Bipolar disorder

An in-depth report on the causes, diagnosis, and treatment of bipolar disorder.

Highlights

What is Bipolar Disorder?

Bipolar disorder is a type of mental illness. 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.

The depressive episodes of bipolar disorder can be very difficult to treat. In 2013, the FDA approved the atypical antipsychotic lurasidone (Latuda) for treatment of bipolar depression in adults.

In 2013, the American Psychiatric Association (APA) released the revised edition of its diagnostic manual for psychiatric conditions. Among the changes for bipolar disorder:

• Bipolar disorder is no longer classified as a "mood disorder" like depression. It is now in a separate category called "Bipolar and Related Disorders"
• To be diagnosed with bipolar disorder, a patient must now exhibit changes in activity and energy, as well as mood.
• There is no longer a diagnosis of "mixed episode" bipolar disorder. Instead, a psychiatrist can use a specifier called "with mixed features" when episodes of mania have depressive features, or episodes of depression have manic features. A new specifier called "anxious distress" is used for anxiety features.
• The APA's manual includes a new diagnosis called "disruptive mood dysregulation disorder" which is related to depressive disorders, not bipolar disorder. The APA included it in part to address concerns about the potential overdiagnosis and overtreatment of bipolar disorder in children.

Introduction

Bipolar disorder, formerly called manic-depression, is a mental illness characterized by periods of extreme moods that swing between two opposite poles:

• Mania, which is characterized by exaggerated euphoria, irritability, or both.
• Depression, which is characterized by overwhelming feelings of sadness, hopelessness, and loss of pleasure.

Types of Bipolar Disorder

The American Psychiatric Association classifies bipolar disorder according to the pattern and severity of the symptoms. The main types of bipolar disorder are:

• Bipolar Disorder I. Bipolar disorder I is marked by manic episodes that are preceded or followed by hypomania or depressive episodes. (Hypomania is mild mania; the euphoric symptoms are less severe and do not last as long.) Mania is defined as a period of abnormally and persistently elevated, expansive, or irritable mood accompanied by increased goal-directed activity or energy. These changes in mood and energy last at least 1 week and are present most of the day, nearly every day. Mania can have 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 can last for several months. Depressive episodes tend to last 6 to 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. Patients with bipolar disorder II do not experience pure manic episodes but have 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 increased risk for suicide.
• Cyclothymic Disorder. Cyclothymic disorder is not as severe as either bipolar disorder II or I but 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 or it may continue as a low-grade chronic condition.
• Other Specified Bipolar Disorder and Related Disorders. Bipolar disorder that does not meet the full criteria for one of the above categories is grouped into this category. Examples include people who have experienced major depressive episodes alternating with short hypomanic episodes that lasted only a few days.

A bipolar classification can also have a "specifier" to describe certain features specific to that patient's condition.

For example, a patient with bipolar I disorder may have a manic episode "with mixed features" to describe episodes of mania accompanied by severe depression. Similarly, a patient with bipolar II disorder who experiences depression accompanied by mania or hypomania is described as having a depressive episode "with mixed features."

The specifier "with anxious distress" is used to describe patients who experience symptoms of anxiety that are not part of the bipolar diagnostic criteria.

Causes

The exact causes of bipolar disorder are unknown. It is likely due to 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 such as schizophrenia, epilepsy. 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 bipolar episodes.

In certain instances, bipolar symptoms can be caused by substance abuse, medication reactions, or some medical conditions (such as systemic lupus erythematosus or stroke).

Risk Factors

Age

Bipolar disorder usually first occurs between the ages of 15 to 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

Other Psychiatric Illnesses

Many patients with bipolar disorder often have accompanying psychiatric disorders. They include:

• Anxiety disorders
• Attention-deficit hyperactivity disorder (ADHD)
• Eating disorders (especially with bipolar II disorder)
• Substance abuse disorders

Anxiety and eating disorders are often associated with depressive mood states, while substance abuse more frequently accompanies manic symptoms. Although drug and alcohol abuse may be a form of self-medication, substance abuse can trigger or worsen bipolar symptoms.

Medical Illnesses

People with bipolar disorder often suffer from migraine headaches. They are also more likely than people without this disorder to have metabolic syndrome, a cluster of symptoms that includes abdominal obesity, unhealthy cholesterol and triglyceride levels, high blood pressure, and insulin resistance. Metabolic syndrome can increase the risk for type 2 diabetes, heart disease, and stroke. Some research suggests there may be an underlying genetic link between metabolic syndrome and bipolar disorder.

