Bipolar disorder

Highlights

What is Bipolar Disorder?

Bipolar disorder is a type of mood disorder. It usually develops in a person’s mid-teens or early adult years but can affect people of all ages. With proper treatment, many patients are able to control their mood swings. Untreated bipolar disorder can lead to many serious problems, including substance abuse, financial crises, interpersonal difficulties, and increased risk of suicide.

Bipolar Disorder Symptoms

In bipolar disorder, manic symptoms alternate with depressive symptoms. Manic symptoms include:

  • Exaggerated euphoria
  • Irritability
  • Poor concentration
  • High energy and decreased need for sleep
  • Inflated sense of self-esteem
  • Rapid and excessive speech
  • Racing thoughts
  • Increased intensity in activities
  • Impulsivity and poor judgment

Diagnosis

Bipolar disorder is diagnosed based on specific criteria defined by the American Psychiatric Association. There are several different types of bipolar disorder.

Treatment

Bipolar disorder is treated with mood stabilizing drugs. They include:

  • Lithium is the main medication used for bipolar disorder and is usually the first drug prescribed.
  • Antiseizure medications used for bipolar disorder treatment include valproic acid (Depakene, generic), divalproex sodium (Depakote, generic), and lamotrigine (Lamictal, generic).
  • Certain types of atypical antipsychotics, which are standard drugs for schizophrenia treatment, are used for treatment of bipolar disorder.
  • In some cases, antidepressant drugs may be prescribed to control depressive episodes of bipolar disorder. However, their use is controversial. In some patients, antidepressants can trigger mania.

Many of these drugs are used in combination with one another. Side effects vary depending on the drug. Some of these drugs are not safe for pregnant women or should be used with caution.

Psychotherapy is an important component of treatment. Other types of therapies (like electroconvulsive therapy) may also be used.

Drug Approvals and Warnings

  • In 2011, the FDA approved a generic version of the atypical antipsychotic olanzapine (Zyprexa).
  • In 2011, the FDA warned that serious allergic reactions have been reported in patients taking the atypical antipsychotic asenapine (Saphris). Symptoms include difficulty breathing; swelling of face, tongue or throat; feeling lightheaded; itching. Patients should immediately contact their doctors if they experience any of these symptoms.

Introduction

Bipolar disorder, formerly called manic-depression, is characterized by moods that swing between two opposite poles:

  • Periods of mania with exaggerated euphoria, irritability, or both
  • Episodes of depression

Although chemical imbalances in the brain are a key component of bipolar disorder, it is a complex condition that involves genetic, environmental, and other factors.

Bipolar Disorder Categories

Bipolar disorder is classified according to the pattern and severity of the symptoms as bipolar disorder I, bipolar disorder II, or cyclothymic disorder. Patients with one type may develop another. Nevertheless, they are distinct enough to merit separate classifications. Some doctors believe these conditions are actually separate disorders with different biologic factors that account for their differences.

Bipolar Disorder I. Bipolar disorder I is characterized by at least one manic episode or mixed episode (symptoms of both mania and depression occurring simultaneously), and one or more depressive episodes, that last for at least 7 days. In most cases, manic episodes precede or follow depressive episodes in a regular pattern. Episodes are more acute and severe than in the other two categories.

Without treatment, patients average four episodes of dysregulated mood each year. With mania, either euphoria or irritability may mark the phase. In addition, there are significant negative effects (such as sexual recklessness, excessive and impulsive shopping, and sudden traveling) on a patient's social life, performance at work, or both. Untreated mania lasts at least a week, and it can last for months. Typically, depressive episodes tend to last 6 - 12 months, if left untreated.

Bipolar Disorder II. Bipolar disorder II is characterized by episodes of predominantly major depressive symptoms, with occasional episodes of hypomania, which last for at least 4 days. Hypomania is similar to mania, but the symptoms (typically euphoria) are less severe and do not last as long.

Patients with bipolar disorder II do not experience manic or mixed episodes, and most return to fully functional levels between episodes. However, these patients have a more chronic course, significantly more depressive episodes, and shorter periods of being well between episodes than patients with bipolar disorder I. Bipolar II disorder is highly associated with the risk for suicide.

Cyclothymic Disorder. While cyclothymic disorder is not as severe as either bipolar disorder II or I, the condition is more chronic. Hypomanic symptoms tend toward irritability as compared to the more euphoric symptoms of bipolar II.

The disorder lasts at least 2 years, with single episodes persisting for more than 2 months. Cyclothymic disorder may be a precursor to full-blown bipolar disorder in some people or it may continue as a low-grade chronic condition.

Bipolar Disorder Not Otherwise Specified (NOS). Bipolar disorder that does not meet one the above criteria is classified as Bipolar Disorder NOS.

Bipolar Disorder with Rapid Cycling. Bipolar disorder with rapid cycling involves four or more manic, hypomanic, or depressive episodes within a 12-month period. Mood swings can shift rapidly from mania to depression over the course of several days or hours. Rapid cycling can occur with any type of bipolar disorder. The condition is usually temporary.

Causes

Doctors do not know what causes bipolar disorder, but it is likely a combination of biochemical, genetic, and environmental factors.

Neurotransmitters (chemical messengers in the brain) that may be associated with bipolar disorder include dopamine, serotonin, and norepinephrine.

Multiple genes, involving several chromosomes, have been linked to the development of bipolar disorder. Research increasingly indicates that bipolar disorder may also share genetic factors with other disorders including schizophrenia, epilepsy, and anxiety disorders. It is not clear if some of these disorders are variations of a single disease or separate disorders.

For people who have a genetic or biochemical predisposition for bipolar disorder, environmental factors (such as stressful life events or emotional trauma) may play a role, in combination with other factors, in triggering this disorder.

