Bipolar Disorder

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                    Symptoms include a persistent sad mood;              ...

                    to treatment than non-rapid-cycling bipo­     Statistical Manual of Mental Disorders...

                    major research groups worldwide are cur­       Brain Imaging

                    viduals with bipolar disorder, they tend       healthy people and those with specifi...

                    of better treatments and enhanced treat­       study found olanzapine to help reliev...

                    Psychotherapy                                  tings to settings in the “real world....

                    The Systematic Treatment                      about NIMH clinical trials can be

                    Stress, Life Events, and                        ence problems—the highest rate acros...

                    across a 12-month period.29 While the            thymia. Compared to adolescents wit...

                    how well lithium and other mood stabiliz­       since too much or too little thyroid...

                    ders. These illnesses include schizophre­        More Than 2,000 Grants and

                    At the beginning of the 21st century, NIMH    I     Information for scientists on NI...


                    1 Goodwin FK & Jamison KR, 1990. Manic-            1...

                                              bipolar disorder protocol. Biological Psychiatry,    Child...
This is the electronic version of a National Institute of Mental Health (NIMH) publication,
available from http://www.nimh...
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Bipolar Disorder Research at the NIMH

  1. 1. Bipolar Disorder Research At the National Institute of Mental Health Bipolar disorder, also called manic- depression and mania flare up across the FACT SHEET F depressive illness, is a serious disorder of life course, often disrupting work, school, the brain. More than 2.3 million family, and social life. Despite the fact that American adults, or about one percent of an episode may remit on its own due to the population in a given year, have bipo­ the cyclic nature of the illness, treatment lar disorder. Abnormalities in brain bio­ to achieve and maintain a balanced state chemistry and in the structure and/or is extremely important. Without effective activity of certain brain circuits are treatment, the illness can lead to suicide in responsible for the extreme shifts in nearly 20 percent of cases.1 mood, energy, and functioning that char­ Research is the key to understanding Office of Communications and acterize bipolar disorder. Fortunately, the bipolar disorder. The National Institute of Public Liaison intense and disabling symptoms of bipo­ Mental Health (NIMH), the world’s leading lar disorder often can be relieved through mental health biomedical research organi­ 6001 Executive Blvd. treatment involving combinations of zation, conducts and supports studies on Room 8184, MSC 9663 medications and psychotherapy. the causes, diagnosis, and treatment of Bethesda, MD 20892-9663 Bipolar disorder typically emerges in bipolar disorder. A variety of research Phone: 301-443-4513 late adolescence or early adulthood but in approaches are being used, including neu­ TTY: 301-443-8431 some cases begins earlier. Episodes of roscience studies, basic science approaches FAX: 301-443-4279 to brain and behavior, genetic investiga­ E-mail: tions, epidemiological studies, and clinical Website: “Manic-depression distorts moods research. Clinical treatment research is and thoughts, incites dreadful underway to determine the best use of behaviors, destroys the basis of available treatments and treatment combi­ April 2000 rational thought, and too often nations. Better treatments and, eventually, erodes the desire and will to live. It ways to prevent and cure the illness will is an illness that is biological in its be found only through careful scientific origins, yet one that feels psycholog­ ical in the experience of it; an illness study. that is unique in conferring advan­ tage and pleasure, yet one that Symptoms and Types of Bipolar brings in its wake almost unen­ durable suffering and, not infre­ Disorder quently, suicide. Bipolar disorder is characterized by I am fortunate that I have not episodes of depression, mania, or mixed died from my illness, fortunate in state that typically recur and become more having received the best medical frequent across the life span.1 In most care available, and fortunate in hav­ patients, these episodes, especially early in ing the friends, colleagues, and fam­ the course of illness, are separated by well ily that I do.” Kay Redfield Jamison, Ph.D. periods during which there are few to no An Unquiet Mind, 1995, p. 6. symptoms. A small percentage of people Reprinted with permission from experience chronic, unremitting symptoms Alfred A. Knopf, a division of Random House, Inc. despite treatment. D E PA R T M E N T O F H E A LT H A N D H U M A N S E R V I C E S • P U B L I C H E A LT H S E R V I C E • N AT I O N A L I N S T I T U T E S O F H E A LT H
  2. 2. BIPOLAR DISORDER Depression Symptoms include a persistent sad mood; An NIMH Snapshot loss of interest or pleasure in activities that were once enjoyed; significant change The National Institute of Mental Health in appetite or body weight; difficulty sleep­ (NIMH) is one of 25 components of the ing or oversleeping; physical slowing or National Institutes of Health (NIH), the agitation; loss of energy; feelings of worth­ Government’s principal biomedical and behav­ lessness or inappropriate guilt; difficulty ioral research agency. NIH is part of the U.S. thinking or concentrating; and recurrent Department of Health and Human Services. thoughts of death or suicide. The depres­ The actual total fiscal year 1999 NIMH budget sive episodes of people with bipolar disor­ was $859 million. der are often indistinguishable from those I I I of patients with unipolar major depressive disorder. NIMH Mission To reduce the burden of mental illness through research on mind, brain, and behavior. Mania I I I Symptoms include abnormally and persis­ tently elevated (high) mood or irritability How Does the Institute Carry Out occurring with at least three of the follow­ Its Mission? ing: overly-inflated self-esteem; decreased I NIMH conducts research on mental disor­ need for sleep; increased talkativeness; ders and the underlying basic science of racing thoughts; distractibility; increased brain and behavior. goal-directed activity or physical agitation; I NIMH supports research on