Bipolar disorder, previously known as manic depression, is a mood disorder characterized by periods of depression and periods of abnormally-elevated happiness that last from days to weeks each. If the elevated mood is severe or associated with psychosis, it is called mania; if it is less severe, it is called hypomania. During mania, an individual behaves or feels abnormally energetic, happy or irritable, and they often make impulsive decisions with little regard for the consequences. There is usually also a reduced need for sleep during manic phases. During periods of depression, the individual may experience crying and have a negative outlook on life and poor eye contact with others. The risk of suicide is high; over a period of 20 years, 6% of those with bipolar disorder died by suicide, while 30–40% engaged in self-harm. Other mental health issues, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.
While the causes of bipolar disorder are not clearly understood, both genetic and environmental factors are thought to play a role. Many genes, each with small effects, may contribute to the development of the disorder. Genetic factors account for about 70–90% of the risk of developing bipolar disorder. Environmental risk factors include a history of childhood abuse and long-term stress. The condition is classified as bipolar I disorder if there has been at least one manic episode, with or without depressive episodes, and as bipolar II disorder if there has been at least one hypomanic episode (but no full manic episodes) and one major depressive episode. If these symptoms are due to drugs or medical problems, they are not diagnosed as bipolar disorder. Other conditions that have overlapping symptoms with bipolar disorder include attention deficit hyperactivity disorder, personality disorders, schizophrenia, and substance use disorder as well as many other medical conditions. Medical testing is not required for a diagnosis, though blood tests or medical imaging can rule out other problems.
Mood stabilizers—lithium and certain anticonvulsants such as valproate and carbamazepine as well as atypical anti-psychotics such as aripiprazole—are the mainstay of long-term pharmacologic relapse prevention. Anti-psychotics are additionally given during acute manic episodes as well as in cases where mood stabilizers are poorly tolerated or ineffective. In patients where compliance is of concern, long-acting injectable formulations are available. There is some evidence that psychotherapy improves the course of this disorder. The use of antidepressants in depressive episodes is controversial: they can be effective but have been implicated in triggering manic episodes. The treatment of depressive episodes, therefore, is often difficult. Electroconvulsive therapy (ECT) is effective in acute manic and depressive episodes, especially with psychosis or catatonia. Admission to a psychiatric hospital may be required if a person is a risk to themselves or others; involuntary treatment is sometimes necessary if the affected person refuses treatment.
Bipolar disorder occurs in approximately 1% of the global population. In the United States, about 3% are estimated to be affected at some point in their life; rates appear to be similar in females and males. Symptoms most commonly begin between the ages of 20 and 25 years old; an earlier onset in life is associated with a worse prognosis. Interest in functioning in the assessment of patients with bipolar disorder is growing, with an emphasis on specific domains such as work, education, social life, family, and cognition. Around one-quarter to one-third of people with bipolar disorder have financial, social or work-related problems due to the illness. Bipolar disorder is among the top 20 causes of disability worldwide and leads to substantial costs for society. Due to lifestyle choices and the side effects of medications, the risk of death from natural causes such as coronary heart disease in people with bipolar disorder is twice that of the general population.
Signs and symptoms
Bipolar mood shifts
Late adolescence and early adulthood are peak years for the onset of bipolar disorder. The condition is characterized by intermittent episodes of mania and/or depression, with an absence of symptoms in between. During these episodes, people with bipolar disorder exhibit disruptions in normal mood, psycho-motor activity (the level of physical activity that is influenced by mood)—e.g. constant fidgeting during mania or slowed movements during depression—circadian rhythm and cognition. Mania can present with varying levels of mood disturbance, ranging from euphoria, which is associated with "classic mania", to dysphoria and irritability. Psychotic symptoms such as delusions or hallucinations may occur in both manic and depressive episodes; their content and nature are consistent with the person's prevailing mood.
