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` in Adults
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` National Institute of Mental Health
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` U.S. Department of HealtH anD HUman ServiceS • national institutes of Health
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`Page 1 of 32
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`JAZZ EXHIBIT 2010
`Par Pharm. Inc. (Petitioner) v. Jazz Pharms. Ireland Ltd. (Patent Owner)
`Case IPR2016-00002
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`Contents
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`What is bipolar disorder? _____________________________________________ 1
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`What are the signs and symptoms of bipolar disorder? __________________ 1
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`How is bipolar disorder diagnosed? ____________________________________ 4
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`What illnesses often co-exist with bipolar disorder? _____________________ 6
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`What are the risk factors for bipolar disorder? __________________________ 6
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`Genetics _________________________________________________________ 6
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`Brain structure and functioning ___________________________________ 7
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`How is bipolar disorder treated? _______________________________________ 8
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` Medications ______________________________________________________ 9
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`Psychotherapy __________________________________________________ 14
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`Other treatments ________________________________________________ 16
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`What research is NIMH doing to improve treatments
`for bipolar disorder? _________________________________________________ 17
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`How can I help a friend or relative who has bipolar disorder? ____________ 18
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`How can caregivers find support? ____________________________________ 19
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`How can I help myself if I have bipolar disorder? _______________________ 19
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`Where can I go for help? _____________________________________________ 20
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`What if I or someone I know is in crisis? _______________________________ 20
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`Citations ___________________________________________________________ 21
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`For more information on bipolar disorder ______________________________ 25
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`Page 3 of 32
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`This booklet discusses bipolar disorder in
`adults. For information on bipolar disorder
`in children and adolescents, see the NIMH
`booklet, Bipolar Disorder in Children and
`Adolescents.
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`Page 4 of 32
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`What is bipolar disorder?
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` ity to carry out daily tasks. Symptoms of bipolar
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` and people with this illness can lead full and productive lives.
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` Bipolar disorder often appears in the late teens or early adult years. At least half of
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`hood, while others may develop symptoms late in life.
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`Bipolar disorder is not easy to spot when it starts. Some people suffer for years
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`before they are properly diagnosed and treated. Like diabetes or heart disease,
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`bipolar disorder is a long-term illness that must be carefully managed throughout
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`your life.
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`What are the signs and symptoms of bipolar
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`People with bipolar disorder experience unusually intense emotional states that
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`occur in distinct periods called “mood episodes.” Each mood episode represents
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`a drastic change from a person’s usual mood and behavior. An overly joyful
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`or overexcited state is called a manic episode, and an extremely sad or hopeless
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`state is called a depressive episode. Sometimes, a mood episode includes symp-
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`toms of both mania and depression. This is called a mixed state. People with bipo-
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`lar disorder also may be explosive and irritable during a mood episode. Extreme
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`changes in energy, activity, sleep, and behavior go along with these changes in
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`Bipolar Disorder in Adults • 1
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`Symptoms of bipolar disorder are described below.
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` Symptoms of depression or a
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` depressive episode include:
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` Mood Changes
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`• An overly long period of feeling
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`• Loss of interest in activities once
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`enjoyed, including sex.
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`Behavioral Changes
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`• Extreme irritability.
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`Behavioral Changes
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`• Having an unrealistic belief in your
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`2 • National Institute of Mental Health
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` Bipolar disorder can be present even when mood swings
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` order. Without proper treatment, people with hypomania
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` Bipolar disorder may also be present in a mixed state, in which you might experi-
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` feel very agitated, have trouble sleeping, experience major changes in appetite,
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` and have suicidal thoughts. People in a mixed state may feel very sad or hopeless
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` Sometimes, a person with severe episodes of mania or depression has psychotic
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` to reflect the person’s extreme mood. For example, if you are having psychotic
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` symptoms during a manic episode, you may believe you are a famous person,
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` during a depressive episode, you may believe you are ruined and penniless, or you
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` have committed a crime. As a result, people with bipolar disorder who have psy-
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` chotic symptoms are sometimes misdiagnosed with schizophrenia.
