disorder.

Controversy
A debate rages in the medical community on the prevalence of bipolar disorders. Concerns have arisen about the potential for overdiagnosis of BD. One controversy has been the validity of the construct of a mental disorder across different cultural perspectives (Lopez &amp; Guarnaccia 2000, Sher &amp; Trull 1996). Culture-bound syndromes represent recurrent patterns of maladaptive behaviors and/or troubling experiences specifically associated with different cultures or localities (APA, 1994b). It can be difficult to distinguish between age-appropriate restlessness, the fidgeting of children with ADHD, and the purposeful busy activity of mania (Harrington &amp; Myatt, 2003). Further complicating the diagnosis: Abused or traumatized children can seem to have bipolar disorder when they are actually reacting to horrors in their lives. Assumptions regarding behavior, particularly in regard to diagnosing bipolar disorder, ADHD, and mania in children and adolescents, have raised considerable questions regarding unnecessary treatment. Antipsychotic drugs prescribed for the treatment of BD may increase risk to health including heart problems, diabetes, liver failure, and death. "Consequences of overdiagnosis … include exposure to a greater medication burden (in some cases requiring additional monitoring) as well as lesser likelihood of clinical improvement." When checking for a misdiagnosis of Bipolar disorder or confirming a diagnosis of Bipolar disorder, it is useful to consider what other medical conditions might be possible misdiagnoses or other alternative conditions relevant to diagnosis.

Causes
According to the U.S. government's National Institute of Mental Health (NIMH), "There is no single cause for bipolar disorder — rather, many factors act together to produce the illness." "Because bipolar disorder tends to run in families, researchers have been searching for specific genes passed down through generations that may increase a person's chance of developing the illness." "In addition, findings from gene research suggest that bipolar disorder, like other mental illnesses, does not occur because of a single gene.".

Supporting the concept of genetic etiology was a study conducted by A. James Giannini and Andrew E. Slaby. Retrospectively reviewing the case histories of approximately 500 patients they described correlates with anatomical abnormalities.Bipolar patients had a significantly higher occurence ofmitral valve prolapse (MVP),temporomandibular joint disease (TMJ), and scoliosis.They hypothesized that genetic sites involved in bipolar disorder were in close proximity to genes related to TMJ, MVP and scoliosis. Although this work was conducted on patients admitted to a general hospital in the years 1989-1990, it has not yet been replicated for verification.

It is well established that bipolar disorder is a genetically influenced condition which can respond very well to medication (Johnson &amp; Leahy, 2004; Miklowitz &amp; Goldstein, 1997; Frank, 2005). (See treatment of bipolar disorder for a more detailed discussion of treatment.)

Psychological factors also play a strong role in both the psychopathology of the disorder and the psychotherapeutic factors aimed at alleviating core symptoms, recognizing episode triggers, reducing negative expressed emotion in relationships, recognizing prodromal symptoms before full-blown recurrence, and, practising the factors that lead to maintenance of remission (Lam et al, 1999; Johnson &amp; Leahy, 2004; Basco &amp; Rush, 2005; Miklowitz &amp; Goldstein, 1997; Frank, 2005). Modern evidence based psychotherapies designed specifically for bipolar disorder when used in combination with standard medication treatment increase the time the individual stays well significantly longer than medications alone (Frank, 2005). These psychotherapies are interpersonal and social rhythm therapy for bipolar disorder, family focused therapy for bipolar disorder, psychoeducation, cognitive therapy for bipolar disorder, and prodrome detection. All except psychoeducation and prodrome detection are available as books.

Abnormalities in brain function have been related to feelings of anxiety and lower stress resilience. When faced with a very stressful, negative major life event, such as a failure in an important area, an individual may have his first major depression. Conversely, when an individual accomplishes a major achievement he may experience his first hypomanic or manic episode. Individuals with bipolar disorder tend to experience episode triggers involving either interpersonal or achievement-related life events. An example of interpersonal-life events include falling in love or, conversely, the death of a close friend. Achievement-related life events include acceptance into an elite graduate school or by contrast, being fired from work (Miklowitz &amp; Goldstein, 1997). Childbirth can also trigger a postpartum psychosis for bipolar women, which can lead in the worst cases to infanticide.