According to the DSM-5 criteria, mania is distinguished from hypomania by the duration: hypomania is present if elevated mood symptoms persist for at least four consecutive days, while mania is present if such symptoms persist for more than a week. Unlike mania, hypomania is not always associated with impaired functioning. The biological mechanisms responsible for switching from a manic or hypomanic episode to a depressive episode, or vice versa, remain poorly understood.
Manic episodes
Also known as a manic episode, mania is a distinct period of at least one week of elevated or irritable mood, which can range from euphoria to delirium. The core symptom of mania involves an increase in energy of psycho-motor activity. Mania can also present with increased self-esteem or grandiosity, racing thoughts, pressured speech that is difficult to interrupt, decreased need for sleep, disinhibited social behavior, increased goal-oriented activities and impaired judgment, which can lead to exhibition of behaviors characterized as impulsive or high-risk, such as hyper-sexuality or excessive spending. To fit the definition of a manic episode, these behaviors must impair the individual's ability to socialize or work. If untreated, a manic episode usually lasts three to six months.
In severe manic episodes, a person can experience psychotic symptoms, where thought content is affected along with mood. They may feel unstoppable, or as if they have a special relationship with God, a great mission to accomplish, or other grandiose or delusional ideas. This may lead to violent behavior and, sometimes, hospitalization in an inpatient psychiatric hospital. The severity of manic symptoms can be measured by rating scales such as the Young Mania Rating Scale, though questions remain about the reliability of these scales.
The onset of a manic or depressive episode is often foreshadowed by sleep disturbance. Manic individuals often have a history of substance abuse developed over years as a form of "self-medication".
Hypomanic episodes
Hypomania is the milder form of mania, defined as at least four days of the same criteria as mania, but which does not cause a significant decrease in the individual's ability to socialize or work, lacks psychotic features such as delusions or hallucinations, and does not require psychiatric hospitalization. Overall functioning may actually increase during episodes of hypomania and is thought to serve as a defense mechanism against depression by some. Hypomanic episodes rarely progress to full-blown manic episodes. Some people who experience hypomania show increased creativity, while others are irritable or demonstrate poor judgment.
Hypomania may feel good to some individuals who experience it, though most people who experience hypomania state that the stress of the experience is very painful. People with bipolar disorder who experience hypomania tend to forget the effects of their actions on those around them. Even when family and friends recognize mood swings, the individual will often deny that anything is wrong. If not accompanied by depressive episodes, hypomanic episodes are often not deemed problematic unless the mood changes are uncontrollable or volatile. Most commonly, symptoms continue for time periods from a few weeks to a few months.
Depressive episodes
Symptoms of the depressive phase of bipolar disorder include persistent feelings of sadness, irritability or anger, loss of interest in previously enjoyed activities, excessive or inappropriate guilt, hopelessness, sleeping too much or not enough, changes in appetite and/or weight, fatigue, problems concentrating, self-loathing or feelings of worthlessness, and thoughts of death or suicide. Although the DSM-5 criteria for diagnosing unipolar and bipolar episodes are the same, some clinical features are more common in the latter, including increased sleep, sudden onset and resolution of symptoms, significant weight gain or loss, and severe episodes after childbirth.
The earlier the age of onset, the more likely the first few episodes are to be depressive. For most people with bipolar types 1 and 2, the depressive episodes are much longer than the manic or hypomanic episodes. Since a diagnosis of bipolar disorder requires a manic or hypomanic episode, many affected individuals are initially misdiagnosed as having major depression and incorrectly treated with prescribed antidepressants.
Mixed affective episodes
In bipolar disorder, a mixed state is an episode during which symptoms of both mania and depression occur simultaneously. Individuals experiencing a mixed state may have manic symptoms such as grandiose thoughts while simultaneously experiencing depressive symptoms such as excessive guilt or feeling suicidal. They are considered to have a higher risk for suicidal behavior as depressive emotions such as hopelessness are often paired with mood swings or difficulties with impulse control. Anxiety disorders occur more frequently as a comorbidity in mixed bipolar episodes than in non-mixed bipolar depression or mania. Substance (including alcohol) abuse also follows this trend, thereby appearing to depict bipolar symptoms as no more than a consequence of substance abuse.
