Bipolar disorder

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• The connection between mania and melancholia dates back to the 2nd Century CE.
  • Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses.
• German psychiatrist Emil Kraepelin (1856–1926) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of mood stabilizers.
  • In 1902, Kraepelin created the term manic depressive psychosis to describe these patients.
• In 1957, Karl Leonhard, a German psychiatrist, coined the terms bipolar and unipolar to describe subclassifications of manic depressive psychosis (bipolar disorder).
  • Bipolar was used to describe cases with manic episodes.
  • Unipolar was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.

• Humans have experienced cycles of varying moods and energy levels for thousands of years.
• The terms melancholia and mania originated in Ancient Greece.
  • Melancholia originates from the Greek words melas and chole, meaning “black” and “bile” or “gall”^[1] respectively.
  • Mania originates from the Greek words ania and manos, meaning “to produce great mental anguish” and “relaxed or loose” respectively.
• Both mania and melancholia were thought to arise from imbalances in the body’s humors. Mania was thought to result from excess amounts of yellow bile, while melancholia was thought to result from excess black bile.
• The connection between mania and melancholia dates back to the 2nd Century CE.^[2]
  • Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses^[3] during a period where many viewed melancholia as a type of mania.
  • Aretaeus of Cappadocia, a medical philosopher who lived between the years 30 and 150 CE, is credited with the earliest accounts of a connection between melancholia and mania. Aretaeus wrote many texts that survive today in which he described manic-depressive disease that he believed originated in black bile.
• Early Chinese authors established clear classification of bipolar disorder as a mental illness. For example, author and encyclopedist Gao Lian (c. 1583) described the disorder in Eight Treatises on the Nurturing of Life.^[4]
• The modern psychiatric understanding of manic-depressive illness is often traced to the 1850s.
  • On January 31, 1854, French psychologist Jules Baillarger presented a description of a biphasic mental illness characterized by alternating periods of mania and depression to the French Imperial Academy of Medicine. Baillarger termed the illness “folie à double forme” (dual-form insanity).
• German psychiatrist Emil Kraepelin (1856-1926) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of mood stabilizers.
  • In 1902, Kraepelin created the term manic depressive psychosis to describe these patients.
  • He observed that periods of acute illness (manic or depressive) were often preceded and followed by symptom-free periods in which patients were able to function normally.^[2]
• Following the Second World War, Australian psychiatrist Dr. John Cade conducted research on the effectiveness of different compounds in treating veterans with manic-depressive illness. Through his research, Dr. Cade found that lithium carbonate was effective at treating manic-depressive illness^[3]. Lithium was not widely used as a treatment immediately following Dr. Cade’s discovery as many held fears of its toxicity. However, following the use of lithium in the treatment of manic-depressive disorder in some hospitals beginning in the 1950s and reports of the benefits of lithium treatment in medical journals in the 1960s, the Food and Drug Administration approved the use of lithium as a treatment for manic-depressive illness in 1970^[4].
• In 1952, the phrase “manic-depressive reaction” was included in the first American Psychiatric Association Diagnostic Manual, demonstrating the belief that the disease was a result of a reaction of biogenetic factors to social/environmental factors.^[5]
• In 1957, Karl Leonhard, a German psychiatrist, coined the terms bipolar and unipolar to describe subclassifications of manic depressive psychosis (bipolar disorder).^[6]
  • Bipolar was used to describe cases with manic episodes.
  • Unipolar was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.
• In 1968, ICD-8 and DSM-II both called the condition “manic-depressive illness,” demonstrating the increasing biological thinking surrounding the condition.^[7]
• The current term for the condition, bipolar disorder, recently became popular, though some prefer the old nosology and claim that “manic-depressive illness” better described the multifaceted illness.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Bipolar disorder is commonly categorized as either bipolar type I, where an individual experiences full-blown mania, or bipolar type II, in which the hypomanic “highs” do not go to the extremes of mania, and cyclothymic disorder where mood cycles between episodes of hypomania and dysthymia. The latter two are much 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. Psychosis can occur, particularly in manic periods. There are also ‘rapid cycling’ subtypes. Because there is so much variation in the severity and nature of mood-related problems, the concept of a bipolar spectrum is often employed. There is no consensus as to how many ‘types’ of bipolar disorder exist. Bipolar disorder can also be classified based on the phase of illness the patient may be in.^[1] Many people with bipolar disorder experience severe anxiety and are very irritable (to the point of rage) when in a manic state, while others are euphoric and grandiose.

The bipolar disorder spectrum includes the following:

• Bipolar I Disorder
• Bipolar II Disorder
• Cyclothymic Disorder
• Substance/Medication-Induced Bipolar Disorder
• Bipolar Disorder Due to Another Medical Condition
• Other Specified Bipolar Disorder Due to Another Medical Condition
• Unspecified Bipolar Disorder

Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well. It is a sub-diagnosis of bipolar disorder, and conforms to the classic concept of manic-depressive illness. The essential feature of bipolar I disorder is a clinical course that is characterized by the occurrence of one or more manic episodes or mixed episodes. Often individuals have also had one or more major depressive episodes. Episodes of substance-induced mood disorder (due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure) or of mood disorder due to a general medical condition do not count toward a diagnosis of bipolar I disorder. In addition, the episodes are not better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder not otherwise specified.