these topics and excessive involvement in risky behav­ at universities and hospitals around the iors or activities (e.g., unwise spending United States. sprees, reckless driving, sexual affairs). I NIMH collects, analyzes, and dissemi­ nates information on the causes, occurrence, “Mixed” state and treatment of mental illnesses. Symptoms of mania and depression are I NIMH supports the training of more than present at the same time. The symptom 1,000 scientists to carry out basic and clini­ picture frequently includes agitation, trou­ cal research. ble sleeping, significant change in I NIMH communicates information to sci­ appetite, psychosis, and suicidal thinking. entists, the public, the news media, and pri­ Depressed mood accompanies manic acti­ mary care and mental health professionals vation. about mental illnesses, the brain, mental Sometimes severe mania or depres­ health, and research in these areas. sion is accompanied by periods of psy­ chosis. Psychotic symptoms include hal­ lucinations (hearing, seeing, or otherwise sensing the presence of stimuli that are not actually there) and delusions (false fixed beliefs that are not subject to rea­ grandiosity during mania, worthlessness son or contradictory evidence and are not during depression). explained by a person’s usual cultural Bipolar disorder with rapid cycling concepts). Psychotic symptoms associated is defined as four or more episodes of ill­ with bipolar disorder typically reflect the ness within a 12-month period. This form extreme mood state at the time (e.g., of the illness tends to be more resistant
  3. 3. BIPOLAR DISORDER to treatment than non-rapid-cycling bipo­ Statistical Manual of Mental Disorders, lar disorder. 4th Edition (DSM-IV).2 The particular combinations and Many patients with bipolar disorder severity of symptoms vary among people are initially misdiagnosed.3 This occurs with bipolar disorder. Some people expe­ most often either when a person with rience very severe manic episodes, during bipolar II disorder, whose hypomania is which they may feel “out of control,” not recognized, is diagnosed with unipo­ have major impairment in functioning, lar depression, or when a patient with and suffer psychotic symptoms. Other severe psychotic mania is misjudged to people have milder hypomanic episodes, have schizophrenia. However, since bipo­ characterized by low-level, non-psychotic lar disorder, like other mental illnesses, symptoms of mania such as increased cannot yet be identified physiologically energy, euphoria, irritability, and intru­ (for example, by a blood test or a brain siveness, that may cause little impair­ scan), diagnosis must be made on the ment in functioning but are noticeable to basis of symptoms, course of illness, and, others. Some people suffer severe, inca­ when available, family history. pacitating depressions, with or without psychosis, that prevent them from work­ Genetics Research ing, going to school, or interacting with family or friends. Others experience more Data from family, twin, and adoption moderate depressive episodes, which may studies unequivocally demonstrate the feel just as painful but impair function­ involvement of genetic factors in the ing to a lesser degree. Inpatient hospital­ transmission of bipolar disorder.4 ization is often necessary to treat severe Research to date leads to the conclusion episodes of mania and depression. that in most families the etiology of bipo­ A diagnosis of bipolar I disorder is lar disorder is complex, with vulnerabili­ made when a person has experienced at ty being produced by the interaction of least one episode of severe mania; a multiple genes and nongenetic factors. diagnosis of bipolar II disorder is made Scientists expect that identification of when a person has experienced at least genes conferring vulnerability to bipolar one hypomanic episode but has not met disorder, and the brain proteins they code the criteria for a full manic episode. for, will make it possible to develop bet­ Cyclothymic disorder, a milder illness, ter diagnostic procedures, treatments, is diagnosed when a person experiences, and preventive interventions targeted at over the course of at least two years (one the underlying illness process. year for adolescents and children), The NIMH Bipolar Disorder Genetics numerous periods with hypomanic symp­ Initiative, launched in 1989, continues to toms and numerous periods with depres­ gather genetic material and state-of-the- sive symptoms that are not severe art diagnostic and clinical data from fam­ enough to meet criteria for major manic ilies with two or more members affected or depressive episodes. People who meet by bipolar disorder. The primary goal of criteria for bipolar disorder or unipolar this initiative is to establish a national depression and who experience chronic resource that makes DNA and clinical psychotic symptoms, which persist even information widely available to qualified with clearing of the mood symptoms, suf­ investigators in the scientific community. fer from schizoaffective disorder. The The genetic and clinical information is diagnostic criteria for all mental disor­ distributed in a way that keeps the ders are described in the Diagnostic and research volunteers anonymous. Ten
  4. 4. BIPOLAR DISORDER major research groups worldwide are cur­ Brain Imaging rently studying DNA and clinical data from over 650 individuals with bipolar Brain imaging technologies are helping sci­ disorder and related conditions in an entists learn what goes wrong in the brain effort to find genes that confer vulnera­ to produce mental illness. NIMH bility to bipolar disorder. Further infor­ researchers are using advanced imaging mation on the Initiative is available at techniques to examine brain function and structure in people with bipolar disorder. Successful genetic studies of complex An important area of imaging research disorders like bipolar disorder will focuses on identifying and characterizing require very large samples drawn from neural circuits—networks of interconnect­ diverse populations, and/or samples ed nerve cells in the brain, interactions drawn from genetically isolated popula­ among which form the basis for normal tions. In order to facilitate such research, and abnormal behaviors. Researchers NIMH recently funded three major collab­ hypothesize that abnormalities in the orative projects to collect data that will structure and/or function of certain brain significantly augment the information circuits could underlie bipolar and other already available in the NIMH Bipolar mood disorders. Better understanding