Risk Factors

Age

Bipolar disorder usually first occurs between the ages of 15 - 30 years, with an average age of onset at 25 years. However, bipolar disorder can affect people of all ages, including children. Bipolar disorder that occurs late in life often accompanies medical and neurological problems (particularly cerebrovascular disease, such as stroke). It is less likely to be associated with a family history of the disorder than earlier-onset bipolar disorder.

Gender

Bipolar disorder affects both sexes equally, but there is a higher incidence of rapid cycling, mixed states, and cyclothymia in women. Early-onset bipolar disorder tends to occur more frequently in men and it is associated with a more severe condition. Men with bipolar disorder also tend to have higher rates of substance abuse (drugs, alcohol) than women.

Family History

Bipolar disorder frequently occurs within families. Family members of patients with bipolar disorder are also more likely to have other psychiatric disorders. They include schizophrenia, schizoaffective disorder, anxiety disorders, ADHD, and major depression.

Complications

Psychiatric Comorbidities

Many patients with bipolar disorder often have accompanying psychiatric disorders.

Depression. Patients with bipolar disorder, especially type II or cyclothymic disorder, have frequent episodes of major depression. Because of depression, patients with bipolar disorder have an increased risk for suicide.

Anxiety Disorders. Anxiety disorders, such as panic disorder, phobias, and post-traumatic stress disorder, commonly coexist in these patients. Patients who suffer from an anxiety disorder in addition to bipolar disorder are at increased risk for suicide.

Attention-Deficit Hyperactivity Disorder. Symptoms of bipolar disorder in children are often confused with attention-deficit hyperactivity disorder (ADHD). Furthermore, the two conditions can coincide. [See Diagnosis section of this report.]

Substance Abuse. Patients with bipolar disorder frequently abuse drugs and alcohol. Although drug and alcohol abuse may be a form of self-medication, substance abuse can trigger or worsen bipolar symptoms. Cigarette smoking is very common among patients with mental illness, including bipolar disorder, due in part to nicotine’s effects on the brain.

Behavioral and Emotional Effects

A small percentage of bipolar disorder patients demonstrate heightened productivity or creativity during manic phases. More often, however, the distorted thinking and impaired judgment that are characteristic of manic episodes can lead to dangerous behavior including:

  • Spending money with reckless abandon, causing financial ruin in some cases
  • Angry, paranoid, and even violent behaviors
  • Openly promiscuous behavior

Such behaviors are often followed by low self-esteem and guilt, which are experienced during the depressed phases. During all stages of the illness, patients need to be reminded that the mood disturbance will pass and that its severity can be diminished by treatment. Manic episodes also affect a patient’s family members and social circle and can create difficulties and tensions in interfamily and interpersonal relationships.

Both the depressive as well as manic phases of bipolar disorder can have a significant negative impact on a patient’s ability to function productively at work.

Prognosis

Bipolar disorder can be severe and long-term, or it can be mild with infrequent episodes. Patients with the disease may experience symptoms in very different ways. A typical patient with bipolar disorder averages 8 - 10 manic or depressive episodes over a lifetime. However, some people experience more and others fewer episodes.

Patients with bipolar disorder generally have higher death rates from suicide, heart problems, and death from all causes than those in the general population. Patients who get treatment, however, experience great improvement in survival rates.

Typical Bipolar Cycles. In most cases of bipolar disorder, the depressive phases outnumber manic phases, and the cycles of mania and depression are neither regular nor predictable. Many patients experience mixed mania, or a mixed state, in which both mania and depression coexist for at least 7 days.

Rapid Cycling. About 15% of patients with the disorder have a temporary, complicated phase known as rapid cycling. With this phase the manic and depressive episodes alternate at least four times a year and, in severe cases, can even progress to several cycles a day. Rapid cycling tends to occur more often in women and in those with bipolar II. Typically, rapid cycling starts in the depressive phase, and frequent and severe episodes of depression may be the hallmark of this event. This phase is difficult to treat, particularly since antidepressants can trigger the switch to mania and set up a cyclical pattern.

Differences Between Children and Adults. Research suggests that symptoms of bipolar disorder in children and adolescents differ from those of adults. While adults with bipolar disorder usually have distinct and persistent periods of mania and depression, children with bipolar disorder fluctuate rapidly in their mood and behavior. Mania in children is characterized by irritability and belligerence whereas adults tend to experience euphoria. Children with bipolar depression are frequently angry and restless, and may have additional mood and behavioral disorders such as anxiety, attention deficit hyperactivity disorder, conduct disorder, and substance abuse problems.

It is not yet clear how often childhood bipolar disorder persists into adulthood or if treating childhood bipolar disorder can help prevent future illness.

Symptoms

Symptoms of bipolar disorder tend to fluctuate dramatically between two extremes: mania and depression. Sometimes a patient may have an episode in which both symptoms of mania and depression are present at the same time. This is called a “mixed state."

Symptoms vary among patients. The types of symptoms experienced also depend on the type of bipolar disorder. Patients with bipolar I disorder typically have severe manic episodes that alternate with shorter bouts of depressive symptoms. Patients with bipolar II disorder, experience longer periods of depression that alternate with manic episodes that are shorter in duration and less severe (hypomania) than those associated with bipolar I disorder.

