Bipolar Affective Disorder

Introduction
Background

Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and persistent mental illnesses. Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated and/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. Bipolar disorder is a serious lifelong struggle and challenge.1

Bipolar disorder, or manic-depressive illness, has been recognized since at least the time of Hippocrates, who described such patients as "amic" and "melancholic." In 1899, Emil Kraepelin defined manic-depressive illness and noted that persons with manic-depressive illness lacked deterioration and dementia, which he associated with schizophrenia.

Bipolar disorder constitutes one pole of a spectrum of mood disorders including bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major depression. Bipolar I disorder is also referred to as classic manic-depression, characterized by distinct episodes of major depression contrasting vividly with episodes of mania, which lead to severe impairment of function. In comparison, bipolar II disorder is a milder disorder consisting 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 related information, see Medscape's Bipolar Disorder Resource Center.
Pathophysiology

The etiology and pathophysiology of bipolar disorder have not been determined, and no objective biological markers 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.

Bipolar disorder is a complex genetic disorder however, meaning that it is likely caused by multiple different common disease alleles, each contributing relatively low risk for the disorder on their own. It can be difficult to find such disease genes without very large sample sizes, on the order of thousands of subjects.

Fortunately, four genome-wide association studies of large samples of subjects with bipolar disorder have now been published2,3,4,5 and a collaborative analysis of the latter 3 studies give combined support for two particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a sample of 4,387 case and 6,209 controls.5 ANK3 is an adaptor protein found at axon initial segments that regulates the assembly of voltage-gated sodium channels and both ANK3 and subunits of the calcium channel are down-regulated in mouse brain in response to lithium, indicating a possible therapeutic mechanism of action of one of the most effective treatments for bipolar disorder.6

The first genome-wide association study of bipolar disorder used a much smaller sample size2 , an initial sample of 461 patients with bipolar disorder from the NIMH consortium and a follow-up sample of 563 patients collected in Germany, however it 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 (GSK3β). Lithium-mediated inhibition of GSK3β is thought to result in down-regulation of molecules involved in cell death and upregulation of neuroprotective factors (see below). Additionally, GSK3β is a central regulator of the circadian clock and lithium-mediated modulation of circadian periodicity is thought to be a critical component of its 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 manic-like behavior in mice.7

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 biological 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 specifically in the ventral tegmental area of the mouse brain. This area is rich in D2 receptors. Joseph Coyle hypothesizes in his commentary in the paper on 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.

Findings from gene expression studies of postmortem brain tissue from persons with bipolar disorder versus controls have yielded exciting new insights into the pathophysiology of the disorder. In particular, levels of expression of oligodendrocyte-myelin-related genes appear to be decreased in brain tissue from persons with bipolar disorder.8,9,10

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.

Interestingly, gene expression and neuroimaging studies of persons with schizophrenia and major depression also demonstrate similar findings, indicating that mood disorders and schizophrenia, may share some biological underpinnings, possibly related to psychosis. 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.

Another approach to delineating the pathophysiology of bipolar disorder involves studying changes in gene expression induced in rodent brains after administration of pharmacologic agents used to treat bipolar disorder. For example, investigators have demonstrated that 2 chemically unrelated drugs (lithium and valproate) used to treat bipolar disorder both up-regulate the expression of the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains. 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.

For a review of novel drugs and therapeutic targets for severe mood disorders that focus on increasing neuroplasticity and cellular resiliency please see Mathew et al, 2008.11

Post and associates proposed a mechanism involving electrophysiologic kindling and behavioral sensitization processes, a method that also resonates with the previous hypothesis based on neuronal injury. Post asserts that an individual who is susceptible to bipolar disorder experiences an increasing number of minor neurologic insults, perhaps caused by drugs of abuse, excessive glucocorticoid stimulation resulting from acute or chronic stress, or other factors, which eventually result in mania.12 Subsequently, sufficient brain damage might persist such that mania could recur even with no or minor environmental or behavioral stressors. This type of 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 clinical observations that the more episodes a person experiences, the more he or she will have in the future, underscoring the need for long-term treatment.
Frequency
United States