of Genetics Initiative. In one study, scien­ the neural circuits involved in regulating tists at nine research institutions across mood states will influence the develop­ the United States will gather clinical and ment of new and better treatments, and genetic data from at least 500 families in will ultimately aid in diagnosis. which two or more siblings suffer from bipolar disorder.5 In another, American Structural Imaging and Israeli researchers will use shared NIMH has supported considerable methods of data collection, diagnosis, research with the new technology of and clinical assessment to study 300 magnetic resonance imaging (MRI) to additional families.6 A third project will examine the structure of brain tissue in study over 300 families collected from various mental disorders, including bipo­ the population of the Azores, a nine- lar disorder. The first such studies have island archipelago off the coast of appeared only within the past ten years, Portugal.7 NIMH also recently issued a with the pace of progress accelerating Program Announcement steadily since that time. The goal of this (­ research is to discover the ways in which files/PA-99-120.html) to encourage col­ specific areas of the brain in people with laborations among genetic research bipolar disorder may differ from healthy groups worldwide, by which multiple individuals. samples of bipolar disorder pedigrees can One of the most consistent findings be assembled into one large data set for to date has been the appearance of spe­ combined analysis. New genetic analytic cific abnormalities, or lesions, in the methods and technologies like gene chips white matter of the brain in patients with offer great potential for identifying spe­ bipolar disorder.8 White matter consists cific gene sites responsible for vulnerabil­ of groups of nerve cell fibers surrounded ity to bipolar disorder in such large sam­ by fatty sheaths that appear white in ples of families. color. These sheaths help the transmis­ sion of electrical signals within the brain. While the white matter abnormalities appear in many parts of the brain in indi-
  5. 5. BIPOLAR DISORDER viduals with bipolar disorder, they tend healthy people and those with specific to be concentrated in areas that are brain disorders, including unipolar and responsible for emotional processing. bipolar disorder and schizophrenia. This These brain changes increase in frequen­ technique provides a powerful tool for cy with age both in people with bipolar understanding how the brains of individu­ disorder and individuals with no mental als with mental disorders process informa­ illness, but they appear more often than tion differently from healthy individuals, expected in young patients with bipolar and for understanding and even predicting disorder. This finding suggests that the how people with these diseases might white matter abnormalities seen with respond to different types of drug therapy. MRI are related to the presence of the For example, NIMH supported researchers disorder. However, some patients with have studied how brain regions of healthy bipolar disorder do not show the white people and of people with depression matter changes, and conversely, some respond differently when emotionally entirely healthy individuals have the evocative pictures are viewed, and how lesions. Also, it is not yet clear whether drug treatment changes the response to these changes contribute to the onset of these pictures in individuals with depres- the disorder, or are in some way a result sion.10 Modified versions of both the fMRI of becoming ill. While these MRI abnor­ and PET techniques, which allow scientists malities likely indicate one type of mal­ to directly study changes in brain chem­ function in the brain circuits involved in istry and the activity of specific signaling bipolar disorder, more research is clearly molecules (neurotransmitters) in both needed to understand their significance healthy individuals and people with mood and their utility for early diagnosis and disorders, are enabling researchers to bet­ treatment. ter understand the fundamental character­ istics of bipolar disorder. Functional Imaging Functional neuroimaging is an important Treatment Research tool for NIMH-supported researchers study­ NIMH is dedicated to improving treat­ ing bipolar and other mood disorders. ments for bipolar disorder and is invest­ Studies using positron emission tomogra­ ing considerable research effort in pur­ phy (PET), a technique that measures suit of this goal. Although many people brain function in terms of blood flow or with bipolar disorder can be helped by glucose metabolism, have found abnormal currently available treatments, signifi­ activity in specific brain regions including cant challenges remain. Rapid cycling is the prefrontal cortex, basal ganglia, and a form of the illness that is difficult to temporal lobes during manic and depres­ manage. Medication side effects are often sive episodes.9 It is not yet known whether troublesome and can lead to reduced these functional abnormalities are a cause treatment adherence. Some regimens or consequence of mood disorders. work well for years and then gradually When neurons become more active, lose their effectiveness. NIMH researchers their demand for oxygen, delivered via the are working at multiple levels—from blood supply, increases. Using a special molecular genetics, to neuroimaging, to measurement technique called functional behavioral science, to clinical trials—to magnetic resonance imaging (fMRI), scien­ learn what underlies these and other tists can measure these changes in blood treatment-related problems and to apply oxygen levels in different brain areas in this knowledge toward the development
