BIPOLAR AFFECTIVE DISORDER Background

Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and persistent mental illnesses. Bipolar disorder is a serious lifelong struggle and challenge.[1] It is also useful to note that other mental health disorders and general medical conditions are more prevalent in patients with bipolar disorders.[2] Among the general medical conditions, cardiometabolic conditions such as cardiovascular disease, diabetes, and obesity are a common source of morbidity and mortality for persons with bipolar disorder. Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania. The symptoms of mania include a decreased need for sleep, pressured speech, increased libido, reckless behavior without regard for consequences, grandiosity, and severe thought disturbances, which may or may not include psychosis. Between these highs and lows, patients usually experience periods of higher functionality and can lead a productive life. Unipolar major depressive disorder and bipolar disorder share depressive symptoms, but bipolar disorder is defined by episodes of mania or hypomania. A community lifetime prevalence (in its broadest measure) of 4% has been suggested. The costs of bipolar disorder include the direct costs of treatment along with the even more significant indirect costs of excess unemployment, decreased productivity, and excess mortality; it is a severely impairing illness that affects many aspects of patients' lives.[3] Bipolar disorder constitutes 1 pole of a spectrum of mood disorders that includes including bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major depression. BPI, also referred to as classic manic-depression, is characterized by distinct episodes of major depression contrasting vividly with episodes of mania, which lead to severe impairment of function. In comparison, BPII is a milder disorder that consists of depression alternating with periods of hypomania. Hypomania may be thought of as a less severe form of mania that does not include psychotic symptoms or lead to major impairment of social or occupational function. For more information, see Pediatric Bipolar Affective Disorder.

Case history
At the age of 25, D.A.K., a postgraduate student in chemistry, found himself at the emergency department (ED) of the university hospital, where the campus police had brought him. He had been working late at the laboratory alone when the police came. He had been awake for the past 4 days working on an experiment that he believed would save the world. D.A.K.s professors had voiced concerns as the often quiet and well-mannered student had recently begun to take over the class discussions and interrupt lectures. More remarkable than the behavior itself was the change it represented. In the preceding semester, D.A.K. had been

uncharacteristically quiet and withdrawn. Many suspected that he was depressed, but they could find no apparent reason for his behavior. Then he isolated himself from friends and family and stopped seeing his girlfriend of 2 years. D.A.K. had a family history of depression on his mothers side, with a grandmother who had received electroconvulsive therapy (ECT) years ago in a state hospital. On his fathers side, his uncle had received lithium and had been diagnosed with manic depression. A vague history of colorblindness was also noted. D.A.K. had a younger sister who was often described as moody. In the ED, D.A.K. was belligerent, talked rapidly but coherently, and demanded to return to the laboratory so that he could save his experiment and thus the world. He wanted a lawyer and denied being suicidal but threatened those who, he claimed, were standing in his way. He accused the faculty of being against him, threatened legal action against those incarcerating him, denied hallucinations but clearly saw himself in highly grandiose terms, was orientated times 3, had good recall, and was colorful and verbose in his response to proverbs. No history of drug or alcohol use was noted, except for a large consumption of coffee in the preceding several weeks. He had no obvious medical problems. D.A.K. kept demanding to leave and return to the laboratory to save everyone. He was a huge challenge to the emergency physicians, who could not wait for the psychiatric resident to arrive.

Pathophysiology
The pathophysiology of bipolar disorder has not been determined, and no objective biologic markers have yet been found to correspond definitively with the disease state. However, twin, family, and adoption studies all indicate that bipolar disorder has a genetic component. In fact, first-degree relatives of a person with bipolar disorder are approximately 7 times more likely to develop bipolar disorder than the rest of the population. The genetic component of bipolar disorder appears to be complex: the disorder is likely to be caused by multiple different common disease alleles, on the order of hundreds to thousands, each of which contributes a relatively low degree of risk on its own. Such disease genes can be difficult to find without very large sample sizes, on the order of thousands of subjects. The first series of genome-wide association studies (GWAS) for bipolar disorder were published in 2007 and 2008,[4, 5, 6, 7] and a collaborative analysis of the last 3 studies gave combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a sample of 4,387 cases and 6,209 controls.[7] ANK3 is an adaptor protein found at axon initial segments that regulates the assembly of voltage-gated sodium channels. Both ANK3 and subunits of the calcium channel are downregulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action of 1 of the most effective treatments for bipolar disorder.[8] Further evidence for association of bipolar disorder to CACNA1C was reported in 2011 in an ever-growing sample (now numbering 11,974 bipolar disorder cases and 51,792 controls), providing overwhelming support for this gene as a bipolar susceptibility locus.[9]

CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltage-gated calcium ion channel found in the brain. L-type calcium channel blockers have been used to treat bipolar disorder, and there has been speculation that at least some mood stabilizers may mediate their effects via modulating calcium channel signaling in bipolar illness. A joint analysis of the bipolar GWAS data was carried out, including GWAS data from another large-scale study of schizophrenia published in the same issue. Again, both ANK3 and CACNA1C came up positive in the combined data set, suggesting a shared genetic basis for these disorders. A previous National Institutes of Health (NIH) report on recent genomewide association studies also underscored that bipolar disorder and schizophrenia could indeed share common susceptibility genes on chromosome 6.[10] These data herald future revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) according to an etiologic rather than descriptive basis. The first GWAS of bipolar disorder used a much smaller sample size than subsequent attempts[4] , including an initial sample of 461 patients with bipolar disorder from the National Institute of Mental Health (NIMH) consortium and a follow-up sample of 563 patients collected in Germany. This gene was not highlighted in the most recent and largest bipolar GWAS published by Sklar et al 2011.[9] Nevertheless, this study remains of interest, in that the strongest association signals were detected in genes also involved in biochemical pathways regulated by lithium. The strongest hit was at a marker within the first intron of diacylglycerol kinase eta (DGKH) gene. DGKH is a key protein in the lithium-sensitive phosphatidyl inositol pathway. Three of the other associated genes in this study also interact with the Wnt signaling pathway upstream and downstream of glycogen synthase kinase 3-beta (GSK3). Lithium-mediated inhibition of GSK3 is thought to result in downregulation of molecules involved in cell death and upregulation of neuroprotective factors. Additionally, GSK3 is a central regulator of the circadian clock, and lithium-mediated modulation of circadian periodicity is thought to be a critical component of lithiums therapeutic effect. In fact, another major coup for bipolar disorder research has been the finding that a dominant-negative mutation in the CLOCK gene normally contributing to circadian periodicity in humans results in behavior mimicking mania in mice.[11] Manic behavior in CLOCK mutant mice includes hyperactivity, decreased sleep, reduced anxiety, and an increased response to cocaine. The latter finding also provides a shared biologic basis for the high rate of substance abuse observed in clinical populations of subjects with bipolar disorder. Furthermore, the experimenters were able to abolish the manic behaviors by rescuing expression of normal CLOCK gene product specifically in the ventral tegmental area of the mouse brain.[12] This area is rich in D2 (dopamine) receptors. Joseph Coyle hypothesizes in his commentary in the paper in the same issue that the efficacy of atypical antipsychotics in acute mania might, in part, be achieved by their ability to lower activity in neurons specifically within the ventral tegmental area. Although large-scale association studies of bipolar disorder are beginning to yield results, one of the greatest obstacles to finding genes for such complex behavior is the imprecision inherent in diagnosis of the disorder itself; objective criteria are lacking. Therefore, some of