Symptoms of Mania

Symptoms associated with manic episodes include:

  • Exaggerated euphoria. A feeling of great happiness or well-being
  • Irritability. Can include aggressive behavior and agitation.
  • Distractibility. Characterized by the inability to concentrate on or pay attention to any activity for very long.
  • Insomnia. Having high energy and difficulty sleeping.
  • Grandiosity. Patients with this symptom have an inflated sense of self-esteem, which, in severe cases, can be delusional. Patients may experience feelings of being all-powerful or feel that they are godlike or have celebrity status.
  • Rapid speech and racing thoughts. The patient may talk quickly and excessively and move rapidly from one idea to another.
  • Increased activity. The patient may show an increase in intensity in goal-directed activities related to social behavior, sexual activity, work or school.
  • Poor judgment. Excessive involvement in high-risk activities may occur (such as unrestrained shopping, promiscuity). Impulsivity and poor judgment may be severe enough to damage workplace or social functioning or relationships with others. Some patients require hospitalization to prevent harm to themselves or to others.
Symptoms of Depression

The symptoms of depression experienced in bipolar disorder are almost identical to those of major depression, the primary form of unipolar depressive disorder. They include:

  • Sad mood
  • Fatigue or loss of energy
  • Sleep problems such as insomnia, excessive sleeping, or shallow sleep with frequent awakenings
  • Appetite changes
  • Diminished ability to concentrate or to make decisions
  • Agitation or markedly sedentary behavior
  • Feelings of guilt, pessimism, helplessness, or low self-esteem
  • Loss of interest or pleasure in life
  • Thoughts of or attempts at suicide

Diagnosis

Doctors diagnose bipolar disorder based on criteria of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM). These criteria include the presence of manic, depressive, or mixed episodes, how frequently these symptoms occur, and how often they last.

Ruling out Similar Conditions

When making a diagnosis of bipolar disorder, it is important that the doctor rule out other conditions that may be causing symptoms of bipolar disorder.

Distinguishing Mania from Normal Euphoria or Joy. A major difficulty with a diagnosis of bipolar disorder is the tendency for a patient to be unable to recognize his or her own condition, particularly when in the manic state. Patients often deny their symptoms, which may be perceived as positive feelings. The doctor should take a careful and complete history of any and all episodes of depression, mania, or both.

Hypomania, the less severe variant of mania, may be particularly difficult to distinguish from normal joy or euphoria. It can often be distinguished by the following characteristics:

  • Hypomania persists for at least 4 days
  • Patients with hypomania are easily distracted and overly talkative
  • Patients with hypomania have difficulty functioning

Distinguishing Unipolar from Bipolar Depression. It is often difficult to differentiate between unipolar (the depression associated with major depressive disorder) and bipolar depression. This is especially true for patients with bipolar II disorder. Bipolar depression and major depressive disorder may differ in the following ways:

  • Bipolar depression typically lasts 2 - 3 months -- not as long as in major depression (although left untreated some bipolar disorder episodes can last 6 - 12 months or longer).
  • People with unipolar depression can still experience a variety of other moods, but none meet the criteria for a manic state.
  • Bipolar depressive episodes tend to develop more gradually than do those caused by major depression.

An accurate diagnosis is important because patients with bipolar disorder who are inappropriately medicated solely with antidepressants have an increased risk of rehospitalization.

Attention-Deficit Hyperactivity Disorder (ADHD). Children or adolescents with bipolar disorder may be inappropriately diagnosed with attention-deficit hyperactivity disorder. ADHD and bipolar disorder often cause inattention and distractibility, and the two disorders may be difficult to distinguish, particularly in children. In some cases, ADHD in children or adolescents can even be a marker for an emerging bipolar disorder. The primary distinction between bipolar disorder and ADHD is the presence of a manic or hypomanic episode, which occurs in patients with bipolar disorder but not those with ADHD.

Schizophrenia. Severe manic episodes that include delusions and hallucinations may be confused with schizophrenia. The key factors that distinguish bipolar disorder from schizophrenia include:

  • The presence of one or more manic or hypomanic episodes in bipolar disorder, but not in schizophrenia
  • A flat emotional expression, with a monotonous speaking voice among people with schizophrenia
  • People with bipolar disorder are typically very expressive
Laboratory Tests

Patients should be tested for drugs or alcohol if the doctor suspects that they have been using these substances. Blood tests for thyroid function should also be performed.

Diagnosis in Children

The number of children diagnosed with bipolar disorder has increased dramatically during the past decade. Psychiatrists debate whether bipolar disorder was formerly under-diagnosed in children or whether it is being over-diagnosed now. Part of the controversy concerns the diagnostic criteria used for children and adolescents. Some bipolar symptoms, such as irritable mania, share characteristics with common childhood anger outbursts or behavioral disorders such as conduct disorder and attention deficit hyperactivity disorder. In addition, many children with bipolar disorder also have behavioral and developmental disorders. These overlapping conditions can complicate diagnosis.

The American Academy of Child and Adolescent Psychiatry (AACP) recommends that doctors use specific screening questions to diagnose bipolar disorder. These questions are designed to evaluate periods of mood changes associated with sleep disorders and restlessness. Doctors should also ask about family histories of mood disorders. The AACP cautions that the validity of diagnosing bipolar disorder in children younger than 6 years old has not been established.

Bipolar disorder is treated with powerful psychiatric drugs that can cause serious side effects. It is very important to make sure that a child’s symptoms are due to bipolar disorder, rather than emotional or behavioral issues, before prescribing these medications.

Treatment

Bipolar disorder is a recurrent disease that can be unpredictable. It is treatable, however, and many patients go to have healthy and productive lives. The major goals of treatment are to:

  • Treat and reduce the severity of acute episodes of mania or depression when they occur
  • Reduce the frequency of episodes
  • Avoid cycling from one phase to another
  • Help the patient function as well as possible between episodes

The doctor will first try to determine what may have triggered the attack and identify any accompanying medical or emotional problems that might interfere with or complicate treatment.