  6. 6. BIPOLAR DISORDER of better treatments and enhanced treat­ study found olanzapine to help relieve psy­ ment strategies. chotic depression in patients with a diag­ nosis of major depression or bipolar I dis- Medication order.15 Other research has supported the For years, lithium has been the “gold stan­ efficacy of olanzapine for acute mania,16 dard” pharmacological treatment for bipo­ an indication that has recently received lar disorder. When taken regularly, lithium FDA approval. The efficacy of risperidone can effectively control mania and depres­ is also under study. sion in many patients and can reduce the A nutritional approach under investi­ likelihood of episode recurrence.1 However, gation for maintenance treatment of scientists still do not know exactly how it bipolar disorder involves omega-3 fatty works, nor do they understand why it acids found in fish oil. Preliminary works well for some people but not others. research has found a combination of the In attempt to answer these questions, NIMH researchers are investigating the Treatment of Bipolar Depression biochemical mechanisms of action of lithi- um.11 12 This and future work will inform Antidepressant medications have long the development of new and better treat­ been used to treat the depressive phase of ments. bipolar disorder. However, research has For patients who either do not shown that antidepressants, when taken respond to lithium or cannot tolerate its without a mood-stabilizing medication, side effects, which can include weight can increase the risk of switching into gain, tremor, and excessive urination, mania or hypomania, or of developing there are several anticonvulsant medica­ rapid cycling, in people with bipolar dis­ tions that may serve as alternative mood order. Therefore, mood-stabilizing medica­ stabilizers. Valproate and carbamazepine tions are generally required, alone or in have been used for the past two decades combination with antidepressants, to pro­ for treatment of acute mania and preven­ tect patients with bipolar disorder from tion of cycling. However, valproate is the this switch. Lithium and valproate are only anticonvulsant approved by the U.S. the most commonly used mood stabiliz­ Food and Drug Administration (FDA) for ing drugs today. Research studies are use with bipolar disorder—specifically, evaluating the potential mood stabilizing for the acute treatment of mania. NIMH properties of newer medications. researchers are currently investigating the efficacy of newer anticonvulsant drugs, including lamotrigine and gabapentin, as mood stabilizers for treat­ two main omega-3 fatty acids to be better ment refractory bipolar disorder.13 than placebo, when added to ongoing Topiramate is also receiving attention in conventional medications, in avoiding an clinical studies. acute illness episode and in improving a NIMH-funded research has evaluated variety of symptoms over four months.17 the efficacy of atypical antipsychotic med­ However, due to several limitations in ications in the treatment of bipolar disor­ this preliminary study, more definitive der. One recent NIMH study demonstrated research is required to validate the mood stabilizing and antimanic effects of appeal of a naturally occurring, apparent­ clozapine in patients with treatment-resist- ly safe substance in the treatment of ant bipolar disorder.14 Another NIMH bipolar disorder.
  7. 7. BIPOLAR DISORDER Psychotherapy tings to settings in the “real world.” Interest in using psychotherapy in combi­ Many past studies have established the nation with medication for bipolar disorder safety and efficacy of various treatments has grown in recent years with the recog­ for bipolar disorder—that is, how well nition of the continuing high rate of they work in very specific groups of relapse, some of which appears preventa­ patients under ideal conditions. However, ble, during pharmacological maintenance few studies have adequately tested the treatment.18 NIMH researchers are con­ effectiveness of particular treatments or ducting studies to evaluate the benefits of treatment strategies—how well they specific types of adjunctive psychotherapy work, for example, in patients who live in in the long-term management of bipolar the community, come from diverse back- disorder. These psychotherapies include grounds, have co-occurring illnesses, or Psychoeducation (PE), Cognitive-Behavioral experience atypical patterns of manic and Therapy (CBT), Family Focused Therapy depressive episodes. In addition, quality (FFT), and Interpersonal and Social of life, ability to work, social functioning, Rhythm Therapy (IPSRT). PE involves treatment adherence, and treatment cost- teaching patients with bipolar disorder effectiveness are among the important, about their illness and its treatment. real world issues that only effectiveness Emphasis is placed on recognizing early research can adequately assess. In con­ signs of relapse so that patients can seek trast to efficacy research, effectiveness medical care before a full-blown illness studies have very few exclusionary crite­ episode develops. CBT helps patients modi­ ria and enroll very large numbers of par­ fy detrimental or inappropriate thought ticipants—several hundred to thou­ patterns and behaviors associated with sands—so that the findings will be repre­ bipolar disorder. FFT employs strategies to sentative of and broadly applicable to an reduce the level of distress within the fam­ entire population group. ily that may either contribute to or result To improve the standards of treat­ from the ill person’s symptoms. IPSRT uses ment for bipolar disorder, NIMH has techniques aimed at regularizing daily rou­ taken the lead in treatment effectiveness tines and improving interpersonal relation- research on this illness. Major goals are: ships. Research indicates that regular daily I to establish treatment effectiveness routines and sleep schedules may protect both in the short and long term; against manic episodes.19 A large-scale I to develop guidelines for treating NIMH study (called STEP-BD, described patients who do not respond to standard below) will compare the effectiveness of single therapies; intensive CBT, FFT, and IPSRT, each in com­ I to evaluate combinations of pharma­ bination with medication, for treatment of cological and psychosocial treatments; acute depressive episodes and for preven­ I to define a core set of outcome meas­ tion of recurrent episodes in people with ures to make findings across studies bipolar disorder. comparable; and I to translate research findings more Efficacy vs. Effectiveness Research quickly into routine clinical practice. In recent years there has been an increas­ NIMH recently awarded a multi-mil- ing emphasis on extending clinical trials lion dollar contract for a bipolar disorder research—research that examines how research study designed to achieve these well treatments work in patients—from goals. The study is called the Systematic tightly controlled, inpatient hospital set­ Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