Comorbid conditions
People with bipolar disorder often have other co-existing psychiatric conditions such as anxiety (present in about 71% of people with bipolar disorder), substance use (56%), personality disorders (36%) and attention deficit hyperactivity disorder (10–20%) which can add to the burden of illness and worsen the prognosis. Certain medical conditions are also more common in people with bipolar disorder as compared to the general population. This includes increased rates of metabolic syndrome (present in 37% of people with bipolar disorder), migraine headaches (35%), obesity (21%) and type 2 diabetes (14%). This contributes to a risk of death that is two times higher in those with bipolar disorder as compared to the general population.
Substance abuse is a common comorbidity in bipolar disorder; the subject has been widely reviewed.
Causes
The causes of bipolar disorder likely vary between individuals and the exact mechanism underlying the disorder remains unclear. Genetic influences are believed to account for 73–93% of the risk of developing the disorder indicating a strong hereditary component. The overall heritability of the bipolar spectrum has been estimated at 0.71. Twin studies have been limited by relatively small sample sizes but have indicated a substantial genetic contribution, as well as environmental influence. For bipolar I disorder, the rate at which identical twins (same genes) will both have bipolar I disorder (concordance) is around 40%, compared to about 5% in fraternal twins. A combination of bipolar I, II, and cyclothymia similarly produced rates of 42% and 11% (identical and fraternal twins, respectively). The rates of bipolar II combinations without bipolar I are lower—bipolar II at 23 and 17%, and bipolar II combining with cyclothymia at 33 and 14%—which may reflect relatively higher genetic heterogeneity.
The cause of bipolar disorders overlaps with major depressive disorder. When defining concordance as the co-twins having either bipolar disorder or major depression, then the concordance rate rises to 67% in identical twins and 19% in fraternal twins. The relatively low concordance between fraternal twins brought up together suggests that shared family environmental effects are limited, although the ability to detect them has been limited by small sample sizes.
Genetic
Behavioral genetic studies have suggested that many chromosomal regions and candidate genes are related to bipolar disorder susceptibility with each gene exerting a mild to moderate effect. The risk of bipolar disorder is nearly ten-fold higher in first-degree relatives of those with bipolar disorder than in the general population; similarly, the risk of major depressive disorder is three times higher in relatives of those with bipolar disorder than in the general population.
Although the first genetic linkage finding for mania was in 1969, linkage studies have been inconsistent. Findings point strongly to heterogeneity, with different genes implicated in different families. Robust and replicable genome-wide significant associations showed several common single-nucleotide polymorphisms (SNPs) are associated with bipolar disorder, including variants within the genes CACNA1C, ODZ4, and NCAN. The largest and most recent genome-wide association study failed to find any locus that exerts a large effect, reinforcing the idea that no single gene is responsible for bipolar disorder in most cases. Polymorphisms in BDNF, DRD4, DAO, and TPH1 have been frequently associated with bipolar disorder and were initially associated in a meta-analysis, but this association disappeared after correction for multiple testing. On the other hand, two polymorphisms in TPH2 were identified as being associated with bipolar disorder.
Due to the inconsistent findings in a genome-wide association study, multiple studies have undertaken the approach of analyzing SNPs in biological pathways. Signaling pathways traditionally associated with bipolar disorder that have been supported by these studies include corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, Phospholipase C signaling, glutamate receptor signaling, cardiac hypertrophy signaling, Wnt signaling, Notch signaling, and endothelin 1 signaling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the dorsolateral prefrontal cortex portion of the brain in post-mortem studies: CACNA1C, GNG2, and ITPR2.
Bipolar disorder is associated with reduced expression of specific DNA repair enzymes and increased levels of oxidative DNA damages.