Patients with bipolar disorder that is not well controlled may not have routine medical care and health screenings, and thus face an increased risk for dying from heart disease and cancer. Smoking, drinking, and other forms of substance abuse can also lead to medical problems (such as heart disease, cirrhosis, and malnutrition). In addition, certain medications used to treat bipolar disorder can cause weight gain, metabolic disorders, and heart problems.

Behavioral and Emotional Complications

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, as well as the workplace.

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

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 to 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.

In most cases of bipolar disorder, the depressive phases outnumber manic phases, and the cycles of mania and depression are neither regular nor predictable. Patients can also experience states in which both mania and depression coexist. With treatment, many people are able to have long periods living free of symptoms, although they may still experience intermittent episodes. Treatment can also help reduce the severity of symptoms when they do occur.

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.

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, feeling "on top of the world."
• 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 feel they are all-powerful or godlike, or that they 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, gambling, and 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

• 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 mania and depression, how frequently these symptoms occur, and how often they last.

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.

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 similar to bipolar disorder.

Bipolar disorder needs to be distinguished from unipolar disorder, which is clinically referred to as major depressive disorder. The main difference between bipolar and unipolar depression is that a person with unipolar depression does not experience any episodes of mania. An accurate diagnosis is critical because patients with bipolar disorder who are inappropriately medicated solely with antidepressants (without also taking a mood stabilizer) have a serious risk of switching to manic or rapid cycling symptoms.

Certain symptoms of anxiety disorders, such as racing thoughts, can resemble those of bipolar disorder. It is also possible for patients to have both bipolar and anxiety disorders.

Children or adolescents with bipolar disorder may be inappropriately diagnosed with attention-deficit hyperactivity disorder. ADHD and bipolar disorder can both often cause inattention, distractibility, and racing speech.

DMDD is a new condition included in the latest edition of the diagnostic manual of the American Psychiatric Association (APA). One of the APA's goals in creating this category was to prevent the misdiagnosis of bipolar disorder in children who may actually have DMDD.

Children with DMDD have severe and constant temper outbursts. In contrast, children with bipolar disorder have intermittent irritability that is associated with episodes of mania and depression. Children with DMDD do not go on to develop bipolar disorder, but they are at increased risk for later developing major depression or anxiety disorders.

Psychotic features (such as delusions and hallucinations) that are predominant in schizophrenia can also occur with bipolar II disorder. However, with schizophrenia, these symptoms are usually present without mood-related symptoms.

Drug and alcohol abuse, and certain medications, can trigger manic symptoms that resemble those of bipolar I disorder. In addition, people with bipolar disorder often abuse drugs and alcohol. A diagnosis of bipolar disorder can be established if symptoms remain even though the substances are no longer being used.

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. Symptoms of overactive thyroid (hyperthyroidism) can mimic mania, while those of underactive thyroid (hypothyroidism) can be associated with depression.

Diagnosis in Children

The number of children diagnosed with bipolar disorder has increased dramatically during the past decade and there is concern that children are being overdiagnosed with the condition. 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 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

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 side effects. Noncompliance is common.
• Patients may have more than one mental health or medical problem and need different drugs to treat each condition. Such medications can interact with drugs used to treat bipolar disorder or increase side effects.
• 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

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.

The following are some of the standard drugs used for treatment of bipolar disorder:

• 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. Atypical antipsychotics approved for treating bipolar disorder include olanzapine (Zyprexa, generic), risperidone (Risperdal, generic), quetiapine (Seroquel, generic), ziprasidone (Geodon, generic), aripiprazole (Abilify), and asenapine (Saphris).
• Antidepressants. Antidepressants alone are not recommended, but may sometimes be used for depressive symptoms that do not respond to lithium and antiseizure drugs. The first choices for antidepressants are bupropion (Wellbutrin, generic) or a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac, generic) or paroxetine (Paxil, generic).

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

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

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 for Manic Episodes

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.

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.

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, generic), ziprasidone (Geodon, generic), aripiprazole (Abilify), and asenapine (Saphris).
• 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.