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` People with bipolar disorder may also abuse alcohol or substances, have relation-
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`Bipolar Disorder in Adults • 3
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`Page 7 of 32
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`How is bipolar disorder diagnosed?
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` Bipolar disorder usually lasts a lifetime. Episodes of mania and depression typically
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` free of symptoms, but some people may have lingering symptoms.
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` Doctors diagnose bipolar disorder using guidelines from the Diagnostic and
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` Statistical Manual of Mental Disorders (DSM). To be diagnosed with bipolar
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` disorder, the symptoms must be a major change from your normal mood or
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`behavior. There are four basic types of bipolar disorder:
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` 1. Bipolar I Disorder—defined by manic or mixed episodes that last at least seven
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` ate hospital care. Usually, depressive episodes occur as well, typically lasting at
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` least 2 weeks.
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` 3. Bipolar Disorder Not Otherwise Specified (BP-NOS)—diagnosed when symp-
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` or II. However, the symptoms are clearly out of the person’s normal range of
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`behavior.
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` 4. Cyclothymic Disorder, or Cyclothymia—a mild form of bipolar disorder.
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`4 • National Institute of Mental Health
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`A severe form of the disorder is called Rapid-cycling
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` mania, or mixed states, all within a year.2 Rapid cycling
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` seems to be more common in people who have their first
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` bipolar episode at a younger age. One study found that
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` 4 years earlier—during the mid to late teen years—than
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` When getting a diagnosis, a doctor or health care provider should conduct a physi-
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` cal examination, an interview, and lab tests. Currently, bipolar disorder cannot be
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` identified through a blood test or a brain scan, but these tests can help rule out
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` other factors that may contribute to mood problems, such as a stroke, brain tumor,
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` or thyroid condition. If the problems are not caused by other illnesses, your health
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` diagnosing and treating bipolar disorder.
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` The doctor or mental health professional should discuss with you any family his-
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` symptoms. The doctor or mental health professional should also talk to your close
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` People with bipolar disorder are more likely to seek help when they are depressed
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`tory is needed to assure that bipolar disorder is not mistakenly diagnosed as major
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`depression. Unlike people with bipolar disorder, people who have depression only
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`(also called unipolar depression) do not experience mania.
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`Bipolar disorder can worsen if left undiagnosed and untreated. Episodes may
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`become more frequent or more severe over time without treatment.6 Also, delays in
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`getting the correct diagnosis and treatment can contribute to personal, social, and
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`work-related problems.7 Proper diagnosis and treatment help people with bipo-
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`lar disorder lead healthy and productive lives. In most cases, treatment can help
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`reduce the frequency and severity of episodes.
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`Bipolar Disorder in Adults • 5
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`Page 9 of 32
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`What illnesses often co-exist
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` Substance abuse is very common among people
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` with bipolar disorder, but the reasons for this link are
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` unclear.8 Some people with bipolar disorder may try to
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`treat their symptoms with alcohol or drugs. Substance
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`abuse can also trigger or prolong bipolar symptoms,
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`and the behavioral problems associated with mania can
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`Anxiety disorders, such as post-traumatic stress disorder (PTSD) and social
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` phobia, also can co-occur with bipolar disorder.9, 10, 11 Bipolar disorder can co-
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` symptoms that overlap with bipolar disorder, such as restlessness and being easily
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` distracted. However, the symptoms of ADHD are persistent, whereas those of
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` bipolar disorder are episodic.
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` In addition, people with bipolar disorder are at higher risk for thyroid disease,
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` migraine headaches, heart disease, diabetes, obesity, and other physical ill-
` nesses.12, 13 These illnesses may cause symptoms of mania or depression, or they
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` may be caused by some medications used to treat bipolar disorder.
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`What are the risk factors for bipolar disorder?
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`Scientists are studying the possible causes of bipolar disorder. Most agree that
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`there is no single cause. Rather, many factors likely act together to produce the
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`illness or increase risk for developing it.