Bipolar II Disorder is a bipolar spectrum disorder characterized by at least one hypomanic episode and at least one major depressive episode; with this disorder, depressive episodes are more frequent and more intense than manic episodes. The presence of a hypomanic episode is used mainly to differentiate it from unipolar depression. It is believed to be underdiagnosed because hypomanic behavior often presents as high-functioning behavior. Patients with bipolar II disorder are less likely to seek help from providers. 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.

Cyclothymia is a mood disorder. This disorder is a milder form of bipolar II disorder consisting of recurrent mood disturbances cycling between hypomania and dysthymic mood. A single episode of hypomania is sufficient to diagnose cyclothymic disorder; however, most individuals also have dysthymic periods. The diagnosis of cyclothymic disorder is never made when there is a history of mania or major depressive episode or mixed 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.^[2]

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. People may feel they have been ‘chosen’, or are ‘on a special mission’, which are considered grandiose or delusional ideas. 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. 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 two or more weeks.

Hypomania is generally a less extreme state than mania, and people in the hypomanic phase generally experience fewer of the symptoms of mania than those in a full-blown manic episode. During an episode of Hypomania, 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, where there is a flight of ideas, extremely clever thinking, and an increase in energy.

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).^[3] Mixed episodes can be the most volatile of the bipolar states, as moods can easily and quickly be triggered or shifted. Suicide attempts, substance abuse, and self-mutilation may occur during this state.

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.^[4][5] 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. ^[6] There are references that describe very rapid (ultra-rapid) or extremely rapid ^[7] (ultra-ultra or ultraradian) cycling. One definition of ultra-ultra rapid cycling is defining distinct shifts in mood within a 24-48 hour period.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

A number of factors can be involved in bipolar disorder including genetic, biochemical, psychodynamic, and environmental factors. paternal age increase the risk of bipolar disorder in one’s offspring that could be due to increased genetic mutations during spermatogenesis. Stressful life events may be associated with onset of bipolar disorder and a more severe course of illness.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. Bipolar disorder is associated with immune system dysregulation.

• Paternal age increase the risk of bipolar disorder in offspring due to increased genetic mutations during spermatogenesis. As an example, a national registry study found that the risk of bipolar disorder in offspring of fathers 45 years and older was six times greater.^[1]

• Stress and a history of childhood physical abuse associated with onset of bipolar disorder and a more severe course of illness.^[2][3]

• More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.[4][./Bipolar_disorder_causes#cite_note-4 [4]]
• Genes that are involved in bipolar disorder have been studied, but no single gene has been identified.^[5] it may involve many genes with small effects.^[6]
• Studies found several genetic variants are associated with bipolar disorder. One possible locus is CACNA1C, which codes for a calcium channel that is involved in channel gating.^[7][8] other genes are ANK3, and CLOCK genes especially bipolar type I disorder.^[9][10]
• A meta-analysis suggests that other biologic pathways are cardiac β-adrenergic signaling, cardiac hypertrophy signaling, corticotropin releasing hormone signaling, endothelin 1 signaling, glutamate signaling, and phospholipase C signaling.^[11]
• In addition, a meta-analysis studies identified three single-nucleotide polymorphisms on chromosomes 3 and 10. One of them is located on a brain expressed gene that encodes calcium channel subunits; calcium signaling regulates neuronal growth and development.^[12][13]

• Bipolar disorder is associated with immune system dysregulation. Cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) and cytokine receptors are elevated in patients with bipolar disorder^[14]
• A meta-analysis found that levels of C reactive protein were higher in patients than controls, and the difference was small to moderate.^[15]

• A number of neurotransmitters have been linked to this disorder.
• Catecholamine hypothesis, state that increase in epinephrine and norepinephrine causes mania and a decrease in epinephrine and norepinephrine causes depression.
• Drugs that increase levels of monoamines, including serotonin, norepinephrine, or dopamine, can all potentially trigger mania for instance drug of abuse like cocaine.^[16]
• Patients with substance use-induced psychosis may develop schizophrenia or bipolar disorder within five years.^[17]
• A postmortem study of the frontal lobes of individuals with these disorders revealed that the glutamate levels were increased^[18].

• A meta-analysis shows that decreased activation of gray matter in a cortical-cognitive brain network, which has been associated with the emotion regulation in patients with bipolar disorder. ^[19]
• There is functional and anatomic alterations in brain networks. for instance, there is activation in ventral limbic brain regions that mediate the experience of emotions. ^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Bipolar disorder must be differentiated from cyclothymic disorder, major depressive disorder, schizophrenia, and substance abuse.^[1]

Bipolar disorder must be differentiated from:^[1]

• Anxiety disorders
• Attention-deficit/hyperactivity disorder
• Cyclothymic disorder
• Major depressive disorder
• Panic disorder
• Personality disorders
• Schizophrenia spectrum and other related psychotic disorders
• Substance abuse
• Intoxication induced delirium
• Medication side effects

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

The estimated lifetime prevalence of bipolar disorder among adults worldwide is 1 to 3 percent, and the lifetime prevalence of bipolar I and bipolar II disorder was 2.8 percent. The mean age of onset for bipolar I disorder is 18 years and for bipolar II disorder 20 years. The one-year prevalence of bipolar I disorder in people aged 65 years and older is approximately 0.4 percent and the lifetime rate is 0.8 percent. These rates were less than rates in younger individuals.