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

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 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 to 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 to 4 weeks, an antidepressant may be added. Antidepressants alone are not recommended. The first choices for antidepressants are bupropion (Wellbutrin, generic) or a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac, generic).

Other drugs are also approved specifically for treatment of bipolar depression. Symbyax combines the atypical antipsychotic olanzapine with the SSRI antidepressant fluoxetine. Quetiapine (Seroquel, generic) is an atypical antipsychotic which is approved for both treatment of bipolar mania and bipolar depression. Lurasidone (Latuda) is an atypical antipsychotic approved in 2013 for treating adults with depression associated with bipolar I disorder. It can be used either alone or in combination with lithium or valproate.

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 for 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:

• Lithium can help reduce the risk for suicide. 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 to 30 days) may help to delay recurrence. Stopping lithium quickly poses a high risk for relapse and for suicide.

Treatment for Rapid Cycling

The first step in treating rapid cycling is to try to identify and resolve other factors, such as drug abuse or hypothyroidism (underactive thyroid), which may have caused this condition. Antidepressants, particularly SSRIs, may contribute to rapid cycling and are usually tapered off.

Rapid cycling can be challenging to control and there is no consensus on how which drugs are most effective in treating it. Patients may need to try different medications to see what works.

In general, lithium and valproate are the first-line treatments for rapid cycling associated with bipolar I disorder, and lamotrigine for bipolar II disorder. Atypical antipsychotics such as aripiprazole, olanzapine, and quetiapine may also be tried. 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 for Pregnant Patients

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.

A woman with bipolar disorder who is considering pregnancy should consult with her gynecologist/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 to 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 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 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 more severe in young people. Parents should consider the potential risks and benefits of treatment for their children.

Lithium is generally used as the first-line treatment, with valproate or atypical antipsychotics as alternatives. If treatment with a single drug does not work, a combination of drugs may be used. For atypical antipsychotic drugs, risperidone (Risperdal, generic), aripiprazole (Abilify), quetiapine (Seroquel, generic), and olanzapine (Zyprexa, generic) are approved for the treatment of mania in children and adolescents with bipolar disorder.

When prescribing atypical antipsychotics to children and adolescents, the benefits of treatment must be weighed against the potential harms of side effects. Atypical antipsychotics can increase the risk for weight gain and type 2 diabetes, heart problems, increased prolactin levels, sedation, and movement disorders (extrapyramidal side effects). Doctors need to carefully monitor pediatric patients for potential development of any of these side effects.

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.

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

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

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 and may lead to rapid cycling. Some patients need to take thyroid medication while on lithium.

If lithium levels in the blood are too high, lithium toxicity (overdose) can occur. Signs of toxicity include diarrhea, dizziness and nausea, vomiting, slurred speech, and tremors. At very high blood levels, severe lithium toxicity can cause kidney failure, psychosis, and coma.

Because lithium is eliminated from the body by the kidneys, any drugs or dietary factors that reduce kidney function 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. They are used for treating epilepsy, bipolar disorder, and other medical conditions. 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.

• 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.

These drugs have a number of side effects that vary depending on the specific drug, the dosage, and duration of use. Most side effects occur early in therapy and then subside. Some of the most common side effects are upset stomach and weight gain. Less common side effects include dizziness, hair thinning and loss, and difficulty concentrating.

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. This risk 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.

Antiseizure drugs can increase the risk for birth defects if taken during pregnancy. Valproate carries the highest risk for causing birth defects and should be avoided, if possible, during the first trimester.

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.

Antipsychotic medications are generally categorized as either "typical antipsychotics" or "atypical antipsychotics." Typical antipsychotics are older medications, which were first developed in the 1950s. Atypical antipsychotics are newer medications that first became available in the 1990s; new ones are still being developed. Atypical antipsychotics are sometimes referred to as "second-generation" to distinguish them from the older "first-generation" typical antipsychotics.

Atypical antipsychotics approved for treatment of bipolar disorder include:

• Olanzapine (Zyprexa, generic) was the first atypical antipsychotic approved for treatment and long-term maintenance of bipolar disorder. It is FDA-approved to treat bipolar mania and mixed states. Symbyax (generic), a drug that combines olanzapine and the antidepressant fluoxetine is approved for treatment of bipolar depression.
• Risperidone (Risperdal, generic), ziprasidone (Geodon, generic), aripiprazole (Abilify), and asenapine (Saphris) are approved for treatment of bipolar mania and mixed states in adults. Quetiapine (Seroquel, generic) is approved for treatment of bipolar mania and bipolar depression, making it the only drug approved for treating both manic and depressive states.
• Lurasidone (Latuda) is approved for treatment of bipolar I depression.
• Risperidone, aripiprazole, quetiapine, and olanzapine are also approved for the treatment of mania in children and adolescents.