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`Genetics
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`Bipolar disorder tends to run in families. Some research has suggested that
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`people with certain genes are more likely to develop bipolar disorder than others.14
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`Children with a parent or sibling who has bipolar disorder are much more likely to
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`develop the illness, compared with children who do not have a family history of
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`bipolar disorder.15 However, most children with a family history of bipolar disorder
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`6 • National Institute of Mental Health
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`Page 10 of 32
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` Technological advances are improving genetic research on bipolar disorder. One
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` example is the launch of the Bipolar Disorder Phenome Database, funded in part
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` by NIMH. Using the database, scientists will be able to link visible signs of the
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` disorder with the genes that may influence them.16
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` Scientists are also studying illnesses with similar symp-
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` developing bipolar disorder.17, 18, 19 Finding these genetic
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` tors can increase a person’s risk.
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` But genes are not the only risk factor for bipolar disorder.
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`that identical twins share all of the same genes. Research suggests that factors
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`besides genes are also at work. It is likely that many different genes and environ-
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`mental factors are involved. However, scientists do not yet fully understand how
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`these factors interact to cause bipolar disorder.
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` Brain structure and functioning
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`activity.
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` Some imaging studies show how the brains of people with bipolar disorder may
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` For example, one study using MRI found that the pattern of brain development in
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` children with bipolar disorder was similar to that in children with “multi-dimensional
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` impairment,” a disorder that causes symptoms that overlap somewhat with bipolar
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` disorder and schizophrenia.20 This suggests that the pattern of brain development
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`in the two conditions may be associated with the risk for unstable moods.
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`Another MRI study found that the brain’s prefrontal cortex in adults with bipo-
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`lar disorder tends to be smaller and function less well compared to adults who
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` don’t have bipolar disorder.21, 22 The prefrontal cortex is a brain structure involved
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` in “executive” functions such as solving problems and making decisions. This
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`Bipolar Disorder in Adults • 7
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`Page 11 of 32
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` mature during adolescence, suggesting that abnormal
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` disorder tends to emerge during a person’s teen years.23
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` Pinpointing brain changes in youth may help us detect ill-
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` The connections between brain regions are important
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` for shaping and coordinating functions such as forming
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` memories, learning, and emotions, but scientists know little
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` about how different parts of the human brain connect. Learning more about these
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` connections, along with information gained from genetic studies, helps scientists
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` better understand bipolar disorder. Scientists are working towards being able to
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` predict which types of treatment will work most effectively.
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`How is bipolar disorder treated?
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` Bipolar disorder cannot be cured, but it can be treated effectively over the long-
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` term. Proper treatment helps many people with bipolar disorder—even those with
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` the most severe forms of the illness—gain better control of their mood swings and
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` related symptoms.24, 25, 26 But because it is a lifelong illness, long-term, continuous
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` treatment is needed to control symptoms.27
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` However, even with proper treatment, mood changes can occur. In the NIMH-
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` (STEP-BD) study—the largest treatment study ever conducted for bipolar
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` disorder—almost half of those who recovered still had lingering symptoms. Having
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` another mental disorder in addition to bipolar disorder increased one’s chances for
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` a relapse.28 For more information about STEP-BD, see http://www.nimh.nih.gov/
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`trials/practical/step-bd/index.shtml.
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`Treatment is more effective if you work closely with a doctor and talk openly about
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`your concerns and choices. An effective maintenance treatment plan usually
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`includes a combination of medication and psychotherapy.
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`8 • National Institute of Mental Health
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`Page 12 of 32
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`Medications
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` Different types of medications can help control symptoms of
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` bipolar disorder. Not everyone responds to medications in
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` the same way. You may need to try several different medica-
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` tions before finding ones that work best for you.
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` Keeping a daily life chart that makes note of your daily
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` mood symptoms, treatments, sleep patterns, and life events
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` can help you and your doctor track and treat your illness
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` most effectively. If your symptoms change or if side effects become intolerable,
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` your doctor may switch or add medications.
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` The types of medications generally used to treat bipolar disorder include mood
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` stabilizers, atypical antipsychotics, and antidepressants. For the most up-to-date
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` Drug Administration (FDA).
