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Bipolar disorder
- Updated 04.09.2024
- Released 04.20.2019
- Expires For CME 04.09.2027
Bipolar disorder
Introduction
Overview
Bipolar disorder, or manic depression, is a serious mental illness that may drastically affect an individual’s ability to function because of mood instability. Given the unpredictability of severe high (mania) and severe low (depression) mood states, people with bipolar disorder may struggle with social and workplace settings. Bipolar disorder affects mood, sleep, concentration, and reasoning. Some individuals may experience psychosis or may struggle with suicidal thoughts. Although the underlying cause of bipolar disorder is not clear, research in neurobiology and genetics provides some insight into this complex illness. Treatment of the disorder is primarily with mood stabilizers but often requires additional adjunctive medications. Additionally, psychosocial support and therapy are essential for maintaining stability. This article aims to provide distinction between bipolar disorder subtypes and includes updates on the current research regarding the underlying pathology as well as guidance on the pharmacologic treatment of the illness.
Key points
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• Bipolar I disorder may be diagnosed after a single manic episode. | |
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• Patients will often experience a combination of depressive, manic, and hypomanic episodes throughout the course of illness. | |
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• The severity and frequency of mood symptoms vary among individuals. | |
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• The role of treatment is to stabilize mood and decrease the severity and frequency of mood episodes. |
Historical note and terminology
Manic depression was first noted by ancient Greek scholars, including Hippocrates, and the term “mania” is derived from the Greek word for “madness” (12). The idea of a madness related to one’s mood persisted until near the end of the 19th century when Emil Kraeplin distinguished between manic-depressive psychosis and dementia praecox (modern schizophrenia) (52). The idea of an illness with two distinct affective poles, mania and depression, was introduced by Karl Leonhard in the 1950s (30). Today, bipolar disorder is recognized as a serious mental illness within the Diagnostic and Statistical Manual of Mental Disorders.
Clinical manifestations
Presentation and course
The diagnosis of bipolar disorder and subtypes are outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (02). Bipolar disorder may be subdivided into bipolar type I and bipolar type II. In bipolar I and bipolar II, the presence of a manic or hypomanic episode, respectively, is a core feature of diagnosis.
The distinction between bipolar type I and bipolar type II depends on the severity of the manic symptoms in the individual and the impairment of function. In bipolar type I, mania requires a “distinct period of persistently elevated, expansive, or irritable mood” for 1 week. Additionally, three (four if mood is irritable) of seven symptoms must be present, including grandiosity, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, distractibility, increased goal-directed activity, and excessive involvement in risk-taking behaviors. The behaviors must be severe enough to cause significant distress or functional impairment. The period may be shorter than 1 week if a patient requires hospitalization. The diagnosis of bipolar I contains specifiers for severity, presence of psychotic features (not better explained by another disorder), and remission status.
Major depressive episodes often occur in bipolar I but are not required for a diagnosis. In contrast, bipolar II disorder requires meeting criteria for at least one hypomanic episode as well as at least one major depressive episode. Diagnosis of a major depressive episode requires 2 or more weeks with at least five of nine symptoms present, including depressed mood, anhedonia, significant changes in weight or appetite, insomnia or hypersomnia, psychomotor changes, energy loss, feelings of worthlessness or guilt, diminished concentration, and recurrent thoughts of death (02).
In bipolar type II, hypomania requires a “distinct period of persistently elevated, expansive, or irritable mood” lasting for 4 consecutive days. Additionally, three (four if mood is irritable) of seven symptoms must be present, including grandiosity, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, distractibility, increased goal-directed activity, and excessive involvement in risk-taking behaviors. The episode is not severe enough to markedly impair function or require hospitalization but represents a noticeable change in functioning.
Prognosis and complications
Prognosis of bipolar disorder varies based on the frequency and severity of the disease as well as efficacy of and adherence to treatment.
Most individuals experience one or more episodes of major depression prior to a manic or hypomanic episode (48). There may be periods of several months to years without symptoms of major depression or mania. In contrast, bipolar disorder with four or more episodes of major depression, hypomania, or mania within 12 months is considered to be rapid cycling. Rapid cycling is more difficult to manage with medication and may severely impair function (39).
Individuals with mania tend to have increased risk-taking behavior with long-lasting implications. Both bipolar I and bipolar II are highly comorbid with substance abuse at some point in a bipolar individual’s lifetime (21; 23). In a study, nearly 50% of women and 80% of men with rapid cycling had been arrested (17). One third to one half of patients with bipolar disorder attempt suicide at some time during the course of the illness, representing a risk of suicide 30 to 60 times higher than in the general population and with increased lethality (13; 33).
Clinical vignette
A 20-year-old college student was involved in many extracurricular groups and activities. She was always very studious and conscientious about the environment. She started sleeping less to get more accomplished. Initially this allowed her to be more productive, but then she started having grandiose ideas about saving the world. Over the course of several days without sleep, she wrote pages upon pages of a manifesto for environmental regulations that she brought to her professors. Her writing was noted to be incomprehensible and unlike her usual work. She began refusing to wear clothes in public to be “closer to nature,” which led to her being arrested and hospitalized.
On initial evaluation, she was speaking rapidly about several topics at once. A medical workup revealed no illicit substances in her system, electrolytes within normal limits, and no change in thyroid function. A head CT revealed no acute abnormalities.
She was admitted to the psychiatry ward and started on an antipsychotic medication and a mood stabilizer. She began sleeping more consistently, and her racing thoughts slowed. She was discharged from the hospital on a mood stabilizer and eventually returned to school.
Biological basis
Etiology and pathogenesis
The diagnosis of bipolar disorder is based on symptom cluster. The precise underlying cause of bipolar disorder is unknown, but evidence suggests strong genetic and neurobiological etiology. Atypical immune system signaling and elevated levels of inflammation have also been identified in bipolar disorder (24).
Genetics. There is strong evidence for a genetic basis of bipolar disorder, with heritability estimates between 70% and 90% based on twin studies (45). Genome-wide association studies suggest complex polygenic inheritance rather than any specific gene consistently associated with bipolar disorder (20). Genes found to be consistently involved and in the largest scale studies are CACNA1 and KCNB1, which function in calcium signaling, and TRANK1, which encodes a protein highly expressed in brain tissues (34). Substantial genetic overlap tends to be found between bipolar disorder and other disorders, particularly schizophrenia (43; 46).
Neurobiology. In studies of cells of patients with bipolar disorder, intracellular calcium signaling is altered (05). Pharmacologic treatment of bipolar disorder with mood stabilizers may attenuate the altered calcium signaling (27; 14). However, the neurobiology underlying bipolar disorder is still not well understood, with hypotheses surrounding deficits in multiple neurotransmitter systems, intracellular signaling, neurogenesis, and the neuroendocrine system (51).
Epidemiology
The lifetime prevalence of bipolar disorder in adults is between 1% and 4% (36). There is an approximately equal gender divide, with 2.2% of males and 2.0% of females with bipolar disorder (06). More than 80% of those with bipolar disorder are seriously impaired (26).
Prevention
Bipolar disorder consists of episodic mania and depression that can severely disrupt life. Although the disorder cannot be prevented, the mood episodes can sometimes be mitigated. The best evidence for preventing severe manic episodes supports the use of mood-stabilizing medication (35) and maintaining a routine sleep schedule (47). Stress needs to be controlled because of the risk of inducing depressive or manic episodes (29). Abstinence from mood altering substances like alcohol and drugs is also important to prevent mood episodes (22). Studies have begun to examine preventive pharmacological and psychological measures to prevent conversion to bipolar disorder in individuals at high risk (42).
Differential diagnosis
Bipolar disorder clinically resembles unipolar major depression as well as schizophrenia and schizoaffective disorder, and these disorders appear to have shared genetic risk (43). Patients with bipolar disorder are likely to experience depressive episodes, but the experience of a hypomanic or manic episode is essential to the diagnosis. Patients with major depression do not experience manic or hypomanic episodes.
It is important for clinical providers to understand that patients are more likely to seek medical treatment when they are depressed rather than manic or hypomanic (49). Therefore, evaluation for prior hypomanic or manic episodes in a depressed patient is important.
Patients with a severe depressive or manic episode may also experience psychosis similar to schizophrenia or schizoaffective disorders. In bipolar disorder with psychosis, the psychosis only occurs during the depressive or manic episode and remits during mood stability. In patients with schizophrenia, there are no mood changes, but psychosis is present. Patients with schizoaffective disorder experience psychosis as well as affective mood changes, but they may or may not be temporally linked.
Cyclothymic disorder involves periods of depressive and hypomanic symptoms that do not meet the full criteria for a major depressive or hypomanic episode. The symptoms of cyclothymia are present at least half of the time for 2 years, with no more than 2 months without symptoms. In children and adolescents, the period is decreased to 1 year.
Some patients with rapid mood lability (ie, mood swings) are incorrectly diagnosed with bipolar type I or type II. For example, patients with borderline personality disorder may experience rapid mood changes over several minutes to hours. Although mixed depressive and manic episodes can occur in bipolar disorder as well, the mood lability in bipolar disorder persists over several days.
Diagnostic workup
Bipolar disorder diagnosis is established by clinician judgment. There are no specific tests for bipolar disorder, but other general medical conditions should be ruled out as causes of symptoms. Therefore, a basic metabolic panel, complete blood count, and thyroid function test should be evaluated. Abnormal electrolytes, infection, or hyperthyroid may mimic some of the manic or depressive symptoms in bipolar disorder. Renal function and hepatic function should also be evaluated prior to consideration of medications. An electrocardiogram is also important for evaluation of possible cardiac arrhythmias or QT prolongation prior to initiation of medications. Urine drug screening to rule out substance-induced manic or depressive symptoms or to be prepared for withdrawal is essential.
There are no specific radiologic findings in bipolar disorder, but brain imaging to rule out structural cerebral disorders (stroke, tumor, bleed) should be part of the initial workup.
Management
Management of bipolar disorder depends on the severity of symptoms as well as the phase of the illness: acute mania, acute depression, or maintenance. Bipolar disorder is typically treated with mood stabilizers and atypical antipsychotics, in conjunction with antidepressants where appropriate (36).
Because bipolar disorder is a serious mental illness that alternates periods of stability and instability, patients who experience two or more episodes are generally prescribed medication for life. The choice of medication depends on the risks and benefits of each medication as well as patient-specific efficacy and tolerability of medication side effects (07).
For acute mania, the U.S. Food and Drug Administration (FDA) has approved mood stabilizers (lithium, valproate, and carbamazepine ER) and antipsychotics (aripiprazole, asenapine, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone) (50). For bipolar depression, the FDA has approved quetiapine, lurasidone, and a combination of olanzapine and fluoxetine (32). For maintenance, FDA approval includes lithium, lamotrigine, aripiprazole, olanzapine, risperidone, quetiapine, and ziprasidone.
For patients with acute mania with psychosis, an antipsychotic is usually initiated concurrently with a mood stabilizer. Antipsychotic medications will work more rapidly than mood stabilizers for sedation and reduction of acute manic symptoms.
For patients with bipolar depression, a careful history of prior manic episodes must be obtained. Although the risk is relatively low, antidepressant medications may induce a manic episode in patients with depression (41). The combination of fluoxetine, an antidepressant, and olanzapine, an antipsychotic, is indicated for bipolar depression.
Lithium salts are one of the oldest treatments of bipolar disorder, yet the molecular mechanism of action remains unclear. Lithium does exert some of its effect through inhibition of glycogen synthase kinase 3 (GSK3) (16). Lithium may be a first choice in patients with acute mania, but is contraindicated in significant renal impairment, dehydration, and significant cardiovascular disease. Lithium toxicity can occur with elevated serum levels (above 1.5 mmol/L) and can be a medical emergency (01).
Lithium is typically dosed two to three times a day starting at 300 to 450 mg per dose and should be dosed to effect or a total daily dose of 1800 mg per day. Serum lithium levels should be checked 5 days after medication initiation or dose adjustments and should be within 0.6 to 1.2 mmol/L (09).
Valproate may also be considered for initiation in patients with bipolar disorder. There are no large-scale head-to-head efficacy trials of lithium and valproate, but valproate should be considered in patients with renal impairment (03). Valproate is typically dosed at 500 to 750 mg per day, with increases in 250 mg until clinical effect or serum concentration is 80 to 120 µg/mL (19). Valproate does have the benefit that weight-based loading at 20 mg/kg may be used for a more rapid control of symptoms (08).
Mood stabilizers are used in conjunction with antipsychotics for symptom control. The choice of mood stabilizer and antipsychotic combination is based on tolerability and efficacy. If symptoms do not improve within 7 to 14 days, medication change is justified. For patients who fail to respond to multiple combinations of mood stabilizer and antipsychotic, electroconvulsive therapy may be an appropriate consideration (38). However, evidence is lacking regarding response to electroconvulsive therapy in mania relative to both unipolar and bipolar depression (15).
Psychotherapy and psychoeducation directed at patients and families show some beneficial outcomes in bipolar disorder (11; 40; 10). Patients with severe manic or depressed symptoms may not be able to actively participate in therapy but should be referred to therapy and education once the severe symptoms have been stabilized.
Because of the complexities of treating fluctuating episodes of mania and depression in bipolar disorder and the difficulties of anticipating specific medication tolerance in patients with and without comorbidities, any treatment for bipolar patients should involve close monitoring and long-term follow-up (18).
Outcomes
Despite treatment with medication, patients may still experience manic, hypomanic, or depressed episodes. The goal of treatment in bipolar disorder is to reduce the frequency and severity of mood episodes. Studies show that the longer or more frequent the mood episodes, the more difficult it is to regain stability (04). Therefore, early recognition of symptoms and initiation and maintenance of treatment are important. Depressive episodes have a particularly negative impact on the quality of life of individuals with bipolar disorder (28).
Medications for bipolar disorder may carry risks. Lithium may cause renal, cardiac, and thyroid complications. Valproate may cause hepatic toxicity as well as weight gain and hair loss. Toxic levels of mood stabilizers are medical emergencies. Atypical antipsychotics may cause metabolic syndromes, including weight gain, hypertension, dyslipidemia, and diabetes (31).
Special considerations
Pregnancy
The risks and benefits of medication discontinuation during pregnancy need to be discussed between the patient and physician. Discontinuing medication may precipitate a severe mood episode in a previously stabilized patient. Lithium may cause cardiac complications in the fetus, including Ebstein anomaly (37). Valproate may cause neural tube defects in the fetus and is not recommended during pregnancy (25). There is mixed evidence regarding the safety of atypical antipsychotics during pregnancy (44).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Alia Martin PhD
Dr. Martin of Victoria University of Wellington has no relevant financial relationships to disclose.
See Profile
Editor
-
Victor W Mark MD
Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.
See Profile
Former Authors
- John Hammond MD
- David S Geldmacher MD
Patient Profile
- Age range of presentation
-
- 19 to 44 years
- Sex preponderance
-
- female = male
- Heredity
-
- high heritability estimates
- Population groups selectively affected
-
- none
- Occupation groups selectively affected
-
- none
ICD & OMIM codes
- ICD-10
-
- Hypomania: F30.0
- Mania without psychotic symptoms: F30.1
- Mania with psychotic symptoms: F30.2
- Other manic episodes: F30.8
- Manic episode, unspecified: F30.9
- Bipolar affective disorder: F31
- Bipolar affective disorder, current episode hypomanic: F31.0
- Bipolar affective disorder, current episode manic without psychotic symptoms: F31.1
- Bipolar affective disorder, current episode manic with psychotic symptoms: F31.2
- Bipolar affective disorder, current episode mild or moderate depression: F31.3
- Bipolar affective disorder, current episode severe depression without psychotic symptoms: F31.4
- Bipolar affective disorder, current episode severe depression with psychotic symptoms: F31.5
- Bipolar affective disorder, current episode mixed: F31.6
- Bipolar affective disorder, currently in remission: F31.7
- Other bipolar affective disorders: F31.8
- Bipolar affective disorder, unspecified: F32
- OMIM
-
- Major affective disorder 1: %125480
- Major affective disorder 2: %309200
- Major affective disorder 3: %609633
- Major affective disorder 4: %611247
- Major affective disorder 5: %611535
- Major affective disorder 6: %611536
- Major affective disorder 7: #612371
- Major affective disorder 8: %612357
- Major affective disorder 9: %612372
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