The lifelong prevalence of bipolar disorder in the United States has been noted to range from 1-1.6%. Studies indicate differences in lifetime prevalence estimates for bipolar I, bipolar II, and subthreshold bipolar disorders: 1.0% for bipolar I disorder, 1.1% for bipolar II disorder, and 2.4-4.7% for subthreshold bipolar disorders.8
International

Lifelong prevalence rate is 0.3-1.5%.
Mortality/Morbidity

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.
Race

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.
Sex

Bipolar I disorder occurs equally in both sexes; however, rapid-cycling bipolar disorder (4 or more episodes a year) is more common in women than in men. Incidence of bipolar II disorder is higher in females than in males.
Age

The age of onset of bipolar disorder varies greatly. The age range for both bipolar I and bipolar II 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.
Clinical
History

The diagnosis of bipolar I disorder requires the presence of a manic episode of at least 1 week's 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).9

* Manic episodes are characterized by the following symptoms:
o At least 1 week of profound mood disturbance is present, characterized by elation, irritability, or expansiveness.
o Three or more of the following symptoms are 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
o The mood disturbance is sufficient to cause impairment at work or danger to the patient or others.
o The mood is not the result of substance abuse or a medical condition.
* Hypomanic episodes are characterized by the following:
o The patient has an elevated, expansive, or irritable mood of at least 4 days' duration.
o Three or more of the following symptoms are 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
o The mood disturbance is observable to others.
o The mood is not the result of substance abuse or a medical condition.
* Major depressive episodes are characterized by the following:
o 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
o The symptoms cause significant impairment and distress.
o The mood is not the result of substance abuse or a medical condition.
* Mixed episodes are characterized by the following:
o Persons must meet both the criteria for mania and major depression; the depressive event is required to be present for 1 week only.
o The mood disturbance results in marked disruption in social or vocation function.
o The mood is not the result of substance abuse or a medical condition.
o The mixed symptomology is quite common in patients presenting with bipolar symptomology. This often causes a diagnostic dilemma.10

Physical

Use the Mental Status Examination (MSE) to diagnose bipolar disorder. This section highlights the major findings for a person with bipolar disorder. Because the patient's mental status depends on whether he or she is depressed, hypomanic, manic, or mixed, the various areas of the MSE are labeled according to the particular phase of the patient.