Environmental
Psycho-social factors play a significant role in the development and course of bipolar disorder, and individual psycho-social variables may interact with genetic dispositions. Recent life events and interpersonal relationships likely contribute to the onset and recurrence of bipolar mood episodes, just as they do for unipolar depression. In surveys, 30–50% of adults diagnosed with bipolar disorder report traumatic/abusive experiences in childhood, which is associated with earlier onset, a higher rate of suicide attempts, and more co-occurring disorders such as post-traumatic stress disorder. The number of reported stressful events in childhood is higher in those with an adult diagnosis of bipolar spectrum disorder than in those without, particularly events stemming from a harsh environment rather than from the child's own behavior. Acutely, mania can be induced by sleep deprivation in around 30% of people with bipolar disorder.
Neurological
Less commonly, bipolar disorder or a bipolar-like disorder may occur as a result of or in association with a neurological condition or injury including stroke, traumatic brain injury, HIV infection, multiple sclerosis, porphyria, and rarely temporal lobe epilepsy.
Proposed mechanisms
Brain imaging studies have revealed differences in the volume of various brain regions between patients with bipolar disorder and healthy control subjects.
The precise mechanisms that cause bipolar disorder are not well understood. Bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions. A neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts. The ventral system (regulates emotional perception) includes brain structures such as the amygdala, insula, ventral striatum, ventral anterior cingulate cortex, and the prefrontal cortex. The dorsal system (responsible for emotional regulation) includes the hippocampus, dorsal anterior cingulate cortex, and other parts of the prefrontal cortex. The model hypothesizes that bipolar disorder may occur when the ventral system is over-activated and the dorsal system is under-activated. Other models suggest the ability to regulate emotions is disrupted in people with bipolar disorder and that dysfunction of the ventricular prefrontal cortex (vPFC) is crucial to this disruption.
Meta-analyses of structural MRI studies have shown that certain brain regions (e.g., the left rostral anterior cingulate cortex, fronto-insular cortex, ventral prefrontal cortex, and claustrum) are smaller in people with bipolar disorder, whereas other regions are larger (lateral ventricles, globus pallidus, subgenual anterior cingulate, and the amygdala). Additionally, these meta-analyses found that people with bipolar disorder have higher rates of deep white matter hyper-intensities.
Functional MRI findings suggest that the vPFC regulates the limbic system, especially the amygdala. In people with bipolar disorder, decreased vPFC activity allows for the dysregulated activity of the amygdala, which likely contributes to labile mood and poor emotional regulation. Consistent with this, pharmacological treatment of mania returns vPFC activity to the levels in non-manic people, suggesting that vPFC activity is an indicator of mood state. However, while pharmacological treatment of mania reduces amygdala hyperactivity, it remains more active than the amygdala of those without bipolar disorder, suggesting amygdala activity may be a marker of the disorder rather than the current mood state. Manic and depressive episodes tend to be characterized by dysfunction in different regions of the vPFC. Manic episodes appear to be associated with decreased activation of the right vPFC whereas depressive episodes are associated with decreased activation of the left vPFC. These disruptions often occur during development linked with synaptic pruning dysfunction.
People with bipolar disorder who are in a euthymic mood state show decreased activity in the lingual gyrus compared to people without bipolar disorder. In contrast, they demonstrate decreased activity in the inferior frontal cortex during manic episodes compared to people without the disorder. Similar studies examining the differences in brain activity between people with bipolar disorder and those without did not find a consistent area in the brain that was more or less active when comparing these two groups. People with bipolar have increased activation of left hemisphere ventral limbic areas—which mediate emotional experiences and generation of emotional responses—and decreased activation of right hemisphere cortical structures related to cognition—structures associated with the regulation of emotions.