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` Mood stabilizers are usually the first choice to treat bipolar disorder. In general,
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` people with bipolar disorder continue treatment with mood stabilizers for years.
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` Lithium (also known as Eskalith or Lithobid) is an effective mood stabilizer. It was
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` the first mood stabilizer approved by the FDA in the 1970’s for treating both manic
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` and depressive episodes.
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` Anticonvulsants are also used as mood stabilizers. They were originally developed
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` to treat seizures, but they also help control moods. Anticonvulsants used as mood
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` stabilizers include:
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`• Valproic acid or divalproex sodium (Depakote), approved by the FDA in 1995
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` for treating mania. It is a popular alternative to lithium. However, young women
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` taking valproic acid face special precautions. See the sidebar, “Should young
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` women take valproic acid?”
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`• Lamotrigine (Lamictal), FDA-approved for maintenance treatment of bipolar
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` disorder. It is often effective in treating depressive symptoms.
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`• Other anticonvulsant medications, including gabapentin (Neurontin), topiramate
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` (Topamax), and oxcarbazepine (Trileptal).
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`Bipolar Disorder in Adults • 9
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`Page 13 of 32
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`Valproic acid, lamotrigine, and other anticonvulsant medications have an FDA
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`warning. The warning states that their use may increase the risk of suicidal
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`thoughts and behaviors. People taking anticonvulsant medications for bipolar or
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`other illnesses should be monitored closely for new or worsening symptoms of
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`depression, suicidal thoughts or behavior, or any unusual changes in mood or
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`behavior. If you take any of these medications, do not make any changes to your
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`dosage without talking to your doctor.
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` What are the side effects of mood stabilizers?
` Lithium can cause side effects such as:
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`• Restlessness
`• Dry mouth
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`• Bloating or indigestion
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`• Acne
`• Unusual discomfort to cold temperatures
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`• Joint or muscle pain
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`• Brittle nails or hair.
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`When taking lithium, your doctor should check the levels of lithium in your blood
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`regularly, and will monitor your kidney and thyroid function as well. Lithium treat-
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`ment may cause low thyroid levels in some people.29 Low thyroid function, called
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`hypothyroidism, has been associated with rapid cycling in some people with bipo-
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`lar disorder, especially women.
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`Because too much or too little thyroid hormone can lead to mood and energy
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`changes, it is important that your doctor check your thyroid levels carefully. You
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`may need to take thyroid medication, in addition to medications for bipolar disor-
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`der, to keep thyroid levels balanced.
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`Common side effects of other mood stabilizing medications include:
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`• Drowsiness
`• Dizziness
`• Headache
`• Diarrhea
`• Constipation
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`10 • National Institute of Mental Health
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`Page 14 of 32
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`• Heartburn
`• Mood swings
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`• Stuffed or runny nose, or other cold-like symptoms.
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`These medications may also be linked with rare but serious side effects. Talk with
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`your doctor or a pharmacist to make sure you understand signs of serious side
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`effects for the medications you’re taking. If extremely bothersome or unusual side
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`effects occur, tell your doctor as soon as possible.
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` Should young women take valproic acid?
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` Valproic acid may increase levels of testosterone (a male hormone) in teenage girls. It could lead
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` to a condition called polycystic ovary syndrome (PCOS) in women who begin taking the medica-
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` tion before age 20.30, 31 PCOS can cause obesity, excess body hair, an irregular menstrual cycle,
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` and other serious symptoms. Most of these symptoms will improve after stopping treatment with
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` valproic acid.32 Young girls and women taking valproic acid should be monitored carefully by a
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`doctor.
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` Atypical antipsychotics are sometimes used to treat symptoms of bipolar disor-
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` der. Often, these medications are taken with other medications, such as antide-
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` pressants. Atypical antipsychotics include:
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`• Olanzapine (Zyprexa), which when given with an antidepressant medication,
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`may help relieve symptoms of severe mania or psychosis.33 Olanzapine can be
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`taken as a pill or a shot. The shot is often used for urgent treatment of agitation
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`associated with a manic or mixed episode. Olanzapine can be used as main-
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`tenance treatment as well, even when psychotic symptoms are not currently
`present.