Challenges of Bipolar Treatment

The treatments for bipolar disorder, while very effective, pose some specific challenges for the patient:

  • Mood variations in bipolar disorder are not predictable, so it is sometimes difficult to tell if a patient is responding to treatment or naturally emerging from a bipolar phase.
  • A patient with bipolar disorder cannot always reliably inform the doctor about the state of the illness.
  • The patient is likely to need more than one medication during the course of the disease. This increases the risk for distressing side effects. Noncompliance is common.
  • Patients often have more than one medical problem and need different drugs to treat each condition. Such medications may interact with drugs used to treat bipolar disorder or increase side effects. For example, children with bipolar disorder have a higher risk for attention deficit-hyperactivity disorder, which is treated with stimulants that can complicate bipolar treatment.
  • Treatment strategies for children and the elderly have not been intensively studied and have not been clearly defined.
  • Patients need to monitor their condition on a lifelong basis.
Specific Drugs and Other Treatments Used in Bipolar Disorder

The following are the treatment options for most patients with bipolar disorder, depending on the bipolar disorder phase or episode. Patients should understand that, even with aggressive therapy, either mania or depression recurs in about 75% of patients.

Drugs Used in Bipolar Disorder. Mood stabilizing drugs are the mainstay for patients with bipolar disorder. They are defined as drugs that are effective for acute episodes of mania and depression and that can be used for maintenance. The standard first-line mood stabilizers are lithium and valproate. Both drugs stimulate the release of the neurotransmitter glutamate, although they appear to work through different mechanisms. Other drugs may also be used. Drugs to treat bipolar disorder should be prescribed and managed by a psychiatrist.

  • Lithium. Lithium has been used for years for bipolar disorder. It remains the best drug for people with pure mania characterized by euphoria and pure depression. Although imperfect, it is also an effective long-term drug for many patients with other bipolar subtypes.
  • Antiseizure Drugs. Valproate (valproic acid, generic) carbamazepine (Tegretol, Carbatrol, Equetro, generic), oxcarbazepine (Trileptal, generic), and lamotrigine (Lamictal, generic) are the antiseizure drugs used most often in treating bipolar illness. Other antiseizure drugs used or investigated for bipolar include gabapentin (Neurontin, generic), zonisamide (Zonegran, generic) and topiramate (Topamax, generic). To date, it is not clear if any of these newer drugs are useful for the treatment of acute mania.
  • Atypical Antipsychotics. Drugs known as atypical antipsychotics are used to treat schizophrenia and also have mood stabilizing properties that are applicable to bipolar disorder. They may be used either alone or in combination with lithium or valproate. Clozapine (Clozaril, generic) was the first of these drugs, but it is not approved for treatment of bipolar disorder. The newer atypical antipsychotics approved for treating bipolar disorder include olanzapine (Zyprexa, generic), risperidone (Risperdal, generic), quetiapine (Seroquel), ziprasidone (Geodon), ariprazole (Abilify), and asenapine (Saphris).
  • Antidepressants. Antidepressants alone are not recommended, but may be used with care for depressive symptoms that do not respond to lithium and antiseizure drugs.. The first choices for antidepressants are bupropion (Wellbutrin, generic) or paroxetine (Paxil, generic). Alternatives include one of the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac, generic), a newer antidepressant such as venlafaxine (Effexor, generic), or a monoamine oxidase inhibitor (MAOI).

These drugs may be used singly or in various combinations. Additional drugs, such as conventional antipsychotics or anti-anxiety drugs, are used as necessary.

Electroconvulsive Therapy. Electroconvulsive therapy is a treatment that may be helpful for select patients who require stabilization or who have severe mania or depression.

Non-Medical Treatments. In addition to medical treatments, psychotherapy and sleep management are also parts of bipolar disorder treatment. They can help reduce symptoms and prevent relapse.

Treatment Guidelines for Manic Episodes

Step 1. Determine the Need for Hospitalization and Eliminate Triggers. The first step in treating an acute manic episode is to rule out any life-threatening conditions and eliminate any triggers, such as antidepressants or other substances that can elevate moods. Patients often require hospitalization at the onset of acute mania.

Step 2. Control Symptoms of Mania with a Mood Stabilizer. Initiation of a mood-stabilizing drug is the critical first step. It may take several weeks for a mood stabilizer to take effect, and other drugs may be needed.

  • Either valproate or lithium is the standard first drug for most manic episodes. Lithium is effective for most hypomanic and manic episodes.
  • Carbamazepine may be used in place of valproate to treat patients with multiple manic episodes, mixed episodes, and rapid cycling. Combinations of these mood stabilizers may be used if the patient does not respond to a single drug.

Step 3. Addition of Other Treatments. Other treatments may be added to speed recovery, treat any psychosis, and achieve remission:

  • If the patient does not respond fully within a week and symptoms are more severe, antipsychotics may be added to mood stabilizers. Atypical antipsychotics are more likely to be used first. They include olanzapine (Zyprexa, generic), risperidone (Risperdal, generic), quetiapine (Seroquel), apriprazole (Abilify), ziprasidone (Geodon), and asenapine (Saphris). Clozapine (Clozaril) is not generally used because of its potential for severe side effects.
  • Older antipsychotic drugs (also called typical antipsychotics), such as haloperidol (Haldol, generic), may be used for acute mania. They may be more likely to cause extrapyramidal effects, which disrupt motor control, and are not generally used on a long-term basis.
  • Benzodiazepines, such as clonazepam (Klonopin, generic) or lorazepam (Ativan, generic), are anti-anxiety drugs that may be beneficial if the patient is experiencing severe mania.
  • Electroconvulsive therapy. This non-drug treatment may help patients who do not respond to medication.

Step 4. Withdrawal of Some Drug Treatments. In cases of improvement and sustained recovery, the antipsychotic or benzodiazepine drugs are slowly withdrawn and only the mood-stabilizing drug is continued.

Step 5. Continuation of Mood Stabilizers. Mood stabilizers are typically continued for about 8 weeks, unless the patient shows signs of shifting to another mood state. If the patient remains stable at that time, the doctor may decide to continue maintenance treatment or to gradually withdraw medications.

Treatment Guidelines for Depressive Episodes

Depressive episodes are a particular challenge because many antidepressant drugs pose a risk for triggering mania. It is not clear if standard antidepressants work for bipolar depression. Depressive episodes are very difficult to control and patients who do not respond to mood stabilizers may endure prolonged depressive episodes up to 2 - 3 months.