  8. 8. BIPOLAR DISORDER The Systematic Treatment about NIMH clinical trials can be Enhancement Program for Bipolar obtained by accessing the NIMH home Disorder (STEP-BD) page at STEP-BD is a large-scale, 5-8 year clinical index.cfm or the National Library of study being conducted at 20 sites across Medicine clinical trials database at the U.S. to determine the most effective treatment strategies for people with bipo­ lar disorder. The study will evaluate both Sleep Loss and Social Rhythms individual and combined pharmacological Findings from NIMH-supported research and psychosocial treatments. indicate that sleep deprivation can trig­ Because STEP-BD is an effectiveness ger a manic episode in some people with study, there are very few exclusionary rapid-cycling bipolar disorder.19 For rea­ criteria. Anyone who is age 15 or older sons that are still unknown, people with and formally diagnosed with bipolar dis­ bipolar disorder appear to have very deli­ order is eligible. (Individuals younger cate “internal clock” mechanisms, and than 18 need parental consent to partici­ disruption of these mechanisms by losing pate.) In addition, individuals may join even a single night’s sleep often results the study during any phase of their ill­ in mania. Developing and adhering to a ness, whether or not they are currently in structured daily routine and sleep sched­ treatment, and whether or not their ule may help protect against mood dis­ symptoms are controlled. turbances. NIMH researchers are investi­ STEP-BD offers all the standard treat­ gating the independent effects of the ment options used for bipolar disorder. internal clock and the sleep-wake cycle The aim is to examine existing, effica­ on mood in patients with rapid-cycling cious treatments to come up with the bipolar disorder.20 best set of strategies for tackling this Based on the clinical observation that very complex illness. Participants may episodes are often precipitated by disrup­ choose their own preferred treatment tions of sleep or other daily routines, a plan with their study doctor or may group of NIMH-funded researchers devel­ decide to have treatments chosen for oped interpersonal and social rhythm them through a randomization process. therapy (IPSRT) to help stabilize the Randomized treatment “pathways” were course of bipolar disorder. IPSRT teaches built into the study to compare compet­ patients techniques to regularize their ing treatment strategies where existing daily routines and improve their interper­ guidelines and expert recommendations sonal relationships. In preliminary stud­ offer no clear treatment of choice. Either ies, IPSRT, in combination with ongoing way, all participants will always receive medication maintenance, reduced depres­ active treatment with one or more mood sive symptoms and improved the quality stabilizing medications. Placebos (inac­ of remission from active bipolar tive pills) will never be used alone in any disorder.21 Patients who received IPSRT part of the study but may be used in as a preventive intervention spent more combination with a mood stabilizer for time in a balanced state and less time in limited periods during the randomized a subclinical depressive condition. treatment pathways. The investigators will track participants for up to 8 years to document and evaluate long-term treatment outcome. More information
  9. 9. BIPOLAR DISORDER Stress, Life Events, and ence problems—the highest rate across all patients with major psychiatric illnesses.24 Social Support Research suggests that many factors likely NIMH researchers are currently investigat­ contribute to these substance abuse prob­ ing the influence of stress, life events, and lems, including self-medication of symp­ social support on the course of bipolar dis­ toms, mood symptoms either initiated or order. These relationships can be deter- perpetuated by substance abuse, and risk mined most accurately by studies that fol­ factors that may influence the occurrence low patients forward through time—that of both disorders.25 is, by prospective research. One prospec­ A review of multiple research studies tive, NIMH-funded study is examining the revealed several factors that increase the impact of life events and social support on risk for co-occurring substance use among the time to recovery and relapse in people individuals with bipolar disorder, including with bipolar disorder.22 early age of illness onset, family history of Another prospective study supported substance use disorders, and presence of by NIMH is investigating the influence of mixed symptoms.26 A current NIMH-fund­ psychosocial factors—life events, stress, ed study is investigating how substance cognitive processes, and personality fac­ abuse affects the frequency, duration, and tors—on the onset and course of severity of episodes in people with bipolar cyclothymia (periods of mild hypomanic disorder.27 Better understanding of the symptoms alternating with periods of mild relationship between substance use and depressive symptoms), and on the onset bipolar disorder will help improve both and course of bipolar disorder among peo­ treatment and preventive interventions for ple with cyclothymia.23 Cyclothymia is a co-occurring substance use, leading to bet­ known risk factor for developing bipolar ter mental health outcome. disorder. However, little is known about Other research has indicated that cer­ what factors determine which people with tain anxiety disorders may co-occur with cyclothymia will develop bipolar disorder, bipolar disorder. In one recent NIMH-sup­ or about the mechanisms involved in the ported study of post-traumatic stress disor­ change from cyclothymia to the more der (PTSD) in people with bipolar disorder severe illness. Findings from this study or schizophrenia, almost all patients will help clarify the role of various psy­ reported having experienced at least one chosocial factors in the course of traumatic event in their lifetime.28 While cyclothymia and in the initial onset and 43 percent of study participants met crite­ subsequent course of full-blown bipolar ria for PTSD, only two percent had the disorder; help explain the relationship diagnosis listed in their medical charts. between unipolar major depression and the The results suggest that PTSD commonly depressive phases of bipolar disorder; and co-occurs with severe mental disorders. suggest new methods for treating and pre- Routine screening for PTSD during medical venting bipolar disorder. visits would lead to improved diagnosis and treatment of this anxiety disorder, Co-occurring Illnesses thus allowing the other co-occurring ill­ ness—bipolar disorder, schizophrenia, The most common co-occurring illnesses etc.—to be more effectively treated. among people with bipolar disorder are Another NIMH-funded study found a substance abuse disorders. Approximately high co-occurrence of both PTSD and 60 percent of people with bipolar disorder obsessive-compulsive disorder (OCD) have drug and/or alcohol abuse or depend­ among patients with bipolar disorder