* Appearance
o Depressed episode: 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.
o Hypomanic episode: These patients 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.
o Manic episode: In many ways, the behavior of a patient in the manic phase reflects behavior opposite 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
o Depressed episode: Sadness dominates the affect of individuals experiencing a depressed episode. They feel sad, depressed, lost, vacant, and isolated. The "2 Hs" often accompany their mood, hopeless and helpless. When in the presence of such patients, one comes away feeling sad and down.
o Hypomanic episode: Their mood is up, expansive, and often irritable.
o Manic episode: The mood is inappropriately joyous, elated, and jubilant. They are euphoric. They also may demonstrate annoyance and irritability, especially if the mania has been present for a significant length of time.
o Mixed episode: The patient exhibits both depression and mania within a brief period (1 wk or less).
* Thought content
o Depressed episode: Patients experiencing a depression have thoughts that reflect their sadness. They are preoccupied with negative ideas and nihilistic concerns, and they metaphorically see "the glass as half empty." They are likely to focus on death and morbid persons. Many think about suicide.
o Hypomanic episode: Patients in this state are optimistic, forward thinking, and have a positive attitude.
o Manic episode: During the manic phase, patients have very expansive and optimistic thinking. They may be excessively self-confident and/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.
o Mixed episode: Patients in this state can oscillate dramatically between depression and euphoria, and they often demonstrate marked irritability.
* Perceptions
o Depression episode: Two forms of a major depression are described. One has psychotic features and the other does not. With psychosis, the patient experiences delusions and hallucinations that are either consistent or inconsistent with the mood. In the former, the patient's 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 contrast, some patients experience delusions that are inconsistent with the depression, such as paranoia or persecutory delusions.
o Hypomanic episode: Patients in this state do not experience perceptual disturbances.
o Manic episode: Approximately three fourths of patients in the manic phase 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.
o Mixed episode: Patients might exhibit delusions and hallucinations consistent with either depression or mania or congruent to both.
* Suicide/self-destruction
o Depressed episode: Depressed patients 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. 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 such that the person is again capable of making and carrying out a plan while the subjective feeling of depression and accompanying suicidal thoughts may persist.
o Hypomanic episode: Incidence of suicide is low.
o Manic episode: Incidence of suicide is low.
o Mixed episode: The depressed phases put the patient at risk for suicide.
* Homicide/violence/aggression
o Depressed episode: Generally, suicide remains the paramount issue. However, certain persons in the depths of a depression not only see the world as hopeless and helpless for themselves but also for others. Frequently, that perspective can create and lead to a homicide followed by a suicide. One example of this occurred when 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.
o Hypomanic episode: Patients who are hypomanic frequently show evidence of irritability and aggressiveness. They can be pushy and impatient with others.
o Manic episode: Persons in mania 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 particularly emerges 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. If their delusions become persecutory in nature, they may defend themselves against others in a homicidal fashion.
o Mixed episode: Persons in a mixed episode may exhibit aggression, especially in the manic phases.
* Judgment/insight
o Depressed episode: Depression clouds and dims these individuals' 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.
o Hypomanic episode: Generally, these people have good but expansive judgment. They may take on too many tasks or become over-involved. 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.
o Manic episode: The hallmark of this phase is seriously impaired judgment. They make terrible decisions in their work and family. They may invest the family fortune in very questionable programs. They may become professionally over-involved in work activities or with coworkers. They start a series of dramatic very unsound fiscal or professional ventures. They do not listen to any feedback, suggestions, or advice from friends, family, or colleagues. They have no insight into the extreme nature of their demands, plans, and behavior. Often, commitment proves the only way to contain them.
o Mixed episode: Major shifts in affect during short lengths of time severely impair their judgment and interfere with their insight.
o 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.

Although the Mental Status has been used here to highlight key aspects of the examination, the clinician must pay particular attention to the patient's physical health. As Fagiolini points out, patients with bipolar disorder have a high incidence of endocrine disorders, cardiovascular disorders, and obesity. These factors must be considerations when prescribing any medcications.12,13
Causes

Bipolar disorder has a number of contributing factors, including genetic, biochemical, psychodynamic, and environmental elements.