Lithium or lamotrigine are the standard first-line treatments for depressive episodes. Many studies indicate that lithium works better for controlling manic states, and that lamotrigine works better for bipolar depression.

If improvement does not occur within 2 - 4 weeks, an antidepressant may be added. Antidepressants alone are not recommended. The first choices for antidepressants are bupropion (Wellbutrin, generic) or paroxetine (Paxil, generic). Alternatives include one of the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac, generic), a newer antidepressant such as venlafaxine (Effexor, generic), or a monoamine oxidase inhibitor (MAOI).

Other drugs are also approved specifically for treatment of bipolar depression. Symbax combines the atypical antipsychotic olanzapine with the SSRI antidepressant fluoxetine. Quetiapine (Seroquel) is an atypical antipsychotic which is approved for both treatment of bipolar mania and bipolar depression.

Other Treatments. Cognitive-behavioral therapy or other psychotherapy programs may help patients cope with depressive episodes by developing ways to manage negative thoughts and behaviors. Electroconvulsive therapy is another treatment option for severe depression.

Treatment Guidelines for Mixed Episodes and Rapid Cycling

The first step in treating rapid cycling is to try to identify and resolve other factors, such as drug abuse or hypothyroidism, which may have caused this condition. Many patients may require a combination of medications to control rapid cycling:

  • Antidepressants, particularly SSRIs, may prompt rapid cycling and are usually tapered off.
  • Lithium or valproate is a first-line treatment for rapid cycling.
  • Lamotrigine is an alternative treatment for rapid cycling.
  • Atypical antipsychotics (olanzapine, aripiprazole, ziprasidone, risperidone, asenapine) are approved to treat mixed episodes. These drugs are used either alone or in combination with lithium or valproate.
  • Electroconvulsive therapy may be useful in some situations.

In addition, other measures should be taken:

  • Patients should avoid anti-anxiety drugs, alcohol, caffeine, and stimulants.
  • Patients should avoid exposure to bright light.
  • All efforts should be made to help the patient sleep normally.
Treatment Guidelines for Maintenance

Drugs Used During Maintenance. Relapse occurs in most patients after treatment of acute attacks, and patients who are at high risk for recurring episodes should consider life-long maintenance therapy. This usually involves mood-stabilizing drugs:

  • Lithium is a first-line mood stabilizer used in maintenance therapy. The anti-epileptic drug valproate is also a first-line treatment. In general, the two work equally well, although there are some differences in side effects.
  • Lamotrigine, another anti-epileptic drug, is approved as a maintenance treatment for bipolar I disorder and may also be used as a first-line drug for treating depressive episodes.
  • Carbamazepine and oxcarbazepine are other anti-epileptic drugs used as alternative maintenance treatments.
  • Atypical antipsychotics may be used for maintenance, particularly in combination with a mood stabilizer.

The general recommendations for maintenance therapy with lithium are as follows:

  • The earlier lithium is started in the disease process, the better. Studies suggest that patients on long-term lithium therapy have survival rates comparable to the general population, but those who permanently drop out of therapy have significantly lower survival rates due to an increased suicide risk.
  • Patients who stop lithium and then start again may be at higher risk for hospitalization and are more likely to need more than one drug.
  • For those who want to stop, a gradual discontinuation (over 15 - 30 days) may help to delay recurrence. Stopping lithium quickly poses a high risk for relapse and for suicide.
Treatment Guidelines for Pregnant Patients with Bipolar Disorder

Treatment of pregnant women with bipolar disorder poses specific challenges. All psychiatric medications can cross the placenta into amniotic fluid. These drugs can also enter breast milk. While certain types of medications present more risks to the fetus than others, not taking medications also carries substantial risks. Untreated women may be less likely to receive appropriate prenatal care, and more likely to engage in risky behaviors, including alcohol and tobacco use. Non-treatment may also cause difficulties with mother-infant bonding and disruptions in the family environment.

Before conceiving, a woman with bipolar disorder should consult with her obstetrician, psychiatrist, and primary care physician. Close follow-up with all of these providers should take place during the pregnancy.

The American College of Obstetricians and Gynecologists (ACOG) has guidelines for psychiatric drug treatment during pregnancy:

  • When possible, a single medication at a higher dosage is preferred over multiple medications.
  • Lithium is associated with a small increased risk for heart defects and other birth defects in the fetus.
  • For a pregnant woman with mild bipolar disorder, the medication may be gradually tapered off before conception. Women who are at moderate risk for relapse are often asked to stop taking lithium until the fetus’ organ formation is complete. Women at high risk for bipolar disorder relapse may need to continue taking lithium throughout the pregnancy.
  • Women should have their lithium levels closely monitored during pregnancy. Lithium levels in the blood that were previously stable may change during pregnancy.
  • If lithium was taken during the first trimester, ultrasound and perhaps echocardiography are generally performed to evaluate the fetal heart.
  • Women who must take lithium during pregnancy should take the lowest possible dosage and stop the drug 1 - 2 days before delivery. Mothers who are taking lithium should not nurse their babies, since lithium is concentrated in breast milk.

For antiseizure drugs, valproate should not be used during the first trimester of pregnancy, if possible. Valproate is specifically associated with neural tube, craniofacial, and heart birth defects as well as growth delay and cognitive impairment. Carbamazepine may also increase facial malformation but, like lamotrigine, is considered a safer drug than valproate for use during pregnancy. [For more information, see In-Depth Report #44: Epilepsy ]

For atypical antipsychotics, safety data is limited and there have been no long-term studies on the effects of children exposed to these drugs during pregnancy. Some studies indicate that these drugs can increase the risk of low birth weight. In general, doctors do not recommend the routine use of atypical antipsychotics during pregnancy.