The "kindling" theory asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events, each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and become recurrent) by itself. There is evidence of hypothalamic-pituitary-adrenal axis (HPA axis) abnormalities in bipolar disorder due to stress. Some individuals experience subsequent mood episodes in the absence of positive or negative life events, however, which can be especially debilitating.

Individuals with late-adolescent/early adult onset of the disorder will very likely have experienced childhood anxiety and depression. Some argue that childhood-onset bipolar disorder should be treated when it occurs to prevent the full development of the disorder.

A family history of bipolar spectrum disorders can impart a genetic predisposition towards developing a bipolar spectrum disorder. Since bipolar disorders are polygenic (involving many genes), there are apt to be many unipolar and bipolar disordered individuals in the same family pedigree. This is very often the case (Barondes, 1998). Anxiety disorders, clinical depression, eating disorders, premenstrual dysphoric disorder, postpartum depression, postpartum psychosis schizoaffective disorder and/or schizophrenia may be part of the patient's family history and reflects a term called "genetic loading".

Bipolar disorder is not either environmental or physiological, it is multifactorial; that is, many genes and environmental factors conspire to create the disorder (Johnson &amp; Leahy, 2004).

Since bipolar disorder is so heterogeneous, it is likely that people experience different pathways towards the illness (Miklowitz &amp; Goldstein, 1997).

For example, recent research done in Japan hypothesizes that dysfunctional mitochondria in the brain may play a role (Stork &amp; Renshaw, 2005).

Heritability or inheritance
The disorder runs in families. More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.

Studies seeking to identify the genetic basis of bipolar disorder indicate that susceptibility stems from multiple genes. Scientists are continuing their search for these genes, using advanced genetic analytic methods and large samples of families affected by the illness. The researchers are hopeful that identification of susceptibility genes for bipolar disorder, and the brain proteins they code for, will make it possible to develop better treatments and preventive interventions targeted at the underlying illness process.

Genetic research
There is increasing evidence for a genetic component in the causation of bipolar disorder, provided by a number of twin studies and gene linkage studies.

The monozygotic concordance rate for the disorder is 70%. This means that if a person has the disorder, an identical twin has a 70% likelihood of having the disorder as well. Dizygotic twins have a 23% concordance rate. These concordance rates are not universally replicated in the literature; recent studies have shown rates of around 40% for monozygotic and less than 10% for dizygotic twins (see Kieseppa, 2004 and Cardno, 1999).

In 2003, a group of American and Canadian researchers published a paper that used gene linkage techniques to identify a mutation in the GRK3 gene as a possible cause of up to 10% of cases of bipolar disorder. This gene is associated with a kinase enzyme called G protein receptor kinase 3, which appears to be involved in dopamine metabolism, and may provide a possible target for new drugs for bipolar disorder.

A 2007 gene-linkage study by an international team coordinated by the NIMH has identified a number of genes as likely to be involved in the etiology of bipolar disorder, suggesting that bipolar disorder may be a polygenic disease. The researchers at NIMH have found a correlation between DGKH (diacylglycerol kinase eta) and bipolar disorder. The portion of the genome that encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway.

In 2008, one study detected association of PPARD gene polymorphisms with bipolar disorder.

Treatment
Bipolar disorder cannot be cured; instead, the emphasis of treatment is on effective management of acute episodes and prevention of further episodes by use of pharmacological and psychotherapeutic techniques.

Hospitalization may occur, especially with manic episodes. This can be voluntary or (if mental health legislation allows it) involuntary (called civil or involuntary commitment). Long-term inpatient stays are now less common due to deinstitutionalization, although can still occur. Following (or in lieu of) a hospital admission, support services available can include drop-in centers, visits from members of a community mental health team or Assertive Community Treatment team, supported employment and patient-led support groups.

Medication
The mainstay of treatment is a mood stabilizer medication; these comprise several unrelated compounds which have been shown to be effective in preventing relapses of manic, or in the one case, depressive episodes. The first known and "gold standard" mood stabilizer is lithium, while almost as widely used is sodium valproate, originally used as an anticonvulsant. Other anticonvulsants used in bipolar disorder include carbamazepine, reportedly more effective in rapid cycling bipolar disorder, and lamotrigine, which is the first anticonvulsant shown to be of benefit in bipolar depression.

Treatment of the agitation in acute manic episodes has often required the use of antipsychotic medications, such as Quetiapine, Olanzapine and Chlorpromazine. More recently, Olanzapine and Quetiapine have been approved as effective monotherapy for the maintenance of bipolar disorder. A head-to-head randomized control trial in 2005 has also shown olanzapine monotherapy to be as effective and safe as lithium in prophylaxis.