Neuroscientists have proposed additional models to try to explain the cause of bipolar disorder. One proposed model for bipolar disorder suggests that hypersensitivity of reward circuits consisting of frontostriatal circuits causes mania, and decreased sensitivity of these circuits causes depression. According to the "kindling" hypothesis, when people who are genetically predisposed toward bipolar disorder experience stressful events, the stress threshold at which mood changes occur becomes progressively lower, until the episodes eventually start (and recur) spontaneously. There is evidence supporting an association between early-life stress and dysfunction of the hypothalamic-pituitary-adrenal axis leading to its over-activation, which may play a role in the pathogenesis of bipolar disorder. Other brain components that have been proposed to play a role in bipolar disorder are the mitochondria and a sodium ATPase pump. Circadian rhythms and regulation of the hormone melatonin also seem to be altered.
Dopamine, a neurotransmitter responsible for mood cycling, has increased transmission during the manic phase. The dopamine hypothesis states that the increase in dopamine results in secondary homeostatic down-regulation of key system elements and receptors such as lower sensitivity of dopaminergic receptors. This results in decreased dopamine transmission characteristic of the depressive phase. The depressive phase ends with homeostatic up-regulation potentially restarting the cycle over again. Glutamate is significantly increased within the left dorsolateral prefrontal cortex during the manic phase of bipolar disorder, and returns to normal levels once the phase is over.
Medications used to treat bipolar may exert their effect by modulating intracellular signaling, such as through depleting myo-inositol levels, inhibition of cAMP signaling, and through altering sub-units of the dopamine-associated G-protein. Consistent with this, elevated levels of Gαi, Gαs, and Gαq/11 have been reported in brain and blood samples, along with increased protein kinase A (PKA) expression and sensitivity; typically, PKA activates as part of the intracellular signaling cascade downstream from the detachment of Gαs subunit from the G protein complex.
Decreased levels of 5-hydroxyindoleacetic acid, a byproduct of serotonin, are present in the cerebrospinal fluid of persons with bipolar disorder during both the depressed and manic phases. Increased dopaminergic activity has been hypothesized in manic states due to the ability of dopamine agonists to stimulate mania in people with bipolar disorder. Decreased sensitivity of regulatory α2 adrenergic receptors as well as increased cell counts in the locus coeruleus indicated increased noradrenergic activity in manic people. Low plasma GABA levels on both sides of the mood spectrum have been found. One review found no difference in monoamine levels, but found abnormal norepinephrine turnover in people with bipolar disorder. Tyrosine depletion was found to reduce the effects of methamphetamine in people with bipolar disorder as well as symptoms of mania, implicating dopamine in mania. VMAT2 binding was found to be increased in one study of people with bipolar mania.
Diagnosis
Bipolar disorder is commonly diagnosed during adolescence or early adulthood, but onset can occur throughout life. Its diagnosis is based on the self-reported experiences of the individual, abnormal behavior reported by family members, friends or co-workers, observable signs of illness as assessed by a clinician, and ideally a medical work-up to rule out other causes. Caregiver-scored rating scales, specifically from the mother, have shown to be more accurate than teacher and youth-scored reports in identifying youths with bipolar disorder. Assessment is 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 (APA) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the World Health Organization's (WHO) International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10). The ICD-10 criteria are used more often in clinical settings outside of the U.S. while the DSM criteria are used within the U.S. and are the prevailing criteria used internationally in research studies. The DSM-5, published in 2013, includes further and more accurate specifiers compared to its predecessor, the DSM-IV-TR. This work has influenced the upcoming eleventh revision of the ICD, which includes the various diagnoses within the bipolar spectrum of the DSM-V.
Several rating scales for the screening and evaluation of bipolar disorder exist, including the Bipolar spectrum diagnostic scale, Mood Disorder Questionnaire, the General Behavior Inventory and the Hypomania Checklist. The use of evaluation scales cannot substitute a full clinical interview but they serve to systematize the recollection of symptoms. On the other hand, instruments for screening bipolar disorder tend to have lower sensitivity.