For antidepressants, doctors decide on the appropriateness of these drugs on a case-by-case basis. The SSRI paroxetine should be avoided by women who plan on becoming pregnant as this drug significantly increases the risk of fetal heart defects. Other SSRIs are generally considered safe for use during pregnancy and breastfeeding

Treatment Guidelines for Children and Adolescents

Doctors are still trying to decide the best treatment approaches to bipolar disorder in children and adolescents. The drugs used for bipolar disorder have considerable side effects, which may be even more severe in younger people. Parents should consider the potential risks and benefits of treatment for their children.

Until recently, lithium was the only drug approved for treating bipolar disorder in children (age 12 years and older). A few atypical antipsychotic drugs, such as risperidone (Risperdal) and ariprazole (Abilify), are approved for children ages 10 - 17 with bipolar I disorder.

Lithium is generally used as the first-line treatment, with valproate and risperidone (or other atypical antipsychotics) as alternatives. If treatment with a single drug does not work, a combination of drugs may be used.

Psychotherapy is also an important addition to drug treatment. Therapy that includes the entire family is important. Electroconvulsive therapy (ECT) may benefit adolescents who have not been helped by medication.

Medications

Lithium

Lithium (Eskalith, Lithobid, generic) is the most widely used and studied mood stabilizing drug for bipolar disorder. Lithium is extremely helpful for most patients. It can help control symptoms of mania and prevent recurrent manic episodes. It can also help treat bipolar depression and reduce suicide risk.

Administration of Lithium. Lithium may take several weeks to become fully effective, so patients should not expect an immediate response during an acute episode.

Lithium blood levels should be monitored regularly to determine the best dosage and to prevent lithium toxicity. In addition, the doctor needs to monitor the patient’s kidney and thyroid function. Lithium can cause low thyroid levels (hypothyroidism), which can affect mood. Some patients need to take thyroid medication while on lithium.

Lithium Toxicity. If lithium levels in the blood are too high, lithium toxicity (overdose) can occur. Signs of toxicity include:

  • Trembling hands
  • Nausea
  • Increased urine output
  • Blurred vision
  • Some loss of coordination

Severe reactions occurring at very high blood levels include:

  • Vomiting
  • Ringing in the ears
  • Convulsions
  • Uncontrolled jerky movements in arms and legs
  • Stupor
  • Coma
  • Very high blood levels of lithium can be fatal

Side Effects. Mild nausea and diarrhea are common initial side effects of lithium that usually go away after a few weeks. Long-term side effects may include:

  • Weight gain, which can lead to increased risk for diabetes
  • Increased thirst
  • Increased urination
  • Hair loss
  • Skin rashes and acne
  • Low thyroid function (symptoms include dry skin, sensitivity to cold temperatures, hair loss, weight gain)
  • Impaired memory and poor concentration

Drug Interactions. Because lithium is eliminated from the body by the kidneys, any drugs or dietary factors that slow the kidneys' actions may increase lithium blood levels and should be used with great caution. Such drugs include:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Thiazide diuretics
  • ACE inhibitors
  • Antipsychotics

Some of these drugs can worsen lithium side effects.

Valproate and Other Antiseizure Drugs

Antiseizure drugs, also called anti-epileptics or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. These drugs may be an alternative for patients who do not tolerate or respond to lithium. They also may be used in combination with lithium, atypical antipsychotics, or other drugs.

Standard Antiseizure Drugs.

  • Valproate drugs -- valproic acid (Depakene, generic), valproate sodium (Depacon), and divalproex sodium (Depakote, generic)-- are approved for treatment of bipolar acute mania and mixed episodes.
  • Lamotrigine ((Lamictal, generic) is approved for maintenance treatment of adults with bipolar I disorder. It is also used to treat bipolar depression.
  • Carbamazepine (Epitol, Tegretol, generic), a standard alternative antiseizure drug used for mood stabilizing, is usually the second anti-seizure medication of choice.
  • Other anti-seizure drugs used or investigated for bipolar disorder include gabapentin (Neurontin, generic), zonisamide (Zonegran, generic) and topiramate (Topamax, generic). To date, it is not clear if any of these newer drugs are useful for the treatment of acute mania.

General Side Effects. The side effects given here are associated with valproate. Other antiseizure drugs have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy and then subsiding. Valproate side effects may include:

  • Gastrointestinal problems such as nausea, vomiting, and heartburn
  • Headaches
  • Visual disturbances
  • Ringing in the ear
  • Hair loss
  • Weight gain (a significant problem with valproate)
  • Agitation
  • Odd movements
  • Menstrual irregularities and a higher risk for polycystic ovary syndrome (PCOS)
  • Birth defects when taken by pregnant women during the first trimester (valproate has the most evidence for causing birth defects)
  • Cognitive impairment and symptoms of Parkinson's disease

Very serious side effects are possible. Antiseizure drugs can increase the risk for suicidal thoughts and behavior as soon as 1 week after starting drug therapy. The risk for suicidality can continue for at least 6 months. All patients who take these drugs should be monitored for worsening depression or unusual changes in behavior.

Stevens-Johnson syndrome (SJS) is a rare but severe and potentially life-threatening, rash that can develop as a side effect of carbamazepine, lamotrigine, oxcarbazepine and other anticonvulsants. Because this is a very serious condition, these drugs are discontinued at the first sign of rash. The risk of serious skin reactions is 10 times higher for patients of Asian ancestry than Caucasians. The FDA recommends that people of Asian ancestry get a genetic test before starting carbamazepine to determine if they are at risk for this side effect.

Other serious side effects, also rare, may include liver damage, aseptic meningitis (with lamotrigine), convulsions, coma, and pancreatitis.

[For more information on antiseizure drugs, see In-Depth Report #44: Epilepsy.]