The use of antidepressants in bipolar disorder has been debated, with some studies reporting a worse outcome with their use triggering manic, hypomanic or mixed episodes, especially if no mood stabiliser is used. However, most mood stabilizers are of limited effectiveness in depressive episodes.

Research
The following studies are ongoing, and are recruiting volunteers:

The Maudsley Bipolar Twin Study, based at the Institute of Psychiatry in London is conducting research about the genetic basis of bipolar disorder using twin methodology. Currently recruiting volunteers: identical and non-identical twins pairs, where either one or both twins has a diagnosis of bipolar I or II.

The Maudsley Bipolar eMonitoring Project, another research study based at the Institute of Psychiatry in London, is conducting novel research on electronic monitoring methodologies (electronic mood diaries and actigraphy) for tracking bipolar symptom fluctuations in Bipolar individuals who are interested in self-managing their condition. The study is currently recruiting volunteers from all over the world (see Remote eMonitoring)

Medical imaging
Researchers are using advanced brain imaging techniques to examine brain function and structure in people with bipolar disorder, particularly using the functional MRI and positron emission tomography. An important area of neuroimaging research focuses on identifying and characterizing networks of interconnected nerve cells in the brain, interactions among which form the basis for normal and abnormal behaviors. Researchers hypothesize that abnormalities in the structure and/or function of certain brain circuits could underlie bipolar and other mood disorders, and studies have found anatomical differences in areas such as the amygdala, prefrontal cortex and hippocampus.

Better understanding of the neural circuits involved in regulating mood states, and genetic factors such as the cadherin gene FAT linked to bipolar disorder, may influence the development of new and better treatments, and may ultimately aid in early diagnosis and even a cure.

New treatments
In late 2003, researchers at McLean Hospital found tentative evidence of improvements in mood during echo-planar magnetic resonance spectroscopic imaging (EP-MRSI), and attempts are being made to develop this into a form which can be evaluated as a possible treatment.

NIMH has initiated a large-scale study at 20 sites across the United States to determine the most effective treatment strategies for people with bipolar disorder. This study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), will follow patients and document their treatment outcome for 5–8 years. For more information, visit the Clinical Trials page of the NIMH Web site.

Transcranial magnetic stimulation is another fairly new technique being studied.

Pharmaceutical research in the United States is extensive and ongoing, as seen at clinicaltrials.gov.

Prognosis
For some, good prognosis results from good treatment, which, in turn, results from an accurate diagnosis. Because bipolar disorder continues to have a high rate of both under-diagnosis and misdiagnosis, it is often difficult for individuals with the condition to receive timely and competent treatment.

Bipolar disorder can be a severely disabling medical condition. However, many individuals with bipolar disorder can live full and satisfying lives. Sometimes medication is needed to enable this. Persons with bipolar disorder are likely to have periods of normal or near normal functioning between episodes.

Ultimately one's prognosis depends on many factors, which may, in fact, be under the individual's control, these may include: the right medicines; the right dose of each; a very informed patient; a good working relationship with a competent medical doctor; a competent, supportive and warm therapist; a supportive family or significant other; and a balanced lifestyle including a regulated stress level, regular exercise and regular sleep and wake times.

There are obviously other factors that lead to a good prognosis as well, such as being very aware of small changes in one's energy, mood, sleep and eating behaviors, as well as having a plan in conjunction with one's doctor for how to manage subtle changes that might indicate the beginning of a mood swing. Some people find that keeping a log of their moods can assist them in predicting changes.

Functioning
A recent 20-year prospective study on bipolar I and II has been described as having characterized bipolar by "a low rate of recovery, a high rate of recurrence, and poor interepisodic functioning." However, the study did not report recovery or recurrence rates but that functioning varied along a spectrum from good to fair to poor, and only with periods of major depression or mania (in BPI) was it poor; that depression was more persistantly associated with disability than mania; that interepisodic functioning was near normal; and that subsyndromal symptoms were generally still substantially impairing, although subsyndromal and symptom-level hypomania in BPII was associated with improved functioning.

Another study confirmed the seriousness of the disorder as "the standardized all-cause mortality ratio among patients with BD is increased approximately 2-fold." Bipolar disorder is currently regarded "as possibly the most costly category of mental disorders in the United States."