the most exciting recent research is focused on defining heritable, quantitative diagnostic measures that capture specific features of bipolar disorder (termed endophenotypes) to refine the search for responsible genes.[13] Such promising measures for bipolar disorder include structural brain phenotypes, sleep and activity measures, neurocognitive measures, and gene expression studies.[14] This collaborative research effort under the aegis of the National Institute of Mental Health (NIMH) has been termed the Bipolar Phenome Project; more information is available in the links provided below. Gene expression studies, one way of measuring the relative activity or inactivity of genes, have already been proven useful for illuminating the pathophysiology of psychiatric disorders, including bipolar disorder. For instance, studies comparing specific regions of postmortem brain tissue from persons with bipolar disorder with tissue from control subjects have consistently shown that levels of expression of oligodendrocyte-myelinrelated genes appear to be decreased in brain tissue from persons with bipolar disorder.[15, 16, 17, 18] As with genetic studies, gene expression profiling studies require very large sample sizes to produce replicable data. Furthermore, they must focus on the correct brain region(s) thought to be functioning differently in bipolar disorder, a point still under some debate. Therefore, research in this area is ongoing and frequently subject to update. Oligodendrocytes produce myelin membranes that wrap around and insulate axons to permit the efficient conduction of nerve impulses in the brain. Therefore, loss of myelin is thought to disrupt communication between neurons, leading to some of the thought disturbances observed in bipolar disorder and related illnesses. Brain imaging studies of persons with bipolar disorder also show abnormal myelination in several brain regions associated with this illness. It can be useful to compare data from gene expression studies with brain imaging studies of persons with bipolar disorder to determine whether abnormalities of structure or function correlate with changes in gene expression. In this case, structural neuroimaging studies also show abnormal myelination in several brain regions associated with bipolar disorder.[19, 20] Interestingly, gene expression and neuroimaging studies of persons with schizophrenia and major depression also demonstrate abnormalities of myelination in various brain regions, indicating that mood disorders and schizophrenia may share some biologic underpinnings, possibly related to psychosis, which can be a symptom of all 3 disorders. These types of data may also lead to the future revision of psychiatric diagnostic manuals based on a new understanding of the etiology of these disorders. In addition to structural neuroimaging studies that look for volumetric changes in brain regions regardless of brain activity, functional neuroimaging studies are performed to find regions of the brain, or specific cortical networks, that are either hypoactive or hyperactive in a particular illness. For example, a meta-analysis by Houenou et al found decreased activation and diminution of gray matter in a cortical-cognitive brain network, which has been associated with the regulation of emotions in patients with bipolar disorder.[21] An increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses was also discovered. This provides evidence for functional and anatomical alterations in bipolar disorder in brain networks associated with the experience and regulation of emotions. Another source of knowledge regarding the pathophysiology of bipolar disorder comes from studies done using animal models.

For instance, investigators can study changes in gene expression/activation, induced in rodent brains after administration of pharmacologic agents used to treat bipolar disorder to look at the mechanism of action of these drugs. For example, investigators have demonstrated that 2 chemically unrelated drugs (lithium and valproate) used to treat bipolar disorder both increase the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains.[22] These types of studies are also performed on human tissue by exposing cultured human monocytes from peripheral blood to lithium and other factors and then measuring changes in gene expression. A postmortem study by Konradi et al of the hippocampus in both patients with bipolar disorder and healthy persons found that the 2 groups did not differ in the total number of hippocampal neurons.[23] However, patients with bipolar disorder had reduced volume of nonpyramidal cell layers, a reduced number of somatostatin-positive and parvalbumin positive neurons, a reduced somal volume in cornu ammonis sector 2/3, and reduced messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1. These findings suggest alteration of hippocampal interneurons in patients with bipolar disorder that might lead to hippocampal dysfunction. Neuroimaging studies of individuals with bipolar disorder or other mood disorders also suggest evidence of cell loss or atrophy in these same brain regions. Thus, another suggested cause of bipolar disorder is damage to cells in the critical brain circuitry that regulates emotion. According to this hypothesis, mood stabilizers and antidepressants are thought to alter mood by stimulating cell survival pathways and increasing levels of neurotrophic factors to improve cellular resiliency. In 2008, Mathew et al published a review of novel drugs and therapeutic targets for severe mood disorders that focus on increasing neuroplasticity and cellular resiliency.[24] Post et al had previously proposed a mechanism involving electrophysiologic kindling and behavioral sensitization processes, which resonates with the neuronal injury hypothesis.[11] They asserted that a person who is susceptible to bipolar disorder experiences an increasing number of minor neurologic insultssuch as those induced by drugs of abuse, stress-related excessive glucocorticoid stimulation, oxidative or immune-mediated damageeventually resulting in mania that further compromises the injured neurons.[11] Sufficient brain damage might persist to cause mania to recur even with no or minor environmental or behavioral stressors. Post et als formulation helps explain the effective role of anticonvulsant medications (eg, carbamazepine and valproate) in the prevention of the highs and lows of bipolar disorder. It also supports the clinical observation that the more episodes a person experiences, the more he or she will have in the future, underscoring the need for long-term treatment.

Updated research Web sites

Research on bipolar disorder is proceeding at a rapid rate, and the traditionally referenced peer-reviewed publications provided in this article may become rapidly outdated. To keep current with research into bipolar disorder, search the following Web sites, which are continually updated.

For information about clinical trials, including both traditional pharmacotherapies and nutritional supplements, please consult http://clinicaltrials.gov and enter the search term "bipolar affective disorder". For information about the research aims and priorities of the NIMH, please consult http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml. For those interested in following refinements in the diagnosis of bipolar disorder, please consult www.dsm5.org. The International Society for Bipolar Disorders (ISBD) also sponsors a yearly conference where the worlds experts present their research findings on all aspects of bipolar disorder. For more about the ISBD, see http://www.isbd.org/EdCenter/aboutisbd/mission.asp; their findings are published yearly in the Annals of the New York Academy of Sciences.

Etiology
A number of factors contribute to bipolar disorder, including genetic, biochemical, psychodynamic, and environmental factors.

Genetic factors
Bipolar disorder, especially BPI, has a major genetic component, with the involvement of the ANK3,CACNA1C, and CLOCK genes.[4, 5, 6, 7, 9, 12, 25] The evidence indicating a genetic role in bipolar disorder takes several forms. First-degree relatives of people with BPI are approximately 7 times more likely to develop BPI than the general population. Remarkably, offspring of a parent with bipolar disorder have a 50% chance of having another major psychiatric disorder. Twin studies demonstrate a concordance of 33-90% for BPI in identical twins. As identical twins share 100% of their DNA, these studies also show that environmental factors are involved and there is no guarantee that a person will develop bipolar disorder, even if they carry susceptibility genes. Adoption studies prove that a common environment is not the only factor that makes bipolar disorder occur in families. Children whose biologic parents have either BPI or a major depressive disorder remain at increased risk of developing an affective disorder, even if they are reared in a home with adopted parents who are not affected. For more information on bipolar disorder in children, see New Findings in Childhood Bipolar Disorder. Using probands from the Maudsley Twin Register in London, Cardno and colleagues showed that schizophrenic, schizoaffective, and manic syndromes share genetic risk factors and that the genetic liability was the same for schizoaffective disorder as for the other 2 syndromes.[26] This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum disorders, as Berrettini[27] previously speculated and as has been confirmed in the recent large-scale GWAS studies mentioned above.[9] Gene expression studies also demonstrate that persons with bipolar disorder, major depression, and schizophrenia share similar decreases in the expression of oligodendrocytemyelin-related genes and abnormalities of white matter in various brain regions.

Biochemical factors
Multiple biochemical pathways likely contribute to bipolar disorder, which is why detecting one particular abnormality is difficult. A number of neurotransmitters have been linked to this disorder, largely based on patients responses to psychoactive agents as in the following examples. Drugs used to treat depression and drugs of abuse (eg, cocaine) that increase levels of monoamines, including serotonin, norepinephrine or dopamine, can all potentially trigger mania, implicating all these neurotransmitters in its etiology. Evidence is mounting on the contribution of glutamate to both bipolar disorder and major depression. A postmortem study of the frontal lobes from persons with both these disorders revealed that the glutamate levels were increased.[28] Calcium channel blockers have been used to treat mania, which also may result from a disruption of calcium regulation in neurons as suggested by experimental and genetic data. The proposed disruption of calcium regulation may be caused by various neurologic insults, such as excessive glutaminergic transmission or ischemia. Interestingly, valproate specifically up-regulates expression of a calcium chaperone protein, GRP 78, which may be one of its chief mechanisms of cellular protection. Hormonal imbalances and disruptions of the hypothalamic-pituitary-adrenal axis involved in homeostasis and the stress response may also contribute to the clinical picture of bipolar disorder.

Neurophysiological factors
In addition to structural neuroimaging studies that look for volumetric changes in brain regions regardless of brain activity, functional neuroimaging studies are performed to find regions of the brain, or specific cortical networks, that are either hypoactive or hyperactive in a particular illness. For example, a meta-analysis by Houenou et al found decreased activation and diminution of gray matter in a cortical-cognitive brain network, which has been associated with the regulation of emotions in patients with bipolar disorder.[21] An increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses was also discovered. This provides evidence for functional and anatomical alterations in bipolar disorder in brain networks associated with the experience and regulation of emotions.

Psychodynamic factors
Many practitioners see the dynamics of manic-depressive illness as being linked through a single common pathway. They see the depression as the manifestation of losses (ie, the loss of self-esteem and the sense of worthlessness). Therefore, the mania serves as a defense against the feelings of depression. Melanie Klein was one of the major proponents of this formulation. A study by Barnett et al found that personality disturbances in extraversion, neuroticism, and openness are often noted in patients with bipolar disorder and may be enduring characteristics.[29]

Environmental factors
In some instances, the cycle may be directly linked to external stresses or the external pressures may serve to exacerbate some underlying genetic or biochemical predisposition. Pregnancy is a particular stress for women with a manic-depressive illness history and increases the possibility of postpartum psychosis.[30] Because of the nature of their work, certain individuals have periods of high demands followed by periods of few requirements. For example, a landscaper and gardener would be busy in the spring, summer, and fall but relatively inactive during the winter, except for plowing snow. Thus, he or she might appear manic for a good part of the year and then would crash and hibernate for the cold months.

Epidemiology
United States statistics
The lifelong prevalence of bipolar disorder in the United States has been noted to range from 1% to 1.6%. Studies indicate differences in lifetime prevalence estimates for BPI, BPII, and subthreshold bipolar disorders: 1.0% for BPI, 1.1% for BPII, and 2.4-4.7% for subthreshold bipolar disorders.[31]

International statistics
Lifelong prevalence rate is 0.3-1.5%. In cross-sectional, face-to-face household surveys of more than 61,000 adults across 11 countries, Merikangas et al, using the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, determined that the aggregate lifetime prevalences were 0.6% for bipolar I disorder, 0.4% for bipolar II disorder, 1.4% for subthreshold bipolar disorder, and 2.4% for bipolar spectrum.[32] Yutzy and colleagues report an increase in the prevalence bipolar affective disorders I and II in recent years. They noted the prevalence from mid 1970s to 2000 ranged from 0.4% to 1.6%. By the late 1990s to the 2000s, it had the climbed from approximately 5% to 7%.[33]

Age-related differences in incidence

The age of onset of bipolar disorder varies greatly. For both BPI and BPII, the age range is from childhood to 50 years, with a mean age of approximately 21 years. Most cases commence when individuals are aged 15-19 years. The second most frequent age range of onset is 20-24 years. Some patients diagnosed with recurrent major depression may indeed have bipolar disorder and go on to develop their first manic episode when older than 50 years. They may have a family history of bipolar disorder. However, for most patients, the onset of mania in people older than 50 years should lead to an investigation for medical or neurologic disorders, such as cerebrovascular disease. For more information, see Pediatric Bipolar Affective Disorder.

Sex-related differences in incidence

BPI occurs equally in both sexes; however, rapid-cycling bipolar disorder (4 or more episodes a year) is more common in women than in men. The incidence of BPII is higher in females than in males. , Most studies report a nearly equal male-to-female ratio in the prevalence of bipolar disorder; however, most studies report an increased risk in women for BPII/hypomania, rapid cycling, and mixed episodes.[34]

Race-related differences in incidence

No racial predilection exists. However, a point of historical interest is that clinicians often tend to consider populations of African Americans and Hispanics as more likely to be diagnosed with schizophrenia than with affective disorders and bipolar disorder.

Prognosis
Bipolar disorder has significant morbidity and mortality rates. In the United States during the early part of the 1990s, the cost of lost productivity resulting from this bipolar disorder was estimated at approximately $15.5 billion annually. Approximately 25-50% of individuals with bipolar disorder attempt suicide, and 11% actually commit suicide. Additionally, a recent study from the United Kingdom suggests that for patients with bipolar disorder, mortality one year after hospital discharge was also higher than that of the general population for natural causes, chiefly respiratory and circulatory disorders.[35] Patients with BPI fare worse than patients with a major depression. Within the first 2 years after the initial episode, 40-50% of patients experience another manic attack. Only 50-60% of patients with BPI who are on lithium gain control of their symptoms. In 7% of these patients, symptoms do not recur, 45% of patients experience more episodes, and 40% go on to have a persistent disorder. Often, the cycling between depression and mania accelerates with age. Factors suggesting a worse prognosis include the following:

Poor job history Alcohol abuse Psychotic features Depressive features between periods of mania and depression Evidence of depression Male sex

Factors suggesting a better prognosis include the following:

Length of manic phases (short in duration) Late age of onset Few thoughts of suicide Few psychotic symptoms Few medical problems

Patient Education

Treatment of patients with bipolar disorder involves initial and ongoing patient education. To this end, a strong therapeutic alliance is essential. Educational efforts must be directed not only toward the patient but also toward their family and support system. Furthermore, evidence continues to mount that these educational efforts not only increase patient compliance and their knowledge of the disease, but also their quality of life.[36] An explanation of the biology of the disease must be provided. This decreases feelings of guilt and promotes medication compliance. Information should be provided on how to monitor the illness in terms of an appreciation of the early warning signs, reemergence, and symptoms. Recognition of changes can serve as a powerful preventive step. Education must also encompass the dangers of stressors. Helping the individual identify and work with stressors provides a critical aspect of patient and family awareness. Efforts should be made to educate the patient about relapses within the total context of the disorder. Individual stories help patients and families. NIMH has a story of a person with manicdepressive illness that can help the patient see the struggle and challenge from another perspective.[37] Others have written about their family struggles and challenges.[38] Important resources for patients and families to gain information on dealing with manicdepressive illness include the following:

National Institute of Mental Health (NIMH) - Public Information and Communications Branch, 6001 Executive Blvd, Rm 8184, MSC 9663, Bethesda, MD 20892-9663; phone, 301-443-4513 (local) or 866-615-6464 (toll-free); fax, 301-4434279 Fax Back System, Mental Health FAX4U 301-443-5158; e-mail: nimhinfo@nih.gov Child & Adolescent Bipolar Foundation - 1000 Skokie Blvd, Suite 570, Wilmette, IL 60091; phone, 847-256-8525; e-mail, cabf@bpkids.org Depression and Related Affective Disorders Association (DRADA) - 2330 West Joppa Rd, Suite 100, Lutherville, MD 21093; phone, 410-583-2919; e-mail, drada@jhmi.edu National Alliance on Mental Illness (NAMI) - Colonial Place Three, 2107 Wilson Blvd, Suite 300, Arlington, VA 22201-3042; phone, 703-524-7600 (local) or 800950-NAMI (6264) (toll-free); fax, 703-524-9094 Depression & Bipolar Support Alliance (DBSA) - 730 North Franklin St, Suite 501, Chicago, IL 60610-7224; phone, 312-642-0049 (local) or 800-826-3632 (toll-free); fax, 312-642-7243 International Foundation for Research and Education on Depression (iFred) - 2017-D Renard Court, Annapolis, MD 21401; phone, 401-268-0044; fax, 443-782-0739; email, info@ifred.org Mental Health America (MHA) - 2000 North Beauregard St, 6th Floor, Alexandria, VA 22311; phone, 703-684-7722 (local) or 800-969-6642 (toll-free); TTY, 800-4435959; fax, 703-684-7722 Bipolar Disorder Support Groups

History
Correct diagnosis of a disorder leads to proper effective treatment. Nowhere is that more relevant than in diagnosing a patient with bipolar affective disorder. Wolkenstein et al have pointed out the advantages of applying all DSM-specific criteria in order to make the correct diagnosis.[39] The diagnosis of bipolar I (BPI) disorder requires the presence of a manic episode of at least 1 weeks duration that leads to hospitalization or other significant impairment in occupational or social functioning. The episode of mania cannot be caused by another medical illness or by substance abuse. These criteria are based on the specifications of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).[40] Manic episodes are characterized by at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness (referred to as gateway criteria). At least 3 of the following symptoms must also be present:

Grandiosity Diminished need for sleep Excessive talking or pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Increased level of goal-focused activity at home, at work, or sexually Excessive pleasurable activities, often with painful consequences

The mood disturbance is sufficient to cause impairment at work or danger to the patient or others. The mood is not the result of substance abuse or a medical condition. Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 days duration. At least 3 of the following symptoms are also present:

Grandiosity or inflated self-esteem Diminished need for sleep Pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Psychomotor agitation at home, at work, or sexually Engaging in activities with a high potential for painful consequences

The mood disturbance is observable to others. The mood is not the result of substance abuse or a medical condition. Major depressive episodes are characterized by the following: For the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of them being either a depressed mood or characterized by a loss of pleasure or interest:

Depressed mood Markedly diminished pleasure or interest in nearly all activities Significant weight loss or gain or significant loss or increase in appetite

Hypersomnia or insomnia Psychomotor retardation or agitation Loss of energy or fatigue Decreased concentration ability or marked indecisiveness Preoccupation with death or suicide; patient has a plan or has attempted suicide The symptoms cause significant impairment and distress. The mood is not the result of substance abuse or a medical condition.

Mixed episodes are characterized by the following:

Persons must meet both the criteria for mania and major depression; the depressive event is required to be present for 1 week only. The mood disturbance results in marked disruption in social or vocation function. The mood is not the result of substance abuse or a medical condition.

The mixed symptomatology is quite common in patients presenting with bipolar symptomatology. This often causes a diagnostic dilemma.[41]

Refining the diagnosis of bipolar disorder

The fifth version of the DSM is underway, and efforts are being made to refine the diagnosis based in part on data from the BRIDGE study (Bipolar Disorders: Improving Diagnosis, Guidance and Education). For example, data from this study support revising the DSM-IV concept of hypomanic episodes: specifically, the inclusion of increased activity in the gateway criteria; the inclusion of 1 or 2 to 3-day episodes as clinically relevant; and the elimination of all exclusion criteria such as hypomania/mania due to the use of antidepressants or other substances.[42] If made official, these types of changes could have a major impact on the prevalence of bipolar disorder. The data certainly suggest that more careful screening of patients with depression for the presence of bipolarity is warranted.[43]

Physical Examination
Use the Mental Status Examination (MSE) to diagnose bipolar disorder. This section highlights the major findings for a person with bipolar disorder. Because the patients mental status depends on whether he or she is depressed, hypomanic, manic, or mixed, the following discussions of the various areas of the MSE include consideration of each of these particular phases

Appearance
Persons experiencing a depressed episode may demonstrate poor to no eye contact. Their clothes may be unkempt, unclean, holed, unironed, and ill-fitting. If the person has lost significant weight, the garments may fit loosely. The personal hygiene of individuals experiencing a depressed episode reflects their low mood, as evidenced by poor grooming, lack of shaving, and lack of washing. In women, fingernails may show different layers of polish or one layer partially removed. They may not have paid attention to their hair. Men may exhibit dirty fingernails and hands. When these individuals move, their depressed affect is demonstrated. They move slowly and very little.

They show psychomotor retardation. They may talk in low tones or in a depressed or monotone voice. Persons experiencing a hypomanic episode are busy, active, and involved. They have energy and are always on the go. They are always planning and doing things. Others notice their energy levels and mood changes. In many ways, the behavior of a patient in the manic phase is the opposite of that of a person in the depressed phase. Patients experiencing the manic phase are hyperactive and might be hypervigilant. They are restless, energized, and active. They talk and act fast. Their attire reflects the mania. Their clothes might have been put on in haste and are disorganized. Alternately, their garments are often too bright, colorful, or garish. They stand out in a crowd because their dress frequently attracts attention.

Affect/mood
In persons experiencing a depressed episode, sadness dominates the affect. These individuals feel sad, depressed, lost, vacant, and isolated. The "2 Hs" h opeless and h elplessoften accompany their mood. When in the presence of such patients, one comes away feeling sad and down. In persons experiencing a hypomanic episode, the mood is up, expansive, and often irritable. In persons experiencing a manic episode, the mood is inappropriately joyous, elated, and jubilant. These individuals are euphoric. They also may demonstrate annoyance and irritability, especially if the mania has been present for a significant length of time. Persons experiencing a mixed episode exhibit both depression and mania within a brief period (1 wk or less).

Thought content
Patients experiencing a depressed episode have thoughts that reflect their sadness. They are preoccupied with negative ideas and nihilistic concerns, and they tend to "see the glass as half empty." They are likely to focus on death and morbid persons. Many think about suicide. Patients experiencing a hypomanic episode are optimistic, forward thinking, and have a positive attitude. Patients experiencing a manic episode have very expansive and optimistic thinking. They may be excessively self-confident or grandiose. They often have a very rapid production of ideas and thoughts. They perceive their minds as being very active and see themselves as being highly engaging and creative. They are highly distractible and quickly shift from one person to another. Patients experiencing a mixed episode can oscillate dramatically between depression and euphoria, and they often demonstrate marked irritability.

Perceptions

Two forms of a major depression are described, one with psychotic features and the other without. With psychosis, the patient experiences delusions and hallucinations that are either consistent or inconsistent with the mood. In the former, the patients delusions of having sinned are accompanied by guilt and remorse, or the patient feels he or she is utterly worthless and should live in total deprivation and degradation; hence, the delusional content remains consistent with the depressed mood. In the latter, some patients experience delusions that are inconsistent with the depression, such as paranoia or persecutory delusions. Patients experiencing a hypomanic episode do not experience perceptual disturbances. Approximately three fourths of patients experiencing a manic episode have delusions. As in major depression, the delusional content is either consistent or inconsistent with the mania. Manic delusions reflect perceptions of power, prestige, position, self-worth, and glory. Patients experiencing a mixed episode might exhibit delusions and hallucinations consistent with either depression or mania or congruent to both.

Suicide/self-destruction
Patients experiencing a depressed episode have a very high rate of suicide. They are the individuals who attempt and succeed at killing themselves. Query patients to determine if they have any thoughts of hurting themselves (suicidal ideation) and any plans to do so. The more specific the plan, the higher the danger. Dubovsky reports that the highest lifetime suicide risk (17.08%) is in men with bipolar disorder and deliberate self-harm.[44] Bellivier and collogues found in a European study of adults with bipolar disorder that 29.9% had a history of at least 1 attempt of suicide (663 of 2219 patients who provided data on lifetime history of suicide attempts). Female sex, history of alcohol abuse, history of substance abuse, young age at first treatment for a mood episode, longer disease duration, greater depressive symptom severity (5-item Hamilton Depression Rating Scale [HAMD-5] total score), current benzodiazepine use, higher overall symptom severity (Clinical Global Impression-Bipolar Disorder [CGI-BP] scale: mania and overall score), and poor compliance were the baseline factors associated with a history of suicidal behavior.[45] As patients emerge from a period of depression, their suicide risk may increase. This may be because, as the illness remits, executive functions are improved to the point where the person is again capable of making and carrying out a plan while the subjective feeling of depression and accompanying suicidal thoughts persist. Patients experiencing a hypomanic or manic episode have a low incidence of suicide. In mixed episodes, the depressed phases put the patient at risk for suicide. For more information see the Medscape Reference article Suicide.

Homicide/violence/aggression

In patients experiencing a depressed episode, suicide generally remains the paramount issue. However, certain persons in the depths of a depression see the world as hopeless and helpless not only for themselves but also for others. Frequently, that perspective can create and lead to a homicide followed by a suicide. As an example, a 42-year-old mother of 2 was experiencing a significant depression as part of her bipolar disorder. She believed the earth was doomed and was a terrible place to dwell. Furthermore, she thought that if she died, her children would be left in a wretched place. Because of this view, she planned to kill her 2 children and then herself. Fortunately, her family recognized the state of affairs, which led to an emergency intervention and her hospitalization. Patients who are hypomanic frequently show evidence of irritability and aggressiveness. They can be pushy and impatient with others. Persons experiencing a manic episode can be openly combative and aggressive. They have no patience or tolerance for others. They can be highly demanding, violently assertive, and highly irritable. The homicidal element is particularly likely to emerge if these individuals have a delusional content to their mania. They are acting out of the grandiose belief that others must obey their commands, wishes, and directives. The patient may become violent toward those "disordent" subjects. If their delusions become persecutory in nature, they may defend themselves against others in a homicidal fashion. Persons experiencing a mixed episode may exhibit aggression, especially in the manic phases.

Judgment/insight
In persons experiencing a depressed episode, the depression clouds and dims their judgment and colors their insights. They fail to make important actions, because they are so down and preoccupied with their own plight. They see no tomorrow; therefore, planning for it is difficult. Frequently, persons in the middle of a depression have done things such as forgetting to pay their income taxes. At that time, they have little insight into their behavior. Often, others have to persuade them to seek therapy because of their lack of insight. Persons experiencing a hypomanic episode generally have good but expansive judgment. They may take on too many tasks or become overinvolved. Often, their distractibility impairs their judgment, and they have little insight into their driven qualities. They see themselves as productive and conscientious, not as hypomanic. In patients experiencing a manic episode, judgment is seriously impaired. These persons make terrible decisions in their work and family. They may invest the family fortune in very questionable programs, become professionally overinvolved in work activities or with coworkers, or start dramatically unsound fiscal or professional ventures. They ignore feedback, suggestions, and advice from friends, family, and colleagues. They have no insight into the extreme nature of their demands, plans, and behavior. Often, commitment proves the only way to contain them. In persons experiencing a mixed episode, major shifts in affect during short lengths of time severely impair their judgment and interfere with their insight.

Cognition
Impairments in orientation and memory are seldom observed in patients with bipolar disorder unless they are very psychotic. They know the time and their location, and they recognize people. They can remember immediate, recent, and distant events. In some cases of hypomanic and even manic episodes, their ability to recall information can be extremely vivid and expanded. In extremes of depression and mania, they may experience difficulty in concentrating and focusing.

Physical health
Although the MSE has been used here to highlight key aspects of the examination, the clinician must pay particular attention to the patients physical health. As Fagiolini points out, patients with bipolar disorder have a high incidence of endocrine disorders, cardiovascular disorders, and obesity, and these factors must be considered when medications are prescribed.[46, 47]

Complications
The main complications of bipolar disorder are suicide, homicide, and addictions. Suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. The risk of self-destructive behavior and death is lifelong. Hongs 2003 study demonstrates a genetic link between bipolar disorder and suicidal behavior, especially in white individuals.[48] According to one study, men with bipolar disorder are at higher risk for suicide.[49] The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study, a 2-year prospective, observational study, suggests the following characteristics found in patients with bipolar disorder who are suicidal, may help identify subjects at risk for suicidal behavior[45] :

Female gender A history of alcohol abuse A history of substance abuse Young age at first treatment for a mood episode Longer disease duration Greater depressive symptom severity (HAMD-5 total score) Current benzodiazepine use Higher overall symptom severity (CGI-BP: mania and overall score) Poor compliance

Homicidal patients, often in the manic phase, can be very demanding and grandiose. In this context, they are angered if others do not immediately comply with their wishes. This can make them turn dramatically violent. In addition, they can become homicidal by acting on delusions. Individuals with bipolar disorder are at risk for an addiction. This creates the problem of a dual diagnosis and, therefore, complicates treatment.

One area of major concern is the relationship between violent crime and bipolar disorder. This danger is particularly present and prominent with patients who have a substance abuse problem.[50] Although some persons with bipolar disorder may become violent, clinicians must be vigilant when treating patients with the dual diagnosis of substance abuse. Quality of life (QOL) has been an important way to look at the effects of mental illness. BPI results in diminished quality of life as measured by health utility and QOL and utility-based health-related quality of life. The QOL losses in patients with BPI were less than those in persons with schizophrenia. The patients with depression sustained the greatest loss in QOL.[51] In a study by Fiedorowicz et al, hypomania symptoms were frequently associated with progression to bipolar disorder, even when symptoms were low intensity; however, most patients did not have hypomania symptoms at baseline.[52] The study concluded that monitoring for progression to bipolar disorder is necessary in patients with long-term major depressive disorder. Some of the most challenging situations involve children and adolescents with severe emotional lability. Often, psychiatrists have applied the bipolar diagnosis to this group. Leibenluft reviewed this situation and concluded that children have increasingly been diagnosed with bipolar disorder.[53] In some cases, the criteria were clearly met, whereas other cases were less clear. Severe mood dysregulation is a syndrome formulated to describe the symptoms of children who do not clearly meet the criteria for bipolar disorder. Leibenlufts findings revealed that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders (not bipolar disorders) in adulthood. In fact, data suggest that children and adolescents with severe mood dysregulation have lower familiar rates of bipolar disorder than children and adolescents with bipolar disorder.

Approach Considerations
A number of reasons exist for obtaining selected laboratory studies. First, the practitioner needs to perform the tests to determine the diagnosis. Because bipolar disorder encompasses both depression and mania and because a significant number of medical causes for each state exists, an extensive range of tests is indicated. The basic principle remains, "do not miss a treatable medical cause for the mental status." Second, the condition necessitates use of a number of medications that require certain body systems to be working properly. For example, lithium requires an intact genitourinary (GU) system and can affect certain other systems, and certain anticonvulsants can suppress bone marrow. Third, because bipolar illness is a lifelong disorder, performing certain baseline studies is important to establish any long-term effects of the medications. A number of infections, especially chronic infections, can produce a presentation of depression in the patient. Any of the encephalitides can dramatically manifest as changes in mental status.

For more information, see Pediatric Bipolar Affective Disorder.

Blood Studies
Complete blood count
A complete blood count (CBC) with differential is used to rule out anemia as a cause of depression. Treatment, especially with certain anticonvulsants, may depress the bone marrowhence the need to check the red blood cell (RBC) and white blood cell (WBC) counts for signs of bone marrow suppression. Lithium may cause a reversible increase in the WBC count.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) is determined to look for any underlying disease process such a lupus or an infection. An elevated ESR would indicate such a disease process.

Fasting glucose
The fasting glucose level is measured to rule out diabetes. Atypical antipsychotics have been associated with weight gain and problems with blood glucose regulation in patients with diabetes.

Electrolytes
Serum electrolyte concentrations are measured to help diagnose problems, especially with sodium, that are related to depression. Hyponatremia (ie, low sodium) can manifest as a depression. Treatment with lithium can lead to renal problems and electrolyte problems. Low sodium levels can lead to higher lithium levels and lithium toxicity. Hence, in screening candidates for lithium therapy as well as those on lithium therapy, checking electrolytes is indicated.

Calcium
Serum calcium is assessed to diagnose hypercalcemia and hypocalcemia associated with mental status changes (eg, hyperparathyroidism). Hyperparathyroidism, as evidenced by an elevated calcium blood level, produces depression. Certain antidepressants, such as nortriptyline, affect the heart; therefore, checking calcium levels is important.

Proteins
Low serum protein levels found in patients who are depressed may be a result of not eating. Low serum protein levels increase the availability of certain medications because these drugs have less protein to which to bind.

Thyroid hormones

Thyroid tests are performed to rule out hyperthyroidism (mania) and hypothyroidism (depression). Treatment with lithium can cause hypothyroidism, which may also contribute to the rapid cycling of mood.

Creatinine and blood urea nitrogen

Kidney failure can present as depression. Treatment with lithium can affect urinary clearances, and serum creatinine and blood urea nitrogen (BUN) levels can increase. Therefore, carefully and regularly monitor these levels.

Substance and Alcohol Screening

Alcohol abuse and abuse of a wide variety of drugs can present as either mania or depression. For example, speed (ie, amphetamines) and cocaine abuse can present as a manialike disorder, and barbiturate abuse can present as a depressionlike disorder. A number of patients with bipolar affective disorder also have a drug or alcohol addiction; therefore, they have dual diagnoses. Performing a substance screen helps make this dual diagnosis. If the patient has a dual diagnosis, monitoring for these substances is important.

Other Laboratory Tests

Urine copper level testing is used to rule out Wilson disease, which produces mental changes. This disease is a rare condition that is easily missed. Antinuclear antibody testing is used to rule out lupus. An HIV test may be helpful. AIDS causes changes in mental status, including dementia and depression. A Venereal Disease Research Laboratory (VDRL) test may be indicated. Syphilis, especially in its later stage, alters mental status.

Magnetic Resonance Imaging

The total value of performing magnetic resonance imaging (MRI) in a patient with bipolar disorder remains unclear; however, a couple of reasons do exist for performing an imaging study. Because manic-depressive illness is a lifelong disease, a strong battery of studies rules out any other medical etiology and establishes a baseline. Some investigators report that patients with mania have hyperintensity in their temporal lobes.

Electrocardiography
Many of the antidepressants, especially the tricyclics and some of the antipsychotics, can affect the heart and cause conduction problems. Lithium also can lead to changes such as reversible flattening or inversion of T waves on electrocardiography (ECG). A pretreatment ECG is important.

Electroencephalography
The reasons for ordering electroencephalography (EEG) in patients with bipolar illness are as follows:

EEG provides a baseline and helps rule out any neurologic problems. Use this test to rule out a seizure disorder and brain tumor. If electroconvulsive therapy (ECT) is contemplated, an EEG may be helpful. EEG monitoring during ECT is used to determine the occurrence and duration of seizure. Some studies have shown that abnormalities in EEG findings have been indicative of anticonvulsant effectiveness. Specifically, an abnormal EEG finding may predict the response to valproate. Some patients may have seizures when on medications, especially antidepressants. In addition, lithium can cause diffuse slowing.

Approach Considerations
The treatment of bipolar disorder is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase. For example, a person who is extremely depressed and exhibits suicidal behavior requires inpatient treatment. In contrast, an individual with a moderate depression who still can work would be treated as an outpatient. Fortunately, most patients recover from the first manic episode, but their course beyond that is variable.[54] If the patient is in a short-term inpatient care unit and has not made significant progress, transfer to a long-term inpatient care unit might be in order. If the patient is in a depressed or manic phase and is not responding to medications, transfer the patient to a facility where electroconvulsive therapy (ECT) can be administered. A consultation with a psychiatric colleague or a psychopharmacologist is always appropriate if the patient does not respond to conventional treatment and medication. All patients with bipolar disorder need outpatient monitoring for both medications and psychotherapy. In addition, they need education. The schedule must be regular, with great flexibility if they need extra sessions. No surgical care is indicated for bipolar disorder. Historically, treatment was attempted with psychosurgical procedures, such as prefrontal lobotomy. Lobotomy is no longer used in the clinical care of patients with bipolar disorder. For more information, see Pediatric Bipolar Affective Disorder.

Inpatient Hospital Treatment

The indications for inpatient treatment in a person with bipolar disorder include the following:

Danger to self Danger to others

Total inability to function Total loss of control Medical conditions that warrant medication monitoring

A patient with bipolar disorder, especially one in a depressive episode, may present with a significant risk for suicide. Serious suicide attempts and specific ideation with plans constitute clear evidence of the need for constant observation and preventive protection; however, in other situations, the danger to the person may come from other aspects of the disease. For example, a person who is depressed enough to not eat might be at risk of death. Alternately, a person in extreme mania who foregoes sleep or food may be in a state of serious exhaustion. Patients with bipolar disorder can also become a threat to others. For example, a patient experiencing a severe depression believed the world was so bleak that she planned to kill her children to spare them from the worlds misery. In the other extreme, a delusional patient having a manic episode believed everyone was against him; he searched for a rifle in order to defend himself and to get them before they got him. Occasionally, depression is so profound that the person cannot function at all. Leaving such a person alone would be dangerous and not therapeutic. Sometimes, patients behaviors are totally out of control; this is a particular concern during a manic episode. In this situation, patients behaviors are so beyond limits that they destroy their career and can be harmful to those around them. Some patients with bipolar disorder have other medical conditions for which medication monitoring is warranted. For example, patients with certain cardiac conditions should be in a medical environment where the effects of the psychotropic medications can be monitored and observed closely. In the clearest case of the bipolar/depressed phase, the patient is suicidal and homicidal in a few situations (this can result in homicide followed by suicide). In these scenarios, commitment is in order and indicated. In other situations, the depression has led to an inability to work, eat, and function; hospitalization is also indicated in these cases. In the situation of a patient in bipolar/manic phase, there often is less clear and dramatic evidence of homicide or suicide, but a pattern of very poor judgment and impairment emerges. Because of the behavior during the manic phase, the person often does major damage to finances, career, and position in the community. This type of self-destructive mania calls for containment with good documentation and family support.

Partial Hospitalization or Day Treatment

In general, patients who are candidates for partial hospitalization or day treatment experience severe symptoms but have some level of control and a stable living environment. For example, a patient with severe depression who has thoughts of suicide but no plans to act upon them and who has a high degree of motivation can get well when given a great deal of interpersonal support, especially during the day, and with the help of a very involved and

supportive family. The family needs to be home every night and should be very concerned with the patients care. Partial hospitalization also offers a bridge to return to work. Returning directly to work often is difficult for patients with severe symptoms, and partial hospitalization provides support and interpersonal relationships.

Outpatient Treatment
Outpatient treatment has 4 major goals, as follows:

Look at areas of stress and find ways to handle them. The stresses can stem from family or work, but if they accumulate, they propel the person into mania or depression. This is a form of psychotherapy. Monitor and support the medication. Medications make an incredible difference. The key is to obtain the benefits while avoiding adverse effects. Patients are ambivalent about their medications. They recognize that the drugs help and prevent hospitalizations, yet they also resent that they need them. The job is to address their feelings and allow them to continue with the medications. Develop and maintain the therapeutic alliance. This is one of the many reasons for the practitioner to deal with the patients ambivalence about the medications. Over time, the strength of the alliance helps keep the patients symptoms at a minimum and helps the patient remain in the community. Provide education (see Patient Education). The clinician must help educate both the patient and the family about bipolar illness. Patients and families need to be aware of the dangers of substance abuse, the situations that would lead to relapse, and the essential role of medications. Support groups for patients and families are of tremendous importance. Psychotherapy helps patients with bipolar disorder. Schttle and colleagues looked at psychotherapy for patients, family, and caregivers. They found that although results were heterogeneous, most studies found relevant positive results in regard to decreased relapse rates, improved quality of life, increased functioning, or more favorable symptom improvement.[55]

Somatic health issues in individuals with bipolar disorder are ubiquitous, underrecognized, and suboptimally treated.[56] Therefore, practitioners must pay attention to patients medical conditions, including cardiovascular concerns, diabetes, endocrine problems, infections, urinary complications, and electrolyte imbalances. In view of the possible medical complications, medical follow-up is important. Persons with bipolar disorder often have difficulty obtaining primary physician care.[57]

Pharmacologic Therapy
Appropriate medication depends on the stage of the bipolar disorder the patient is experiencing. Thus, a number of drugs are indicated for an acute manic episode, primarily the antipsychotics, valproate, and benzodiazepines (eg, lorazepam, clonazepam). The choice of agent depends on the presence of symptoms such as psychotic symptoms, agitation, aggression, and sleep disturbance. (See the list of medications for bipolar disorder in the Table below.)

For patients with bipolar affective disorder in the depressed phase, the Medscape Reference article Depression provides antidepressant guidelines. Bauer and colleagues suggest 2 approaches. First, in a patient with bipolar depression who is not currently being treated with a mood-stabilizing agent (de novo depression, first or subsequent episode), options include quetiapine or olanzapine, with carbamazepine and lamotrigine as alternatives. Antidepressant are options for short-term use, but it remains controversial if it is better to administer them in combination with mood-stabilizing agents or as monotherapy. Most clinicians use antidepressants and an antimanic agent in combination. Second, if the patient is already optimally treated with a mood-stabilizing agent (appropriate dose, good compliance) such as lithium, an option would be lamotrigine. No evidence suggests additional benefit from antidepressants if a patient is already being treated with a mood stabilizer, but this often tried in practice.[58] One cautionary note of interest, Post and colleagues have found that the more different antidepressant trials the patient with bipolar disorder has received, the less responsive they become to treatment.[59] Lithium is the drug commonly used for prophylaxis and treatment of manic episodes. A recent study suggests that lithium may also have a neuroprotective role.[60] However, it is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[61] Lithium therapy may serve to protect and preserve the hippocampal volumes, in contrast to patients with major depression (ie, unipolar), who show diminished hippocampal volumes.[62] Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (ie, major depression). Ansari and Osser have developed a very useful algorithm to treat a bipolar patient in a depressed phase.[63] Finally, another set of medications is chosen for the maintenance and preventive phases of treatment. Diazgranados and colleagues have reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of an N -methyl-D -aspartate (NMDA) antagonist was administered.[64] Increasingly, the role of glutamate in mood disorders is being researched, and experimental evidence shows that the NMDA receptor antagonist ketamine may be helpful in short-term treatment of depression, even in the context of bipolar disorder. Although antidepressant medications are most often prescribed for patients with bipolar disorder who are experiencing an acute depression, a study found that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression.[65] Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs. These medications serve to stabilize the patients mood, as the name implies. They can also dampen extremes of mania or depression. Kessing et al found that, in general, lithium was superior to valproate.[66]

Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[67] These medications serve to stabilize the patients mood, as the name implies. They also can dampen extremes of mania or depression. Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, and asenapine) are also now frequently used to stabilize acute mania, or even to treat bipolar depression in some cases. The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,[68] as is the use of long-acting antipsychotics to help with the maintenance phase. According to a multiple treatments meta-analysis of treatments for acute mania, haloperidol, risperidone, and olanzapine are the most efficacious treatments, significantly outperforming primary mood stabilizers and other antipsychotic medications.[69] In the treatment of depression associated with bipolar disorder II, Swartz and associates report that 95% of relevant trials were published later than 2005. They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. Mixed support was noted for lamotrigine.[70] As outlined in a clinical practice guideline from the American Psychiatric Association,[71] benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. Additionally, the guideline states that manic symptoms may be treated with chlorpromazine, which was deemed superior to placebo in a randomized trial and was deemed comparable to lithium (for controlling manic and psychotic symptoms) in acute treatment comparison trials. Children and adolescents who have bipolar disorder are particularly challenging to treat. Hamrin and Iennaco have conducted an extensive literature review using research findings on medication effectiveness in this population and have developed guidelines and recommendations for medications and management approaches.[72] The US Food and Drug Administration (FDA) has approved several bipolar treatment regimens (see the Table below).[73]

Caution in polyantipsychotic therapy in bipolar disorder

Brooks et al assessed the safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder.[74] The study sought to evaluate the safety and tolerability of second-generation antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar disorder receiving open naturalistic treatment in the 22site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). After controlling for illness onset, age, baseline illness severity, and medication load, patients who were prescribed polytherapy compared with monotherapy had more dry mouth, sexual dysfunction, and constipation and were almost 3 times as likely to incur more psychiatric and medical care. No association with greater global functioning scores or percentage of days spent well was noted.

The study concluded that although polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and increased health service use but not with improved clinical status or function. Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions. Table. FDA-Approved Bipolar Treatment Regimens (Open Table in a new window) Trade Name Manic Mixed Maintenance Depression Valproate Depakote X Carbamazepine extended release Equetro X X Lamotrigine Lamictal X Lithium X X Aripiprazole Abilify X X X Ziprasidone Geodon X X Risperidone Risperdal X X Asenapine Saphris X X Quetiapine Seroquel X X Chlorpromazine Thorazine X Olanzapine Zyprexa X X X Olanzapine/fluoxetine combination Symbyax X In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis.[75] Generic Name

Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is useful in a number of instances. It has proven to be highly effective in the treatment of acute mania. Often, the severity of the symptoms, the lack of response to medications, or the presence of contraindications to certain medications necessitates the use of ECT. I In a study of 400 patients with acute mania who received ECT, 313 showed significant clinical improvement.

Dietary Measures
Unless the patient is on monoamine oxidase inhibitors (MAOIs), no special diet is required. Patients should be advised not to make significant changes in their salt intake, because increased salt intake may lead to reduced serum lithium levels and reduced efficacy, and reduced intake may lead to increased levels and toxicity. A meta-analysis by Starris et al found strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3. However, it does not improve bipolar mania.[76]

Exercise
Patients in the depressed phase are encouraged to exercise. Propose a regular exercise schedule for all patients, especially those with bipolar disorder. Both the exercise and the regular schedule are keys to surviving this illness. However, increases in exercise level, with increased perspiration, can lead to increased serum lithium levels and lithium toxicity.

Medication Summary
Appropriate medication depends on the stage of the bipolar disorder the patient is experiencing. The choice of agent depends on the presence of symptoms such as psychotic symptoms, agitation, aggression, and sleep disturbance. Drug categories include mood stabilizers, anticonvulsants, and antipsychotics.

Anxiolytics, Benzodiazepines
Class Summary
By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and the action of other inhibitory transmitters. View full drug information

Lorazepam (Ativan)

Lorazepam is a sedative hypnotic with a short onset of effects and a relatively long half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including the limbic and reticular formation. Monitor the patient's blood pressure after administering a dose of lorazepam. Adjust the dose as necessary. View full drug information

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

Mood stabilizers

Class Summary
Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[67] These medications serve to stabilize the patients mood, as the name implies. They also can dampen extremes of mania or depression. Lithium is the drug commonly used for prophylaxis and treatment of manic episodes. A recent study suggests that lithium may also have a neuroprotective role.[60] However, it is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[61] Lithium therapy may serve to protect and preserve the hippocampal volumes, in contrast to patients with major depression (ie, unipolar), who show diminished hippocampal volumes.[62] View full drug information

Lithium carbonate (Lithobid)

Lithium is considered a first-line agent for long-term prophylaxis in bipolar illness, especially for classic bipolar disorder with euphoric mania. It also can be used to treat acute mania, though it cannot be titrated up to an effective level as quickly as valproate can. Evidence suggests that lithium, unlike any other mood stabilizer, may have a specific antisuicide effect. Monitoring blood levels is critical with this medication.

Anticonvulsants
Class Summary
Anticonvulsants have been effective in preventing mood swings associated with bipolar disorder, especially in those patients known as rapid cyclers. For the depressed phase, mood stabilizers, such as lithium and lamotrigine, are preferred because antidepressants may propel a patient into a manic episode or exacerbate irritability in mixed-symptom mania. Gabapentin, although not a mood stabilizer, also may have anxiolytic properties. The most widely used anticonvulsants have been carbamazepine, valproate, and lamotrigine. More recently, topiramate and oxcarbazepine also are being tried. View full drug information

Carbamazepine (Equetro)

Carbamazepine is effective in patients who have not responded to lithium therapy. It also can act to inhibit seizures induced through the kindling effect, which is thought to occur by way of repeated limbic stimulation. Carbamazepine has been effective in treating patients who have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy. View full drug information

Valproate sodium, valproic acid, divalproex sodium (Depakene, Depakote, Depakote ER, Depacon, Stavzor)

Valproate has proven effectiveness in treating and preventing mania. It is classified as a mood stabilizer and can be used alone or in combination with lithium. It is useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination of valproic acid and valproate has been effective in treating persons in manic phase, with a success rate of 49%. View full drug information

Lamotrigine (Lamictal, Lamictal ODT)

Lamotrigine is an anticonvulsant that appears to be effective in the treatment of the depressed phase in bipolar disorders. It is used for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults treated for acute mood episodes with standard therapy.

Atypical Antipsychotics
Class Summary
Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. View full drug information

Asenapine (Saphris)

Asenapine's mechanism of action is unknown. It is indicated as monotherapy for the acute treatment of manic or mixed episodes that are associated with bipolar I disorder. Asenapine is also indicated as adjunctive therapy with lithium or valproate. Its efficacy thought to be mediated through a combination of antagonist activity at dopamine 2 and serotonin (5-HT2) receptors. Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors; dopamine D2, D3, D4, and D1

receptors; alpha-1 and alpha-2 adrenergic receptors; and histamine H1 receptors, with moderate affinity for H2 receptors. In vitro assays suggest antagonistic activity elicited at these receptors. Asenapine is indicated for acute treatment of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features). The prescribing information was updated in September 2011 to include data from 52 reports of type 1 hypersensitivity reactions. View full drug information

Ziprasidone (Geodon)

Ziprasidone is an atypical antipsychotic that is approved for the treatment of acute or mixed episodes that are associated with bipolar disorder. It can be used as maintenance treatment as an adjunct to lithium or valproate. View full drug information

Quetiapine (Seroquel, Seroquel XR)

Quetiapine is indicated for acute treatment of manic episodes that are associated with bipolar I disorder. It can be used as monotherapy or adjunctively with agents such as lithium or divalproex. View full drug information

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone is indicated for short-term treatment of acute manic or mixed episodes that are associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate. Risperidone can be used in adults and adolescents aged 10-17 years with bipolar I disorder. View full drug information

Aripiprazole (Abilify, Abilify Discmelt)

Aripiprazole is an atypical antipsychotic used for the acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate. View full drug information

Olanzapine (Zyprexa, Zyprexa Zydis)

Olanzapine is used for the acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder. It can be used alone or in combination with lithium or valproate. It can be used in adults and adolescents aged 13-17 years with bipolar I disorder. View full drug information

Olanzapine and fluoxetine (Symbyax)

The drug combination includes olanzapine, an atypical antipsychotic, and fluoxetine, a selective serotonin reuptake inhibitor. This drug is indicated for the acute treatment of depressive episodes associated with bipolar I disorder in adults. The clinical effects of this agent have not been studied in patients younger than 18 years.