Atypical Antipsychotics

Atypical antipsychotics are standard drugs for schizophrenia. They are also used to treat bipolar disorder alone or in combination with the mood stabilizers that treat mania.

Atypical antipsychotics include clozapine (Clozaril, generic), olanzapine (Zyprexa, generic), risperidone (Risperdal, generic), paliperidone (Invega), quetiapine (Seroquel), aripiprazole (Abilify), ziprasidone (Geodon), and asenapine (Saphris).

  • Olanzapine was the first atypical antipsychotic approved for treatment and longterm maintenance of bipolar disorder. It is FDA-approved to treat bipolar mania and mixed states.
  • Symbyax, a drug that combines olanzapine and the antidepressant fluoxetine is approved for treatment of bipolar depression.
  • Risperidone, ziprasidone, ariprazole, and asenapine are approved for treatment of bipolar mania and mixed states in adults. Ariprazole and risperidone are also approved for the acute treatment of mania and mixed episodes in children ages 10 - 17 with bipolar I disorder.
  • Quetiapine is approved for treatment of bipolar mania and bipolar depression, making it the only drug approved for treating both manic and depressive states.
  • Clozapine is an older atypical antipsychotic. It has not been approved for treatment of bipolar disorder, but has shown promise in investigational studies. However, this drug has more significant side effects than other atypical antipsychotics. It poses a risk of white blood cell reduction (agranulocytosis).

Side Effects. Although atypical antipsychotics have fewer severe side effects than standard antipsychotics, many patients fail to comply with regimens containing them. Common side effects include:

  • Nasal congestion or runny nose
  • Drooling
  • Dizziness
  • Headache
  • Drowsiness -- however, these drugs may also cause restlessness and insomnia.
  • Constipation
  • Rapid heart beat
  • Difficulty urinating
  • Skin rash
  • Increased body temperature
  • Confusion, short-term memory problems, disorientation, and impaired attention

More serious risks include:

  • Diabetes
  • Weight gain and unhealthy cholesterol levels. The risk is highest for olanzapine and clozapine.
  • Seizures
  • Extreme and very serious increases in body temperature
  • Sudden drop in blood pressure (hypotension)
  • Extrapyramidal side effects, which are lack of motor coordination and involuntary movements
  • Cataracts and worsening of any existing glaucoma
  • Increased prolactin levels -- prolactin is a hormone associated with infertility and erectile dysfunction. High levels can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer.
  • Heart problems, including sudden death
  • Serious allergic reactions, especially with asenapine (Saphris)

Diabetes Risk and Atypical Antipsychotics. All atypical antipsychotics can increase the risk of high blood sugar (hyperglycemia) and diabetes. (Olanzapine is more likely to cause high blood sugar levels than other atypical antipsychotic medicines.) The FDA recommends that:

  • Patients with an established diagnosis of diabetes who begin atypical antipsychotic treatment should be regularly monitored for worsening of blood sugar control.
  • Patients with risk factors for diabetes (obesity, family history of diabetes) should undergo fasting blood sugar testing at the beginning of atypical antipsychotic treatment and periodically during treatment.
  • All patients treated with atypical antipsychotics should be monitored for high blood sugar (hyperglycemia) symptoms.
  • Patients who develop hyperglycemia symptoms should undergo fasting blood sugar testing.
Antidepressants

Lithium or lamotrigine (Lamictal, generic) are usually the first choices for treating depressive episodes in bipolar disorder. Antidepressants are sometimes used, but their use is controversial. They may trigger mania in 10 - 30% of patients. In addition, a number of studies report no additional benefits from antidepressants. Specific antidepressants may be beneficial in certain circumstances. However, any patient on antidepressants who develops symptoms of hypomania should stop taking these drugs (under the care of a doctor), since hypomania is often a sign of impending mania. All antidepressants should be tapered off after the mood has been stabilized for a month.

Bupropion. The antidepressant bupropion (Wellbutrin, generic) appears to pose a lower risk for triggering mania than do other antidepressants. Side effects may include restlessness, agitation, sleeplessness, headache, rashes, stomach problems, and in rare cases, hallucinations and bizarre thinking. Bupropion has also been associated with changes in behavior, hostility, agitation, and suicidal thoughts and behaviors. Initial weight loss occurs in about 25% of patients. High doses may cause seizures. This side effect is uncommon and tends to occur in patients with eating disorders (anorexia or bulimia) or those with risk factors for seizures.

Selective Serotonin Reuptake Inhibitors. Serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac, generic), citalopram (Celexa, generic), sertraline (Zoloft, generic), and paroxetine (Paxil, generic), are sometimes used to treat bipolar depression, but their benefits have not yet been established. They may be useful in patients whose depression does not respond to lithium. They do not appear to be useful as an add-on treatment to lithium. Another antidepressant, venlafaxine (Effexor, generic), may also be used in patients with severe cases of depression who do not respond to other treatments.

Side effects of SSRIs may include:

  • Nausea and gastrointestinal problems, which usually wear off over time
  • Agitation, insomnia, mild tremor, and impulsivity
  • Dry mouth, which can increase the risk for cavities and mouth sores
  • Headache
  • Sexual dysfunction

Monoamine Oxidase Inhibitors (MAOIs). Older antidepressants known as monoamine oxidase inhibitors (MAOIs), may sometimes be used for bipolar depression. MAOIs can interact with certain foods and cause severe high blood pressure. Such foods have high tyramine content and include aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products. MAOIs can also have severe interactions with certain drugs, including some common over-the-counter cough medications. In such cases, severe high blood pressure or dangerous reactions can occur. It is important that patients discuss with their doctor any other medications they are taking.

[For more information on antidepressant medications, see In-Depth Report #08: Depression.]

Other Treatments

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a non-drug treatment for bipolar disease and other mental disorders, such as severe depression. It is commonly called shock therapy. ECT has received bad press since it was introduced in the 1930s. But over the years it has been refined, and is now considered a very safe treatment.