Side effects vary depending on the specific drug but can include:

• Sedation, drowsiness, and fatigue (although sometimes the drugs may cause restlessness and insomnia)
• Dry mouth
• Constipation
• Problems with urination
• Nasal congestion or runny nose
• Dizziness
• Headache
• Nausea and vomiting
• Increased appetite
• Sexual dysfunction

The following are more severe side effects or complications that may occur with atypical antipsychotics:

• Extrapyramidal side effects. These severe movement disorders tend to occur more often with typical antipsychotics but can also occur with atypicals; the risk appears to be highest with risperidone. Patients need to be monitored for signs of any extrapyramidal side effects, such as tardive dyskinesia, since they are difficult to treat if they become severe.
• Diabetes (see below). The risk for type 2 diabetes is highest with the atypical antipsychotic olanzapine. However, all atypical antipsychotics may significantly increase the risk for type 2 diabetes in children and adolescents.
• Weight gain and metabolic problems. All atypical antipsychotics, and olanzapine in particular, can increase the risk for weight gain and metabolic problems.
• Unhealthy lipid levels. Particularly with olanzapine, clozapine, and quetiapine, increased risk for unhealthy triglyceride and cholesterol levels. Patients should also have their cholesterol and other lipid levels monitored.
• Increased prolactin levels (hyperprolactinemia). Prolactin is a hormone manufactured in the pituitary gland. Abnormally high levels can cause menstrual problems and abnormal production of breast milk (galactorrhea) in non-breastfeeding girls and women. In boys and men, hyperprolactinemia may cause enlarged breasts (gynecomastia).
• Heart problems , including increased risk for strokes and sudden death.
• Dizziness or lightheadedness upon standing (orthostatic hypotension) caused by sudden drop in blood pressure.
• Neuroleptic malignant syndrome , a rare but life-threatening condition marked by high fever, stiff muscles, confusion, and changes in pulse, heart rate, and blood pressure.
• Severe allergic reactions may occur with asenapine (Saphris).

All atypical antipsychotics can increase the risk of high blood sugar (hyperglycemia) and type 2 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 some patients, more so those with depression associated with bipolar I than bipolar II disorder. In addition, a number of studies report no additional benefits from antidepressants.

Specific antidepressants may be beneficial in certain circumstances, especially when prescribed in combination with a mood stabilizer medication. 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.

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 many patients. High doses may cause seizures. This side effect is uncommon and tends to occur in patients with eating disorders or those with risk factors for seizures.

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 fully established. They may be useful in patients whose depression does not respond to lithium alone.

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

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

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 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 a patient's on-going mental and emotional 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
• Deal with feelings of guilt and remorse that can occur after manic episodes
• Discuss openly private concerns and challenges with a supportive and non-judgmental professional

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

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 mania. 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.

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.

Recommendations for supporting the patient include:

• Learn about bipolar disorder. The more you understand about this complex illness, the better you can help your loved one cope with its challenges.
• Be supportive. Relatives of patients with bipolar disorder need to be strongly supportive because of the high risk for suicide. 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. When hurtful or destructive behavior emerges during a bipolar episode, try not to take it personally.
• Help the patient to comply with treatment. Set up a daily routine for taking medications, and keep a schedule of regular meal times and bed times to ensure adequate sleep and good nutrition.
• Create a treatment contract. 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.
• For emergencies, have ready a hotline number and the telephone number of the patient's psychiatrist.

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 can be very helpful for sharing education about the illness, treatment information, and advocacy resources.

Lifestyle Factors

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

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

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 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acid supplements.

Resources

• www.nimh.nih.gov -- National Institute of Mental Health
• www.dbsalliance.org -- Depression and Bipolar Support Alliance
• www.nami.org -- National Alliance on Mental Illness
• www.mentalhealthamerica.net -- Mental Health America
• www.psychiatry.org -- The American Psychiatric Association
• www.aacap.org -- American Academy of Child and Adolescent Psychiatry