  10. 10. BIPOLAR DISORDER across a 12-month period.29 While the thymia. Compared to adolescents with a course of PTSD was independent of the history of major depressive disorder and to mood disorder, the course of OCD frequent­ a never-mentally-ill group, both the teens ly waxed and waned along with mood with bipolar disorder and those with sub- episodes. More research is needed to deter- clinical symptoms had greater functional mine the nature of this apparent connec­ impairment and higher rates of co-occur­ tion between OCD and bipolar disorder in ring illnesses (especially anxiety and dis­ some patients. ruptive behavior disorders), suicide attempts, and mental health services uti­ lization. The study highlights the need for Children and Adolescents improved recognition, treatment, and pre­ Both children and adolescents can develop vention of even the milder and subclinical bipolar disorder. NIMH research efforts are cases of bipolar disorder in adolescence. attempting to clarify the diagnosis, course, Bipolar disorder in children and ado­ and treatment of bipolar disorder in youth. lescents has been difficult to recognize and Evidence suggests that bipolar disorder diagnose because it does not fit precisely beginning in childhood or early adoles­ the symptom criteria established for cence may be a different, possibly more adults, and because its symptoms can severe form of the illness than older ado­ resemble or co-occur with those of ADHD lescent- and adult-onset bipolar disorder.30 and CD. In addition, symptoms of bipolar When the illness begins before or soon disorder may be initially mistaken for nor­ after puberty, it is often characterized by a mal emotions and behaviors of children continuous, rapid-cycling, irritable, and and adolescents. But unlike normal mood mixed symptom state that may co-occur changes, bipolar disorder significantly with disruptive behavior disorders, particu­ impairs functioning in school, with peers, larly attention deficit hyperactivity disor­ and at home with family. der (ADHD) or conduct disorder (CD), or Although research in adults indicates may have features of these disorders as that the essential treatment for bipolar dis­ initial symptoms. In contrast, later adoles­ order is the use of appropriate doses of cent- or adult-onset bipolar disorder tends mood stabilizing medications, few studies to begin suddenly, often with a classic of the safety and efficacy of these drugs manic episode, and to have a more episod­ have been conducted in children and ado­ ic pattern with relatively stable periods lescents. NIMH is attempting to fill the between episodes. There is also less co­ current gaps in treatment knowledge with occurring ADHD or CD among those with carefully designed studies. Data from later onset illness. adults do not necessarily apply to younger Findings from one NIMH-supported patients, because the differences in devel­ study suggest that the illness may be at opment may have implications for treat­ least as common among youth as among ment efficacy and safety. Thus, research in adults. In this study, one percent of adoles­ children and adolescents is needed to prop­ cents ages 14 to18 were found to have met erly guide clinicians, patients, and fami­ criteria for bipolar disorder or cyclothymia lies. in their lifetime.31 In addition, close to six Current multi-site studies funded by percent of adolescents in the study had NIMH are investigating the value of long- experienced a distinct period of abnormally term treatment with lithium and other and persistently elevated, expansive, or mood stabilizers in preventing recurrence irritable mood even though they never met of bipolar disorder in adolescents.32, 33, 34 full criteria for bipolar disorder or cyclo­ Specifically, these studies aim to determine
  11. 11. BIPOLAR DISORDER how well lithium and other mood stabiliz­ since too much or too little thyroid hor­ ers prevent recurrences of mania or depres­ mone alone can lead to mood and energy sion and control subclinical symptoms in fluctuations, it is important that thyroid adolescents; to identify factors that predict levels are carefully monitored in all outcome; and to assess side effects and patients with bipolar disorder. overall adherence to treatment. Another NIMH-funded study is evaluating the safe­ Older Adults ty and efficacy of valproate for treatment of acute mania in children and adoles­ Although bipolar disorder typically appears cents, and also is investigating the biologi­ between early and mid-life, some people cal correlates of treatment response.35 develop the disorder for the first time late Other NIMH-supported investigators are in life. Research indicates that the factors studying the effects of antidepressant med­ contributing to late-onset bipolar disorder ications in the treatment of the depressive may differ from those influencing early- phase of bipolar disorder in youth.36 onset illness. A recent NIMH-supported study found that older adults with late-onset bipolar Women disorder reported less family history of Although bipolar disorder is equally com­ psychiatric problems, more co-occurring mon in women and men, research indi­ vascular disease, and more social support cates that approximately three times as than older adults with early-onset ill- many women as men experience rapid ness.38 In addition, the study revealed that cycling.37 NIMH researchers and others are stressful life events were more frequent investigating possible causes for this gen­ among individuals with earlier age of der difference, including greater use of depressive symptom onset compared to antidepressant medication among women individuals with later onset. The study (antidepressants may induce mania or findings suggest that while psychosocial hypomania if not used in combination factors may play an important role in with a mood stabilizing drug, such as early-onset illness, physical medical fac­ lithium or valproate), differences in thyroid tors may be particularly important in late- activity (see below), and effects of sex hor­ onset bipolar disorder. Ongoing NIMH- mones. Other research findings have indi­ funded research continues to investigate cated that women with bipolar disorder neuroanatomical and clinical features of may have more depressive episodes and bipolar disorder in older adults.39 This more mixed episodes than men with the research is likely to help scientists better illness.37 understand the psychobiology of bipolar A number of studies have found that disorder in older adults and may lead to among people with bipolar disorder, better diagnosis and management of the women are more likely than men to have a illness in this population. thyroid disorder.1 In addition, lithium treatment may cause low thyroid levels in The Broad NIMH Research some patients, particularly women, which Program may account for some depressive episodes that occur during treatment. Low thyroid In addition to bipolar disorder, NIMH sup- levels also have been associated with ports and conducts a broad based, multi- rapid-cycling bipolar disorder. Thyroid hor­ disciplinary program of scientific inquiry mone supplementation may be needed to aimed at improving the diagnosis, preven­ restore normal thyroid levels. However, tion, and treatment of other mental disor-