`• Aripiprazole (Abilify), which is used to treat manic or mixed episodes.
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`Aripiprazole is also used for maintenance treatment. Like olanzapine, aripipra-
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`zole can be taken as a pill or a shot. The shot is often used for urgent treatment
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`of severe symptoms.
`• Quetiapine (Seroquel), risperidone (Risperdal) and ziprasidone (Geodon) also are
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`prescribed to relieve the symptoms of manic episodes.
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`Bipolar Disorder in Adults • 11
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`Page 15 of 32
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` What are the side effects of atypical antipsychotics?
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` If you are taking antipsychotics, you should not drive until you have adjusted to
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` your medication. Side effects of many antipsychotics include:
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`• Drowsiness
`• Dizziness when changing positions
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`• Blurred vision
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`• Rapid heartbeat
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`• Sensitivity to the sun
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`• Skin rashes
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`• Menstrual problems for women.
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`Atypical antipsychotic medications can cause major weight gain and changes in
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`your metabolism. This may increase your risk of getting diabetes and high cho-
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`lesterol.34 Your doctor should monitor your weight, glucose levels, and lipid levels
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`regularly while you are taking these medications.
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`In rare cases, long-term use of atypical antipsychotic drugs may lead to a condi-
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`tion called tardive dyskinesia (TD). The condition causes uncontrollable muscle
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`movements, frequently around the mouth. TD can range from mild to severe. Some
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`people with TD recover partially or fully after they stop taking the drug, but others
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`do not.
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`Antidepressants are sometimes used to treat symptoms of depression in bipolar
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`disorder. Fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and bupropion
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`(Wellbutrin) are examples of antidepressants that may be prescribed to treat symp-
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`toms of bipolar depression.
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`However, taking only an antidepressant can increase your risk of switching to
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`mania or hypomania, or of developing rapid-cycling symptoms.35 To prevent this
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`switch, doctors usually require you to take a mood-stabilizing medication at the
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`same time as an antidepressant.
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`12 • National Institute of Mental Health
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`Page 16 of 32
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`Report any concerns about side
`effects to your doctor right away.
`You may need a change in the
`dose or a different medication.
`You should not stop taking a
`medication without talking to your
`doctor first. Suddenly stopping a
`medication may lead to “rebound”
`or worsening of bipolar disorder
`symptoms. Other uncomfortable or
`potentially dangerous withdrawal
`effects are also possible.
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` What are the side effects of
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`antidepressants?
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` Antidepressants can cause:
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`• Headache
`• Nausea (feeling sick to your stomach)
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`• Agitation (feeling jittery)
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`• Sexual problems, which can affect both
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` enjoying sex.
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` Some antidepressants are more likely to
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` cause certain side effects than other types.
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` Your doctor or pharmacist can answer questions about these medications. Any
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` unusual reactions or side effects should be reported to a doctor immediately.
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` FDA Warning on Antidepressants
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` Antidepressants are safe and popular, but some studies have suggested that they may have unin-
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` tentional effects on some people, especially in adolescents and young adults. The FDA warning
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` says that patients of all ages taking antidepressants should be watched closely, especially during
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` the first few weeks of treatment. Possible side effects to look for are depression that gets worse,
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` suicidal thinking or behavior, or any unusual changes in behavior such as trouble sleeping, agita-
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` tion, or withdrawal from normal social situations. For the latest information, see the FDA website
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` at http://www.fda.gov.
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`Bipolar Disorder in Adults • 13
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`Page 17 of 32
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` Should women who are pregnant or may become
` pregnant take medication for bipolar disorder?
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` Women with bipolar disorder who are pregnant or may become pregnant
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` face special challenges. Mood stabilizing medications can harm a devel-
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` oping fetus or nursing infant.36 But stopping medications, either suddenly
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`or gradually, greatly increases the risk that bipolar symptoms will recur
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`during pregnancy.37
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`Lithium is generally the pre