Recovery
A naturalistic study from first admission for mania or mixed episode (representing the hospitalized and therefore most severe cases) found that 50% achieved syndromal recovery (no longer meeting criteria for the diagnosis) within six weeks and 98% within two years. 72% achieved symptomatic recovery (no symptoms at all) and 43% achieved functional recovery (regaining of prior occupational and residential status). However, 40% went on to experience a new episode of mania or depression within 2 years of syndromal recovery, and 19% switched phases without recovery.

Recurrence
The following behaviors can lead to depressive or manic recurrence:


 * Discontinuing or lowering one's dose of medication, without consulting one's physician.
 * Being under- or over-medicated. Generally, taking a lower dosage of a mood stabilizer can lead to relapse into mania. Taking a lower dosage of an antidepressant, may cause the patient to relapse into depression, while higher doses can cause destabilization into mixed-states or mania.
 * An inconsistent sleep schedule can destabilize the illness. Too much sleep (possibly caused by medication) can lead to depression, while too little sleep can lead to mixed states or mania.
 * Caffeine can cause destabilization of mood toward irritability, dysphoria, and mania. Anecdotal evidence seems to suggest that lower dosages of caffeine can have effects ranging from anti-depressant to mania-inducing.
 * Inadequate stress management and poor lifestyle choices. If unmedicated, excessive stress can cause the individual to relapse. Medication raises the stress threshold somewhat, but too much stress still causes relapse.
 * Often bipolar individuals are subject to self-medication, the most common drugs being alcohol, and marijuana. Sometimes they may also turn to hard drugs, which can cause the condition to worsen. Studies show that tobacco smoking induces a calming effect on most bipolar people, and a very high percentage suffering from the disorder smoke.

Recurrence can be managed by the sufferer with the help of a close friend, based on the occurrence of idiosyncratic prodromal events. This theorizes that a close friend could notice which moods, activities, behaviours, thinking processes, or thoughts typically occur at the outset of bipolar episodes. They can then take planned steps to slow or reverse the onset of illness, or take action to prevent the episode from being damaging. These sensitivity triggers show some similarity to traits of a highly sensitive person.

Mortality
"Mortality studies have documented an increase in all-cause mortality in patients with BD. A newly established and rapidly growing database indicates that mortality due to chronic medical disorders (eg, cardiovascular disease) is the single largest cause of premature and excess deaths in BD. The standardized mortality ratio from suicide in BD is estimated to be approximately 18 to 25, further emphasizing the lethality of the disorder."

Although many people with bipolar disorder who attempt suicide never actually complete it, the annual average suicide rate in males and females with diagnosed bipolar disorder (0.4%) is 10 to more than 20 times that in the general population.

Individuals with bipolar disorder may become suicidal, especially during mixed states such as dysphoric mania and agitated depression. Persons suffering from Bipolar II have high rates of suicide compared to persons suffering from other mental health conditions, including Major Depression. Major Depressive episodes are part of the Bipolar II experience, and there is evidence that sufferers of this disorder spend proportionally much more of their life in the depressive phase of the illness than their counterparts with Bipolar I Disorder (Akiskal &amp; Kessler, 2007).

History
Varying moods and energy levels have been a part of the human experience since time immemorial. The words "melancholia" (an old word for depression) and "mania" have their etymologies in Ancient Greek. The word melancholia is derived from melas/μελας, meaning "black", and chole/χολη, meaning "bile" or "gall", indicative of the term’s origins in pre-Hippocratic humoral theories. Within the humoral theories, mania was viewed as arising from an excess of yellow bile, or a mixture of black and yellow bile. The linguistic origins of mania, however, are not so clear-cut. Several etymologies are proposed by the Roman physician Caelius Aurelianus, including the Greek word ‘ania’, meaning to produce great mental anguish, and ‘manos’, meaning relaxed or loose, which would contextually approximate to an excessive relaxing of the mind or soul (Angst and Marneros 2001). There are at least five other candidates, and part of the confusion surrounding the exact etymology of the word mania is its varied usage in the pre-Hippocratic poetry and mythologies (Angst and Marneros 2001).

The idea of a relationship between mania and melancholia can be traced back to at least the 2nd century AD. Soranus of Ephesus (98–177 AD) described mania and melancholia as distinct diseases with separate etiologies; however, he acknowledged that “many others consider melancholia a form of the disease of mania” (Cited in Mondimore 2005 p.49).