Differential diagnosis
Bipolar disorder is classified by the International Classification of Diseases as a mental and behavioral disorder. Mental disorders that can have symptoms similar to those seen in bipolar disorder include schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and certain personality disorders, such as borderline personality disorder. A key difference between bipolar disorder and borderline personality disorder is the nature of the mood swings; in contrast to the sustained changes to mood over days to weeks or longer, those of the latter condition (more accurately called emotional dysregulation) are sudden and often short-lived, and secondary to social stressors.
Although there are no biological tests that are diagnostic of bipolar disorder, blood tests and/or imaging are carried out to investigate whether medical illnesses with clinical presentations similar to that of bipolar disorder are present before making a definitive diagnosis. Neurologic diseases such as multiple sclerosis, complex partial seizures, strokes, brain tumors, Wilson's disease, traumatic brain injury, Huntington's disease, and complex migraines can mimic features of bipolar disorder. An EEG may be used to exclude neurological disorders such as epilepsy, and a CT scan or MRI of the head may be used to exclude brain lesions. Additionally, disorders of the endocrine system such as hypothyroidism, hyperthyroidism, and Cushing's disease are in the differential as is the connective tissue disease systemic lupus erythematosus. Infectious causes of mania that may appear similar to bipolar mania include herpes encephalitis, HIV, influenza, or neurosyphilis. Certain vitamin deficiencies such as pellagra (niacin deficiency), Vitamin B12 deficiency, folate deficiency, and Wernicke Korsakoff syndrome (thiamine deficiency) can also lead to mania. Common medications that can cause manic symptoms include antidepressants, prednisone, Parkinson's disease medications, thyroid hormone, stimulants (including cocaine and methamphetamine), and certain antibiotics.
Bipolar spectrum
Since Emil Kraepelin's distinction between bipolar disorder and schizophrenia in the 19th century, researchers have defined a spectrum of different types of bipolar disorder.
Bipolar spectrum disorders include: bipolar I disorder, bipolar II disorder, cyclothymic disorder and cases where sub-threshold symptoms are found to cause clinically significant impairment or distress. These disorders involve major depressive episodes that alternate with manic or hypomanic episodes, or with mixed episodes that feature symptoms of both mood states. The concept of the bipolar spectrum is similar to that of Emil Kraepelin's original concept of manic depressive illness. Bipolar II disorder was established as a diagnosis in 1994 within DSM IV; though debate continues over whether it is a distinct entity, part of a spectrum, or exists at all.
Criteria and subtypes
The DSM and the ICD characterize bipolar disorder as a spectrum of disorders occurring on a continuum. The DSM-5 and ICD-11 lists three specific subtypes:
Bipolar I disorder: At least one manic episode is necessary to make the diagnosis; depressive episodes are common in the vast majority of cases with bipolar disorder I, but are unnecessary for the diagnosis. Specifiers such as "mild, moderate, moderate-severe, severe" and "with psychotic features" should be added as applicable to indicate the presentation and course of the disorder.
Bipolar II disorder: No manic episodes and one or more hypomanic episodes and one or more major depressive episodes. Hypomanic episodes do not go to the full extremes of mania (i.e., do not usually cause severe social or occupational impairment, and are without psychosis), and this can make bipolar II more difficult to diagnose, since the hypomanic episodes may simply appear as periods of successful high productivity and are reported less frequently than a distressing, crippling depression.
Cyclothymia: A history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes.
When relevant, specifiers for peripartum onset and with rapid cycling should be used with any subtype. Individuals who have sub-threshold symptoms that cause clinically significant distress or impairment, but do not meet full criteria for one of the three subtypes may be diagnosed with other specified or unspecified bipolar disorder. Other specified bipolar disorder is used when a clinician chooses to explain why the full criteria were not met (e.g., hypomania without a prior major depressive episode). If the condition is thought to have a non-psychiatric medical cause, the diagnosis of bipolar and related disorder due to another medical condition is made, while substance/medication-induced bipolar and related disorder is used if a medication is thought to have triggered the condition.
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