  12. 12. BIPOLAR DISORDER ders. These illnesses include schizophre­ More Than 2,000 Grants and nia, clinical depression, panic disorder, and obsessive-compulsive disorder. Contracts Increasingly, the public as well as In total, NIMH supports more than 2,000 health care professionals are recognizing research grants and contracts at universi­ these disorders as real and treatable med­ ties and other institutions across the ical illnesses of the brain. Still, there is a nation and overseas. It also conducts basic need for more research that examines in research and clinical studies involving greater depth the relationships among 9,000 patient visits per year at its own genetic, behavioral, developmental, social, facilities on the National Institutes of and other factors to find the causes of Health campus in Bethesda, MD, and else- these illnesses. NIMH is meeting this need where. NIMH research projects focus on: through a series of research initiatives. I basic research on behavior, emotion, and cognition to provide a knowledge base I NIMH Human Genetics Initiative for a better understanding of mental ill­ This project has compiled the world’s nesses I basic sciences, including cellular and largest registry of families affected by schizophrenia, manic-depressive illness, molecular biology, developmental neurobi­ and Alzheimer’s disease. Scientists are ology, neurochemistry, neurogenetics, and able to examine the genetic material of neuropharmacology, to provide essential these family members with the aim of pin- information about the anatomical and pointing genes involved in the diseases. chemical basis of brain function and brain disorders I neuroscience and behavioral aspects I Human Brain Project of acquired immune deficiency syndrome This multi-agency effort is using state-of- (AIDS) and behavioral strategies to reduce the-art computer science technologies to the spread of HIV (human immunodeficien­ organize the immense amount of data cy virus) being generated through neuroscience and I interventions to treat, prevent, and related disciplines, and to make this infor­ reduce the frequency of mental disorders mation readily accessible for simultaneous and their disabling consequences study by interested researchers. I mental health services research, including mental health economics and I Prevention Research Initiative improved methods of services delivery Prevention efforts seek to understand the I co-morbidity among mental disorders development and expression of mental ill­ and with substance abuse and other med­ ness throughout life so that appropriate ical conditions, such as depression and interventions can be found and applied at heart disease multiple points during the course of ill­ I the prevalence of mental disorders ness. Recent advances in biomedical, I risk factors for mental disorders behavioral, and cognitive sciences have led I differences in mental health and NIMH to formulate a new plan that mar­ mental illness among special populations ries these sciences to prevention efforts. I children and adolescents who suffer While the definition of prevention will from or who are at risk for serious mental broaden, the aims of research will become disorders and learning disabilities more precise and targeted. I psychotherapies and pharmacothera­ pies for specific disorders
  13. 13. BIPOLAR DISORDER At the beginning of the 21st century, NIMH I Information for scientists on NIMH stands poised to surmount the burden, grants and contracts programs, including loss, and tragedy of mental illnesses that grant application and review, Requests for afflict millions of Americans. Applications, Requests for Proposals, pro- gram announcements, research training For More Information About and career development, small business programs, program analyses of NIMH NIMH extramural research grants and applica­ The Office of Communications and Public tions, access to NIH Grants policy, and Liaison carries out educational activities other material may be obtained from the and publishes and distributes research NIMH home page: reports, press releases, fact sheets, and publications intended for researchers, health care providers, and the general pub­ lic. A publications list may be obtained on the web at­ list/puborder.cfm or by contacting: Office of Communications and Public Liaison, NIMH Information Resources and Inquiries Branch 6001 Executive Blvd., Room 8184, MSC 9663 Bethesda, MD 20892-9663 Phone: 301-443-4513 FAX: 301-443-4279 Mental Health FAX4U: 301-443-5158 E-mail: NIMH home page address: Anxiety Disorders Information: 1-88-88-ANXIETY (1-888-826-9438) Depression Information: 1-800-421-4211 I Information about research opportu­ nities at the NIMH Intramural Research Program may be obtained from: Office of the Scientific Director, NIMH 9000 Rockville Pike Building 10, Room 4N224, MSC 1381 Bethesda, MD 20892-1831 Phone: 301-496-3501 FAX: 301-480-8348