Research suggests ECT may be particularly beneficial for:

  • Patients who need immediate stabilization of their condition and who cannot wait for medications to work
  • Patients with severe mania -- especially elderly patients
  • Patients who suffer suicidal thoughts during depressive episodes
  • Pregnant patients
  • Patients who cannot tolerate drug treatments
  • Young patients

The Procedure. ECT is performed on an outpatient basis and does not require hospitalization. In general, the ECT procedure is performed as follows:

  • A muscle relaxant and short-acting anesthetic are given to the patient.
  • A small amount of electricity is sent to the brain, causing a generalized seizure that lasts for about 40 seconds.

Side Effects. Side effects of ECT may include temporary confusion, memory lapses, headache, nausea, muscle soreness, and heart disturbances. Concerns about permanent memory loss appear to be unfounded.

The ECT procedure affects heart rate and blood pressure. Doctors should perform a medical evaluation of patients before they receive ECT. Patients, (especially those who are elderly), who have high blood pressure, atrial fibrillation, asthma, or other heart or lung problems may be at increased risk for heart-related side effects.

Psychotherapy and Lifestyle Changes

Psychotherapy is an important addition to medication. There are many approaches. Trained mental health professionals can:

  • Educate patients about bipolar disorder and its treatments
  • Teach patients to recognize and manage early warning symptoms of imminent manic or depressive episodes
  • Help them comply with drug regimens
  • Monitor the patient's on-going status

In addition, psychotherapy can help patients:

  • Adjust to the reality of the illness and understand the negative consequences of mania -- particularly important for patients who consider their mania to be positive, creative, and exhilarating
  • Cope with feelings of guilt and remorse that occur after manic episodes
  • Deal with feelings of imperfection and despair
Cognitive-Behavioral Therapy

Therapists trained in cognitive-behavioral therapy (CBT) may be particularly helpful for many patients. CBT is a structured, conscious method that aims to help a patient recognize negative thoughts and behavioral patterns and to change them. CBT is known to be helpful for other mood disorders, including depression and anxiety, and some studies suggest that it benefits patients with bipolar disorder as well.

Typical goals of CBT for patients with bipolar disorder patients include:

  • Recognize manic episodes before they become full-blown and change behaviors during an episode
  • Cope with depression by developing behaviors and thoughts that may help offset the negative mood
Family Therapy

It is important that partners, family members, or both be involved in therapy. Therapy can help them learn how to accept and cope with the condition.

Support for the Patient. Recommendations for supporting the patient include:

  • Create a treatment contract as a first step. In this contract, the patient and family agree to specific steps for maintaining emotional stability, including compliance with treatment. If such measures fail, all parties agree on further actions to be taken during an acute episode, including hospitalization.
  • Be supportive. Unlike relatives of patients with alcoholism who may be encouraged to get tough, relatives of patients with bipolar disorder must be strongly supportive because of the high risk for suicide with this disorder. Simply listening attentively and being empathic can help. Bipolar disorder results from an imbalance of chemicals in the brain and not from anyone's fault.
  • Get the patient to comply with treatment, even if it means threatening a hospitalization if the patient fails to comply.
  • For emergencies, have ready a hotline number or the telephone number of the patient’s psychiatrist.

Support for the Family. Bipolar disorder can take a serious toll on family members. Loved ones must also learn to care for themselves and reduce the stress that accompanies the illness. Support groups and Internet message boards can be very helpful for caregivers.

Interpersonal and Social Rhythm Therapy

Interpersonal problems (such as family disputes) and disruptions in daily routines or social rhythms (such as loss of sleep or changes in meal times) may make people with bipolar disorder more susceptible to new episodes of their illness. A form of psychosocial treatment called interpersonal and social rhythm therapy (IPSRT) focuses on maintaining a regular schedule of daily activities to reduce these potential triggers and improve emotional stability. Patients also learn how to avoid problems with personal relationships. Preliminary evidence suggests that IPSRT combined with drug therapy may help prevent new manic episodes.

Lifestyle Factors

Exercise. Exercise can help manage weight gain and increase feelings of well-being.

Sleep Management. Good sleep hygiene is particularly important for patients. Techniques used to enforce healthy sleep may help reduce mood cycling.

Diet. A healthy diet low in saturated foods and rich in whole grains, fresh fruits, and vegetables is important for anyone. People with bipolar disorder should be sure to maintain a regular healthy diet. They may need to restrict calories if they are on medications that increase weight.

Some research indicates that consumption of omega-3 polyunsaturated fatty acids found in oily fish (such as mackerel, sardines, salmon, and bluefish) may help reduce the symptoms of a variety of mental illnesses, including bipolar disorder. Researchers are investigating the mental health effects of eicosapentaneoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acid supplements.

Resources

References

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American Academy of Child and Adolescent Psychiatry. Practice parameter on the use of psychotropic medication in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009 Sep;48(9):961-73.

Benazzi F. Bipolar disorder -- focus on bipolar II disorder and mixed depression. Lancet. 2007 Mar 17;369(9565):935-45.

Beynon S, Soares-Weiser K, Woolacott N, Duffy S, Geddes JR. Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials. J Psychopharmacol. 2009 Jul;23(5):574-91. Epub 2008 Jul 17.

Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011 Oct 8;378(9799):1306-15. Epub 2011 Aug 16.

Frye MA. Clinical practice. Bipolar disorder--a focus on depression. N Engl J Med. 2011 Jan 6;364(1):51-9.

Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009 Jan;194(1):4-9.

Geller B, Tillman R, Bolhofner K, Zimerman B. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry. 2008 Oct;65(10):1125-33.

Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry. 2009;10(2):85-116.

Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Möller HJ, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010 Mar;11(2):81-109.

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Review Date: 2/8/2012

Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

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