• The estimated lifetime prevalence of bipolar disorder among adults worldwide is 1 to 3 percent^[1], and the lifetime prevalence of bipolar I and bipolar II disorder was 2.8 percent^[2]
• The mean age of onset for bipolar I disorder is 18 years and for bipolar II disorder 20 years^[3]. The ratio of men to women who develop bipolar disorder is approximately 1:1.
• In the United States, the estimated lifetime prevalence of bipolar I disorder was 1 percent, and bipolar II disorder 1.1 percent. The mean age of onset for bipolar I and bipolar II disorder was 18 and 20 years.^[4]
• Bipolar disorder is the 18^th leading cause of disability in the United States.^[5]
• Individuals with manic or hypomanic episodes, psychosocial functioning is severely impaired in 70 percent; in 90 percent of the affected individuals functioning is severely impaired during episodes of major depression.^[4]
• The one-year prevalence of bipolar I disorder in people aged 65 years and older is approximately 0.4 percent and the lifetime rate is 0.8 percent. These rates were less than rates in younger individuals.^[6]
• Geriatric bipolar patients are predominantly female; 69 percent of late-life bipolar patients were women.^[7]
• The prevalence of bipolar spectrum disorders in children and adolescents is approximately 2 percent.^[8] However it is not well established because several factors make the diagnosis of bipolar disorder in pediatric complex and controversial.^[9]
• Pediatric bipolar disorder is characterized by high rates of comorbidity.^[8]
• Community studies suggest that the prevalence of bipolar disorder may be greater among adolescents (age 13 to 18 years) than children (age ≤12 years)^[10][11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Risk factors for bipolar disorder include genetic predisposition and problems in the relationship status such as divorce, separation, or becoming a a widow.^[1]

• Divorce
• Genetic predisposition
• Separation
• Being a widow^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

Lifelong outcome has rarely been studied, and precise data on the natural outcome are scarce. Some studies demonstrate that most patients continue to suffer from residual depressive or hypomanic symptoms between episodes, and many are functionally impaired. Bipolar disorder, has significant morbidity and mortality rates. Often, the cycling between depression and mania accelerates with age. The main complications of bipolar disorder are suicide, homicide, and addictions.

• In bipolar disorder the lifetime proportions of mania and depression remain stable into old age. Bipolar female subjects manifest more depression than bipolar male; and they have a poorer prognosis than other bipolar conditions, with slower remissions and higher risk for chronicity.^[1]
• The natural length of bipolar disorder episode has not changed over the past 120 years. Patients responding to antidepressants still require a maintenance treatment throughout the underlying episode. The median length of episodes is 3 to 6 months. The recurrence of bipolar disorder is the rule; there is some initial shortening of intervals/cycles, followed by an irregular persistent recurrence, with a median cycling of 18 months.^[2]
• Lifelong outcome has rarely been studied, and precise data on the natural outcome are scarce. Some studies demonstrate that most patients continue to suffer from residual depressive or hypomanic symptoms between episodes, and many are functionally impaired.^[1]
• The natural history of bipolar illness shows that it has a poor prognosis, as reflected by high recurrence, chronicity of episodes and premature death by suicide and somatic disorders.^[1]
  

• Stopping medication or taking it the wrong way can cause your symptoms to come back, and lead to the following complications:
  • Alcohol and/or drug abuse
  • Problems with relationships, work, and finances
  • Suicidal thoughts and behaviors, suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. men with bipolar disorder are at higher risk for suicide.^[3]
  • Homicide often in the manic phase can be very demanding and grandiose. These individuals can become homicidal by acting on delusions.
  • Bipolar disorder type I results in diminished quality of life as measured by health utility and utility-based health-related quality of life. The patients with depression sustained the greatest loss in QOL.^[4]

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 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, 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.

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 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.

Even when on medication, some people may still experience weaker episodes, or have a complete manic or depressive episode. In fact, a recent study found bipolar disorder to be “characterized by a low rate of recovery, a high rate of recurrence, and poor interepisodic functioning.” Worse, the 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.”^[5]

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.
• 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.
• Often bipolar individuals are subject to self-medication, the most common drugs being alcohol, and marijuana. Sometimes they may also turn to hard drugs. Studies show that tobacco smoking induces a calming effect on most bipolar people, and a very high percentage suffering from the disorder smoke. [3]

Recurrence can be managed by the sufferer with the help of a close friend, based on the occurrence of idiosyncratic prodromal events.^[6] 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. ^[7]

“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.”^[8]

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.^[9]

Individuals with bipolar disorder tend to become suicidal, especially during mixed states such asdysphoric 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 & Kessler, 2007).

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