Bipolar disorder (previously known as manic depression) is a psychiatric diagnostic category describing a class of mood disorders in which the person experiences clinical depression and/or mania, hypomania, and/or mixed states. Persons suffering from the disorder are considered to be disabled.

Cases of bipolar disorder are generally divided into two diagnostic categories, Bipolar I and Bipolar II. Left untreated, bipolar disorder can be a severely disabling condition, with a risk of death through suicide.

The difference between bipolar disorder and unipolar disorder (also called major depression) is that bipolar disorder involves both elevated and depressive mood states. The duration and intensity of mood states varies widely among people with the illness. Fluctuating from one mood state to the next is called "cycling". Mood swings can cause impairment or improved functioning depending on their severity. There can be changes in one's energy level, sleep pattern, activity level, social rhythms and cognitive functioning. During these times, some people may have difficulty functioning.

Domains of the bipolar spectrum
Bipolar disorder is, almost without exception, a life-long condition that must be carefully managed throughout the individual's lifetime. Because there are many manifestations of the illness, it is increasingly being called bipolar spectrum disorder. The spectrum concept refers to subtypes of bipolar disorder that are sub-syndromal (below the symptom threshold) and typically misdiagnosed as depression. Nassir Ghaemi, M.D., has also contributed to the development of a bipolar spectrum questionnaire. The full bipolar spectrum includes all states or phases of the bipolar disorders.

Bipolar depression
The vast majority of people diagnosed with, or who may be diagnosed with, bipolar disorder suffer from clinical depression. In fact, there is at least a 3 to 1 ratio of time spent depressed versus time spent among euthymic (normal mood), hypomanic and manic states during the course of the bipolar I subtype of the illness. People with the bipolar II subtype remain depressed for substantially longer (37 times longer) according to the study findings discussed in the epidemiology section below.

According to the Mayo Clinic, in the depressive phase, signs and symptoms include: persistent feelings of sadness, anxiety, guilt or hopelessness, disturbances in sleep and appetite, fatigue and loss of interest in daily activities, problems concentrating, irritability, chronic pain without a known cause, recurring thoughts of suicide.[3]

A 2003 study by Robert Hirschfeld, M.D., of the University of Texas, Galveston found bipolar patients fared worse in their depressions than unipolar patients. (See Bipolar Depression.) In terms of disability, lost years of productivity, and potential for suicide, bipolar depression, which is different (in terms of treatment), from unipolar depression, is now recognized as the most insidious aspect of the illness.

Severe depression may be accompanied by symptoms of psychosis. These symptoms include hallucinations (hearing, seeing, or otherwise sensing the presence of stimuli that are not there) and delusions (false personal beliefs that are not subject to reason or contradictory evidence and are not explained by a person's cultural concepts). They may also suffer from paranoid thoughts of being persecuted or monitored by some powerful entity such as the government or a hostile force. Intense and unusual religious beliefs may also be present, such as patients' strong insistence that they have a God-given role to play in the world, a great and historic mission to accomplish, or even that they possess supernatural powers. Delusions in a depression may be far more distressing, sometimes taking the form of intense guilt for supposed wrongs that the patient believes he or she has inflicted on others.

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Mania
Main article: Mania
Researchers at Duke University have refined Kraepelin’s four classes of mania to include hypomania (featuring mainly euphoria), severe mania (including euphoria, grandiosity, high levels of sexual drive, irritability, volatility, psychosis, paranoia, and hostility and aggression), extreme mania (most of the displeasures, hardly any of the pleasures) also known as dysphoric mania, and two forms of mixed mania (where depressive and manic symptoms collide).[1]

The Mayo Clinic and others list as additional possible symptoms of mania: elation, extreme optimism, rapid unstoppable flow of speech, racing thoughts/flights of ideas, agitation, poor judgment, recklessness or taking chances not normally taken, inordinate capacity for activity, difficulty sleeping or lesser need for sleep, tendency to be easily distracted (may constantly shift from one theme or endeavor to another), inability to concentrate, exuberant and flamboyant or colorful dress, authoritative manner, and tendency to believe they are in their best mental state.[4]

Manic patients may be inexhaustibly, excessively, and impulsively involved in various activities without recognizing the inherent social dangers.

Symptoms of psychosis include hallucinations (hearing, seeing, or otherwise sensing the presence of stimuli that are not there) and delusions (false personal beliefs that are not subject to reason or contradictory evidence and are not explained by a person's cultural concepts). Feelings of paranoia, during which the patient believes he or she is being persecuted or monitored by the government or a hostile force. Intense and unusual religious beliefs may also be present, such as a patient's strong insistence that they have a God-given role to play in the world, a great and historic mission to accomplish, or even that they possess supernatural powers. Delusions may or may not be mood congruent.

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Mania and over-the-counter drugs
Phenylpropanolamine or (PPA) is a sympathomimetic drug similar in structure to amphetamine which is present in over 130 medications, primarily decongestants, cough/cold remedies, and anorectic agents.

A report on phenylpropanolamine from the Dept. of Psychiatry, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Pharmacopsychiatry 1988 stated:

We have reviewed 37 cases (published in North America and Europe since 1960) that received diagnoses of acute mania, paranoid schizophrenia, and organic psychosis and that were attributed to PPA product ingestion. Of the 27 North American case reports, more reactions followed the ingestion of combination products than preparations containing PPA alone; more occurred after ingestion of over-the-counter products than those obtained by prescription or on-the-street; and more of the cases followed ingestion of recommended doses than overdoses.
Some reference books have noted that some people developed mental illness symptoms after flu like symptoms, the probability or link to the over-the-counter medications they were taking for their symptoms was sometimes overlooked.

Failure to recognize PPA as an etiological agent in the onset of symptoms usually led to a diagnosis of schizophrenia or mania, lengthy hospitalization, and treatment with substantial doses of neuroleptics or lithium.
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Hypomania
Main article: Hypomania
Hypomania is a less severe form of mania, without progression to psychosis. Many of the symptoms of mania are present, but to a lesser degree than in overt mania.

People with hypomania are generally perceived as being energetic, euphoric, overflowing with new ideas, and sometimes highly confident and charismatic, and unlike full-blown mania, they are sufficiently capable of coherent thought and action to participate in everyday life.

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Mixed state
Main article: Mixed state (psychiatry)
In the context of bipolar disorder, a mixed state is a condition during which symptoms of mania (or hypomania) and clinical depression occur simultaneously (for example, agitation, anxiety, fatigue, guilt, impulsiveness, insomnia, disturbances appetite, irritability, morbid and/or suicidal ideation, panic, paranoia, psychosis, pressured speech, indecisiveness and rage). [5]

In at least 1/3 of persons with bipolar disorders, the entire attack--or a succession of attacks--occurs as a mixed episode.

Mixed states can be the most dangerous period of mood disorders, during which panic attacks, substance abuse, and suicide attempts increase greatly.

A dysphoric mania consists of a manic episode with depressive symptoms. Increased energy and some form of anger, from irritability to full blown rage, are the most common symptoms. Symptoms may also include auditory hallucinations, confusion, insomnia, persecutory delusions, racing thoughts, restlessness, and suicidal ideation.

Alcohol, drugs of abuse, and antidepressant drugs may trigger or aggravate dysphoric mania in susceptible individuals.

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Cycling
Rapid cycling, defined as having four or more episodes per year, is found in a significant fraction of patients with bipolar disorder.

Ultradian cycling, in which mood cycling can also occur daily or even hourly, is less common. (Although the concept of ultradian cycling has been accepted by many psychiatrists, whether it represents true cycling is far from established.)[6]

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Cognition
Numerous studies show that bipolar disorder affects a patient's ability to think and perform mental tasks, even in states of remission.[2] Deborah Yurgelun-Todd of McLean Hospital in Belmont, Massachusetts has argued these deficits should be included as a core feature of bipolar disorder.

By the same token, research by Kay Redfield Jamison of Johns Hopkins University and others has attributed high rates of creativity and productivity to certain individuals with bipolar disorder. (See Brain Damage.)

There may be no conflict here: Cognitive dysfunction does not necessarily bar creativity.

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Suicide risk
People with bipolar disorder are about three times[citation needed] as likely to commit suicide as those suffering from major depression (12% to 30%).[citation needed] Although many people with bipolar disorder who attempt suicide never actually complete it, the annual average suicide rate in men and women with diagnosed bipolar disorder (0.4%) is 10 to more than 20 times that in the general population [7][8]

Individuals with bipolar disorder tend to become suicidal, especially during mixed states such as dysphoric hypomania and agitated depression. Suicidal symptoms include:

Talking about feeling suicidal or wanting to die
Feeling hopeless, that nothing will ever change or get better
Feeling helpless, that nothing makes a difference
Feeling like a burden to family and friends
Putting affairs in order (for example, organizing finances (paying debts) or giving away possessions to prepare for one's death)
Putting oneself in harm's way, or in situations where there is a danger of being killed
Abusing alcohol or drugs
A patient with these symptoms (or anyone related to said patient) could do the following:

Call the patient's doctor, emergency room, or the emergency telephone number right away to get immediate help
Make sure the suicidal person (be it self or somebody else) is not left alone
Make sure access to large amounts of medication, weapons, or other items that could be used, is prevented
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Diagnosis
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Diagnostic criteria
Main article: Current diagnostic criteria for bipolar disorder
Flux is the fundamental nature of bipolar disorder. Both within and between individuals with the illness, energy, mood, thought, sleep, and activity are among the continually changing biological markers of the disorder. The diagnostic subtypes of bipolar disorder are thus static descriptions--snapshots, perhaps--of an illness in change. Individuals may stay in one subtype, or change into another, over the course of their illness. The DSM V, to be published in 2011, will likely include further subtyping (Akiskal and Ghaemi, 2006).

There are currently 4 types of bipolar illness. The DSM-IV-TR details 4 categories of bipolar disorder, Bipolar I, Bipolar II, Cyclothymia, and Bipolar Disorder NOS (Not Otherwise Specified).

According to the DSM-IV-TR, a diagnosis of Bipolar I disorder requires one or more manic or mixed episodes. A depressive episode is not required for a diagnosis of BP I disorder, although the overwhelming majority of people with BP I suffer from them as well.

Bipolar II, the more common but by no means less severe type of the disorder, is characterized by some episodes of hypomania and disabling, severe depression; crippling depression with episodes of hypomania. A diagnosis of bipolar II disorder requires at least one hypomanic episode. This is used mainly to differentiate it from unipolar depression. Although a patient may be depressed, it is very important to find out from the patient or patient's family or friends if hypomania has ever been present, using careful questioning. This, again, avoids the antidepressant problem. Recent screening tools such as the Hypomanic Check List Questionnaire (HCL-32) have been developed to assist the sometimes difficult detection of Bipolar II disorders.

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.

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).

The criteria for "major depression" may apply to unipolar or bipolar depression.

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Misdiagnosis
There are many problems with symptom accuracy, relevance, and reliability in making a diagnosis of bipolar disorder in the DSM-IV-TR. These problems all too often lead to misdiagnosis.

In fact, University of California at San Diego's Hagop Akiskal M.D. believes that the way the bipolar disorders in the DSM are conceptualized and presented routinely lead many primary care doctors and mental health professionals to misdiagnose bipolar patients with unipolar depression, when a careful history from patient, family, and/or friends would yield the correct diagnosis.

If misdiagnosed with depression, patients are usually prescribed antidepressants, and the person with bipolar depression can become agitated, angry, hostile, suicidal, and even homicidal (these are all symptoms of hypomania, mania, and mixed states).

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Treatment lag
The behavioral manifestations of bipolar disorder are often not recognized by mental health professionals, so people may suffer unnecessarily for many years (over 10 years, according to research conducted by bipolar disorders expert Nassir Ghaemi M.D.) before receiving proper treatment.

That treatment lag is apparently not decreasing, even though there is now increased public awareness of the illness in popular magazines and health websites. Recent TV specials, for example MTV's "True Life: I'm Bipolar", talk shows, and public radio shows have focused on mental illnesses thereby further raising public awareness.

Despite this increased focus, individuals are still commonly misdiagnosed. (See the 2005 American Journal of Managed Care.)

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Children
Bipolar disorder is a frequent co-morbid condition among children who have experienced early chronic maltreatment, such as physical and sexual abuse or neglect, and who have Reactive attachment disorder.

There is a strong genetic component to this disorder, and parents who severely maltreat their children are themselves likely to suffer from significant mental health issues, such as Bipolar disorder.

About 50% of children who have Reactive attachment disorder also have Bipolar I disorder. [3]. Children with Bipolar disorder often do not meet the strict DSM-IV definition, because in pediatric cases the cycling can occur very quickly (see section above on rapid cycling). [4].

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Treatment
Main article: Treatment of bipolar disorder
Currently, bipolar disorder has not been cured, though many psychiatrists and psychologists believe that it can be managed.

The emphasis of treatment is on effective management of the long-term course of the illness, which can involve treatment of emergent symptoms. Treatment methods include pharmacological and psychological techniques.

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Prognosis and the goals of long-term treatment
A 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 underdiagnosis and misdiagnosis, it is often difficult for individuals with the illness to receive timely and competent treatment.

Bipolar disorder is a severely disabling medical condition. In fact, it is the 6th cause of disability in the world, according to the World Health Organization. However, with appropriate treatment, many individuals with bipolar disorder can live full and satisfying lives. Persons with bipolar disorder are likely to have periods of normal or near normal functioning between episodes.

The prognosis for bipolar disorder is, in general, better than that for schizophrenia. However, many atypical antipsychotics, which were originally developed to treat schizophrenia, have also been shown to be effective in bipolar mania.

Ultimately one's prognosis depends on many factors, which are, in fact, under the individual's control: 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 that includes exercise. One of the most important lifestyle changes is regular sleep and wake times; this cannot be stressed enough.

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.

The goals of long-term treatment should be to help the individual achieve the highest level of functioning, and to avoid relapse.

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Relapse
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Even when on medication, some people may still experience weaker episodes, or have a complete manic or depressive episode.

The following behaviors can lead to depressive or manic relapse:

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.
Taking hard drugs – recreationally or not – such as cocaine, alcohol, amphetamines, or opiates. These can cause the condition to worsen.
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.
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Research findings
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Heritability or inheritance
Bipolar disorder runs in families.[9] More than 2/3 of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression, indicating that the disease has a genetic component.

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.

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Genetic research
Bipolar disorder is considered to be a result of complex interactions between genes and environment.

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 <10% for dizygotic twins (see Kieseppa, 2004 [5] and Cardno, 1999 [6]).

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.[7]

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Ongoing 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 methdology. Currently recruiting volunteers: identical and non-identical twins pairs, where either one or both twins has a diagnosis of bipolar I or II.

The MRC eMonitoring Project, another research study based at the Institute of Psychiatry and Newcastle Universities, 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.

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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 prefrontal cortex[8] 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,[9] may influence the development of new and better treatments, and may ultimately aid in early diagnosis and even a cure.

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Personality types or traits
An evolving literature exists concerning the nature of personality and temperament in bipolar disorder patients, compared to major depressive disorder (unipolar) patients and non-sufferers. Such differences may be diagnostically relevant. Using MBTI continuum scores, bipolar patients were significantly more extroverted, intuitive, and perceiving, and less introverted, sensing, and judging than were unipolar patients[citation needed]. This suggests that there might be a correlation between the Jungian extraverted intuiting process and bipolar disorder.

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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.[10],[11]

NIMH has initiated a large-scale study at 20 sites across the U.S. 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[10].

Transcranial magnetic stimulation is another fairly new technique being studied.

Pharmaceutical research is extensive and ongoing, as seen at clinicaltrials.gov.

Gene therapy and nanotechnology are two more areas of future development.

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Causes (Etiology)
According to the US 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—the microscopic "building blocks" of DNA inside all cells that influence how the body and mind work and grow—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." [11].

It is well established that bipolar disorder is a genetically influenced condition which can respond very well to medication (Johnson & Leahy, 2004; Miklowitz & 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, practicing the factors that lead to maintenance of remission (Lam et al, 1999; Johnson & Leahy, 2004; Basco & Rush, 2005; Miklowitz & 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.

Brain scientist Husseini K. Manji M.D. of the NIMH states that at their most basic level, the bipolar disorders involve problems in brain structure and function. He stated that these structural changes respond very well to treatment with lithium and valproate in a University of California, Los Angeles Neuropsychiatric Institute (NPI) Grand Rounds Talkgiven in 2003 (requires Real Player and a high-speed internet connection).

Early in the course of the illness brain structural abnormalities may lead 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 & Goldstein, 1997).

Veteran brain researcher Robert Post M.D. of the U.S. NIMH proposed the "kindling" theory [12] which asserts that people who are genetically predisposed toward bipolar disorder experience a series of stressful events, each of which lowers the threshold at which mood changes occur. Eventually, the mood episode starts (and becomes recurrent) by itself. Not all individuals experience subsequent mood episodes in the absence of positive or negative life events, however.

Individuals with late-adolescent/early adult onset of the disorder will very likely have experienced childhood anxiety and depression. Childhood onset bipolar disorder should be treated early because according to Joseph Calabrese of Case Western Reserve University, childhood forms of the illness may be easier to treat than adult forms of the illness. (See his University of California, Los Angeles NPI Grand Rounds Talk on rapid-cycling in October 2003.)

It is becoming increasingly clear that bipolar and unipolar mood disorders have a genetic component. For example, a family history of bipolar spectrum disorders can impart a genetic predisposition towards developing a bipolar spectrum disorder[13]. 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 and/or schizophrenia may be part of the patient's family history and reflects a term called "genetic loading".

Bipolar disorder is more than just biological and psychological. Since "many factors act together to produce the illness", bipolar disorder is called a multifactorial illness, because many genes and environmental factors conspire to create the disorder (Johnson & Leahy, 2004).

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