A clear understanding of bipolar disorder as a mental illness was recognized by early Chinese authors. The encyclopedist Gao Lian (c. 1583) describes the malady in his Eight Treatises on the Nurturing of Life (Ts'un-sheng pa-chien).

The earliest written descriptions of a relationship between mania and melancholia are attributed to Aretaeus of Cappadocia. Aretaeus was an eclectic medical philosopher who lived in Alexandria somewhere between 30 and 150 AD (Roccatagliata 1986; Akiskal 1996). Aretaeus is recognized as having authored most of the surviving texts referring to a unified concept of manic-depressive illness, viewing both melancholia and mania as having a common origin in ‘black bile’ (Akiskal 1996; Marneros 2001).

Avicenna, a Persian physician and psychological thinker who wrote The Canon of Medicine in 1025, identified bipolar disorder as a manic depressive psychosis, which he clearly distinguished from other forms of madness (Junun) such as as mania, rabies, and schizophrenia (Junun Mufrit or severe madness).



The basis of the current conceptualisation of manic-depressive illness can be traced back to the 1850s; on January 31, 1854, Jules Baillarger described to the French Imperial Academy of Medicine a biphasic mental illness causing recurrent oscillations between mania and depression, which he termed folie à double forme (‘dual-form insanity’). Two weeks later, on February 14, 1854, Jean-Pierre Falret presented a description to the Academy on what was essentially the same disorder, and designated folie circulaire (‘circular insanity’) by him.(Sedler 1983) The two bitterly disputed as to who had been the first to conceptualise the condition.

These concepts were developed by the German psychiatrist Emil Kraepelin (1856–1926), who, using Kahbaum concept of cyclothymia, categorized and studied the natural course of untreated bipolar patients. He coined the term manic depressive psychosis, after noting that periods of acute illness, manic or depressive, were generally punctuated by relatively symptom-free intervals where the patient was able to function normally.

After World War II, Dr. John Cade, an Australian psychiatrist, was investigating the effects of various compounds on veteran patients with manic depressive psychosis. In 1949, Cade discovered that lithium carbonate could be used as a successful treatment of manic depressive psychosis. Because there was a fear that table salt substitutes could lead to toxicity or death, Cade's findings did not immediately lead to treatments. In the 1950s, U.S. hospitals began experimenting with lithium on their patients. By the mid-'60s, reports started appearing in the medical literature regarding lithium's effectiveness. The U.S. Food and Drug Administration did not approve of lithium's use until 1970.

The term "manic-depressive reaction" appeared in the first American Psychiatric Association Diagnostic Manual in 1952, influenced by the legacy of Adolf Meyer who had introduced the paradigm illness as a reaction of biogenetic factors to psychological and social influences. Subclassification of bipolar disorder was first proposed by German psychiatrist Karl Leonhard in 1957; he was also the first to introduce the terms bipolar (for those with mania) and unipolar (for those with depressive episodes only).

In 1968, both the newly revised classification systems ICD-8 and DSM-II termed the condition "manic-depressive illness" as biological thinking came to the fore.

The current nosology, bipolar disorder, became popular only recently, and some individuals prefer the older term because it provides a better description of a continually changing multi-dimensional illness.

Cultural references
Kay Redfield Jamison is a clinical psychologist and Professor of Psychiatry at the Johns Hopkins University School of Medicine, who profiled her own bipolar disorder in her 1995 memoir An Unquiet Mind and argued for a connection between bipolar disorder and artistic creativity in her 1993 book, Touched with Fire.

Several films have portrayed characters with traits strongly suggestive of the diagnosis which have been the subject of discussion by psychiatrists and film experts alike. The 1993 film Mr. Jones is a notable example, with Richard Gere playing a person who swings from a manic episode into a depressive phase and back again, spending time in a psychiatric hospital and displaying many of the features of the syndrome. Allie Fox, the character played by Harrison Ford in the 1992 movie The Mosquito Coast, displays some features including recklessness, grandiosity, increased goal-directed activity and mood lability, as well as some paranoia.

In the NBC drama ER, series of episodes follow Maura Tierney's Abby Lockhart character's relation with her bipolar mother Maggie, and later her brother, who had been misdiagnosed with depression, but who in fact had inherrited BD from Maggie.