  14. 14. BIPOLAR DISORDER References 1 Goodwin FK & Jamison KR, 1990. Manic- 12 Nonaka S, et al., 1998. Chronic lithium depressive illness. New York: Oxford University treatment robustly protects neurons in the cen­ Press. tral nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-medi­ 2 American Psychiatric Association (APA), ated calcium influx. Proceedings of the National 1994. The Diagnostic and Statistical Manual of Academy of Sciences USA, 95(5): 2642-2647. Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Press. 13 Post RM, in progress. New treatments for refractory affective illness. NIMH Grant 3 Goodwin FK & Ghaemi SN, 1998. Number: 1Z01MH02755-02. Understanding manic-depressive illness. 14 Suppes T, et al., 1999. Clinical outcome in a Archives of General Psychiatry, 55(1): 23-25. randomized 1-year trial of clozapine versus 4 Tsuang MT & Faraone SV, 1990. The genetics treatment as usual for patients with treatment- resistant illness and a history of mania. of mood disorders. Baltimore, MD: Johns American Journal of Psychiatry, 156(8): 1164- Hopkins University Press. 1169. 5 Nurnberger J, in progress. Collaborative 15 Rothschild AJ, et al., 1999. Olanzapine genomic study of bipolar disorder. NIMH Grant response in psychotic depression. Journal of Number: 1R01MH59545-01 (project coordina­ Clinical Psychiatry, 60(2): 116-118. tion site). 16 Tohen M, et al., 1999. Olanzapine versus 6 Baron M, in progress. Molecular genetics of placebo in the treatment of acute mania. bipolar disorder. NIMH Grant Number: Olanzapine HGEH Study Group. American 1R01MH59602-02. Journal of Psychiatry, 156(5): 702-709. 7 Pato C, in progress. Genetic analysis of bipo­ 17Stoll AL, et al., 1999. Omega-3 fatty acids in lar disorder. NIMH Grant Number: bipolar disorder: A preliminary double-blind, 1R01MH58693-01A1. placebo-controlled trial. Archives of General Psychiatry, 56: 407-412. 8 Soares JC & Mann JJ, 1997. The anatomy of mood disorders—review of structural neu­ 18 Jamison KR, 1999. Suicide and manic- roimaging studies. Biological Psychiatry, 41: depressive illness: An overview and personal 86-106. account. In Jacobs DG, Ed., The Harvard Medical School Guide to Suicide Assessment 9 Soares JC & Mann JJ, 1997. The functional and Intervention. San Francisco, CA: Jossey- neuroanatomy of mood disorders. Journal of Bass, p. 251. Psychiatric Research, 31(4): 393-432. 19 Leibenluft E, et al., 1996. Relationship 10 Kalin NH, et al., 1997. Functional magnetic between sleep and mood in patients with rapid- cycling bipolar disorder. Psychiatry Research, resonance imaging studies of emotional pro­ 63(2-3): 161-168. cessing in normal and depressed patients: Effects of venlafaxine. Journal of Clinical 20 Leibenluft E, in progress. Chronobiological Psychiatry, 58 (Suppl 16): 32-39. evaluation of rapid-cycling bipolar disorder. 11 Klein P in progress. Molecular mechanism NIMH Grant Number: 1Z01MH02614-07. , for lithium action. NIMH Grant Number: 21 Frank E, et al., 1997. Inducing lifestyle regu­ 1R01MH58324-03. larity in recovering bipolar disorder patients: Results from the maintenance therapies in
  15. 15. BIPOLAR DISORDER bipolar disorder protocol. Biological Psychiatry, Child and Adolescent Psychiatry, 34(4): 454- 41(12): 1165-1173. 463. 22 Johnson S, in progress. Life events, social 32 Kafantaris V, in progress. Lithium in hospi­ support, and bipolar disorder. NIMH Grant talized bipolar manic adolescents. NIMH Grant Number: 5R29MH55950-05. Number: 5K07MH00970-05. 23 Abramson L, in progress. Course of 33 Ryan N, in progress. Psychobiology of child- cyclothymia-role of cognition and stress. NIMH hood anxiety and depression. NIMH Grant Grant Number: 5R10MH52662-03. Number: 5P01MH41712-14. 24 Regier DA, et al., 1990. Comorbidity of men­ 34 Keller M, Strober M, & Ryan N. Lithium pro­ tal disorders with alcohol and other drug phylaxis in adolescents with bipolar illness. abuse: Results from the Epidemiologic NIMH Grant Numbers: 5R10MH48877-05, Catchment Area (ECA) study. Journal of the 5R10MH48878-05, 5R10MH48879-05. American Medical Association, 264: 2511-2518. Collaborative study. 25 Winokur G, et al., 1995. Alcoholism in 35 Davanzo P in progress. Research training in , manic-depressive (bipolar) illness: Familial ill­ juvenile bipolar disorder. NIMH Grant Number: ness, course of illness, and the primary-second­ 5K01MH01601-02. ary distinction. American Journal of Psychiatry, 152: 365-372. 36 Birmaher B, in progress. Research Units on Pediatric Psychopharmacology. NIMH Grant 26 Tohen M, et al., 1998. The effect of comorbid Number: 5N01MH70008-003 (project coordina­ substance use disorders on the course of bipo­ tion site). lar disorder: A review. Harvard Review of Psychiatry, 6(3): 133-141. 37 Leibenluft E, 1997. Issues in the treatment of women with bipolar illness. Journal of 27 Strakowski SM, in progress. Substance abuse Clinical Psychiatry, 58(Suppl. 15): 5-11. comorbidity in first episode mania. NIMH Grant Number: 1R01MH58170-01A1. 38 Hays JC, et al., 1998. Age of first onset of bipolar disorder: Demographic, family history, 28 Mueser KT, et al., 1998. Trauma and post- and psychosocial correlates. Depression and traumatic stress disorder in severe mental ill­ Anxiety, 7(2): 76-82. ness. Journal of Consulting and Clinical Psychology 66(3): 493-499. 39 Krishnan K, in progress. Bipolar disorder in late life. NIMH Grant Number: 5R01MH57027- 29 Strakowski SM, et al., 1998. Course of psy­ 03. chiatric and substance abuse syndromes co­ occurring with bipolar disorder after a first psy­ chiatric hospitalization. Journal of Clinical Psychiatry, 59(9): 465-471. 30 Geller B & Luby J, 1997. Child and adoles­ cent bipolar disorder: A review of the past 10 years. Journal of the American Academy of Child and Adolescent Psychiatry, 36(9): 1168- 1176. 31 Lewinsohn PM, et al., 1995. Bipolar disor­ ders in a community sample of older adoles­ cents: Prevalence, phenomenology, comorbidity, and course. Journal of the American Academy of N I H P U B L I C ATION N O . 0 0 - 4 5 0 2 APRIL 2 0 0 0
  16. 16. This is the electronic version of a National Institute of Mental Health (NIMH) publication, available from To order a print copy, call the NIMH Information Center at 301-443-4513 or 1-866-615-6464 (toll-free). Visit the NIMH Web site ( for information that supplements this publication. To learn more about NIMH programs and publications, contact the following: Web address: E-mail: Phone numbers: Fax numbers: 301-443-4513 (local) 301-443-4279 1-866-615-6464 (toll-free) 301-443-5158 (FAX 4U) 301-443-3431 (TTY) Street address: National Institute of Mental Health Office of Communications Room 8184, MSC 9663 6001 Executive Boulevard Bethesda, Maryland 20892-9663 USA __________________________________________________________________________ This information is in the public domain and can be copied or reproduced without permission from NIMH. To reference this material, we suggest the following format: National Institute of Mental Health. Title. Bethesda (MD): National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services; Year of Publication/Printing [Date of Update/Revision; Date of Citation]. Extent. (NIH Publication No XXX XXXX). Availability. A specific example is: National Institute of Mental Health. Childhood-Onset Schizophrenia: An Update from the National Institute of Mental Health. Bethesda (MD): National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services; 2003 [cited 2004 February 24]. (NIH Publication Number: NIH 5124). 4 pages. Available from: