Clinical manifestations

Presentation and course

The diagnosis of bipolar disorder and subtypes are outlined in the Diagnostic and Statistical Manual of Mental Disorders (02). Bipolar disorder may be subdivided into bipolar type I and bipolar type II.

In bipolar I and bipolar II, major depression may be present. Individuals may experience major depressive episodes with at least 2 weeks of at least 5 of 9 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.

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, 3 (4 if mood is irritable) of 7 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. Presence of psychosis, by DSM criteria, constitutes a manic episode.

In bipolar type II, hypomania requires a “distinct period of persistently elevated, expansive, or irritable mood” lasting for 4 consecutive days. Additionally, 3 (4 if mood is irritable) of 7 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.

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 1 or more episodes of major depression prior to a manic or hypomanic episode (36). The diagnosis of bipolar type I or type II is made after the occurrence of 1 lifetime episode of mania or hypomania, respectively. There may be periods of several months to years without symptoms of major depression or mania. Alternatively, bipolar disorder with 4 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.

Individuals with mania tend to have increased risk-taking behavior with long-lasting implications. Approximately 30% to 40% of people with bipolar disorder have concurrent drug or alcohol abuse/dependence (31). In a study, nearly 50% of women and 80% of men with rapid cycling had been arrested (15). Nearly half of patients with bipolar disorder attempt suicide at some time during the course of the illness (19). Compared to the general population, patients with bipolar disorder attempt suicide 60 times more often and with increased lethality (03).

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 underlying cause of bipolar disorder is unknown, but may involve neurobiological and genetic factors. In studies of cells of patients with bipolar disorder, intracellular calcium signaling is altered (06). Pharmacologic treatment of bipolar disorder with mood stabilizers may attenuate the altered calcium signaling (22; 13).

Genetics. There are several risk genes identified in bipolar disorder, but there is no single specific gene variant linked with the disorder. Children of parents with bipolar disorder have about a tenfold increased risk of bipolar disorder (17).

Genes involved in calcium signaling have generated particular interest, including CACNA1(24). The CACNA1 family of genes encodes the formation of voltage-gated calcium channels. However, the CACNA1 gene and altered calcium signaling are implicated in schizophrenia as well (28).

Epidemiology

The lifetime prevalence of bipolar disorder in adults is between 1% and 2% (11). There is an approximately equal gender divide, with 2.2% of males and 2.0% of females with bipolar disorder (07). More than 80% of those with bipolar disorder are seriously impaired (21).

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 is to maintain a routine sleep schedule (35). Stress needs to be controlled because of the risk of inducing depressive or manic episodes (23). Abstinence from mood altering substances like alcohol and drugs is also important to prevent mood episodes (18).

Differential diagnosis

Bipolar disorder clinically resembles unipolar major depression as well as schizophrenia and schizoaffective disorder. 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. 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. For patients with schizophrenia, there are no affective mood changes, but psychosis is present. Patients with schizoaffective disorder may experience psychosis as well as affective mood changes, but they may or may not be temporally linked.

Cyclothymic disorder includes symptoms of depression and hypomania 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. Although mixed depressive and manic episodes can occur, the mood lability in bipolar disorder persists over several days. Patients with borderline personality disorder may experience rapid mood changes over several minutes to hours.

Diagnostic workup

The laboratory and imaging workup for bipolar disorder includes general medical management. 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 treated with mood stabilizers, antipsychotics, or antidepressants where appropriate.

Because bipolar disorder is a serious mental illness that alternates periods of stability and instability, patients who experience 2 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 (08).

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) (37). For bipolar depression, the FDA has approved quetiapine, lurasidone, and a combination of olanzapine and fluoxetine (27). 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 (33). 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) (14). 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 2 to 3 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 (10).

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 (04). 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 (16). Valproate does have the benefit that weight-based loading at 20 mg/kg may be used for a more rapid control of symptoms (09).

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 is an appropriate consideration (30).

Psychotherapy and psychoeducation benefit some patients with bipolar disorder (32). 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.

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 (05). Therefore, early recognition of symptoms and initiation and maintenance of treatment are important.

Medications for bipolar disorder may also 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 (26).

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 (29). Valproate may cause neural tube defects in the fetus and is not recommended during pregnancy (20). There is mixed evidence regarding the safety of atypical antipsychotics during pregnancy (34).