* Genetics
o Bipolar disorder, especially bipolar I, has a major genetic component. The evidence indicating a genetic role in bipolar disorder takes several forms.
o 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.
o Twin studies demonstrate a concordance of 33-90% for BPI in identical twins.
o 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 bipolar I 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 Medscape's CME Activity New Findings in Childhood Bipolar Disorder.
o Numerous genetic studies of BPI suggest that multiple different genetic loci, each of small effect, contribute to the affected phenotype. Four genome-wide association studies of bipolar disorder have now been published and a collaborative analysis of the 3 largest studies implicate 2 genes coding for proteins that either regulate or are subunits of ion channels ANK3 and CACNA1C.2,3,4,5 These findings suggest that bipolar disorder might be, in part, an ion channelopathy, similar to epilepsy. Another interesting candidate gene for mania is the CLOCK gene involved in circadian periodicity.7 A mouse CLOCK mutant was recently shown to exhibit features of mania.
o An interesting finding in psychiatric genetics heralds the future revision of DSM-IV-TR according to an etiological rather than descriptive basis. 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 for schizoaffective disorder was the same as the other 2 syndromes.14 This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum disorders as Berrettini15 previously speculated.
o A study by Tsuang et al further indicates the genetic contribution to manic-depressive illness with psychotic features. Their findings show the link between schizophrenia and bipolar disorder.16
o As discussed above, gene expression studies also demonstrate that persons with bipolar disorder, major depression, and schizophrenia share similar decreases in the expression of oligodendrocyte-myelin-related genes and abnormalities of white matter in various brain regions.
* Biochemical causes
o Multiple biochemical pathways likely contribute to bipolar disorder, which is why detecting one particular abnormality is difficult.
o A number of neurotransmitters have been linked to this disorder, largely based on patients' responses to psychoactive agents.
o Evidence is mounting of the contribution of glutamate to both bipolar and major depressions. A postmortem study of the frontal lobes with both these disorders revealed that the glutamate levels were increased.17
o The blood pressure drug reserpine, which depletes catecholamines from nerve terminals, was noted incidentally to cause depression. This led to the catecholamine hypothesis, which holds that an increase in epinephrine and norepinephrine causes mania and a decrease in epinephrine and norepinephrine causes depression.
o Drugs like cocaine, which also act on this neurotransmitter system, exacerbate mania.
o Other agents that exacerbate mania include L-dopa, which implicates dopamine and serotonin-reuptake inhibitors, which, in turn, implicate serotonin.
o Calcium channel blockers have been used to treat mania, which also may result from a disruption of calcium regulation in neurons. 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.
o 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.
o Tricyclic antidepressants can trigger mania.18
* Psychodynamic
o Many practitioners see the dynamics of manic-depressive illness as being linked through one common pathway.
o They see the depression as the manifestation of the losses, ie, the loss of self-esteem and the sense of worthlessness. Therefore, that mania serves as a defense against the feelings of depression. (Melanie Klein was one of the major proponents of this formulation.)
* Environmental
o 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.
o Pregnancy is a particular stress for women with a manic-depressive illness history and increases the possibility of postpartum psychosis.19
o Because of the nature of their work, certain individuals have periods of high demands followed by periods of few requirements. For example, one person was a landscaper and gardener. In the spring, summer, and fall, he was busy. During the winter, he was relatively inactive except for plowing snow. Thus, he appeared manic for a good part of the year, and then he would crash and hibernate for the cold months.
Differential Diagnoses
Anxiety Disorders
Posttraumatic Stress Disorder
Cushing Syndrome
Schizoaffective Disorder
Head Trauma
Schizophrenia
Hyperthyroidism
Systemic Lupus Erythematosus
Hypothyroidism

Other Problems to Be Considered

* Cancer
* Neurosyphilis
* Epilepsy (See the Medscape Epilepsy Resource Center.)
* Fahr disease
* AIDS
* Multiple sclerosis
* Medications (eg, antidepressants can propel a patient into mania; other medications may include baclofen, bromide, bromocriptine, captopril, cimetidine, corticosteroids, cyclosporine, disulfiram, hydralazine, isoniazid, levodopa, methylphenidate, metrizamide, procarbazine, procyclidine)
* Circadian rhythm desynchronization
* Attention deficit hyperactivity disorder (ADHD), especially in children and adolescents
* Cyclothymic disorder
* Multiple personality disorder
* Oppositional defiant disorder (in children)
* Substance abuse disorders (eg, with alcohol, amphetamines, cocaine, hallucinogens, opiates)

Workup
Laboratory Studies

Standard laboratory studies

A number of reasons exist to obtain the following 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.

* CBC count with differential: This test is used to rule out anemia as a cause of depression. Treatment, especially with certain anticonvulsants, may depress the bone marrow, hence the need to check the red and white blood counts for signs of bone marrow suppression. Lithium may cause a reversible increase in the WBC count.
* Sedimentation rate: This test is used to look for any underlying disease process such a lupus or an infection. An elevated sedimentation rate would indicate such a disease process.
* Glucose-level fasting: This test is used to rule out diabetes. Atypical antipsychotics have been associated with weight gain and problems with blood glucose regulation in patients with diabetes.
* Electrolytes: This test is used to diagnose electrolyte 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.
* Serum calcium: This test is used 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.
* Serum 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 they have less protein to which to bind.
* Thyroid studies: Perform thyroid tests to rule out hyperthyroidism (mania) and hypothyroidism (depression). Treatment with lithium can cause hypothyroidism, which may also contribute to the rapid cycling of mood.
* Substance and alcohol screen: 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.
* Urine copper level: This test is used to rule out Wilson disease, which produces mental changes. It is a rare disease that can be easily missed.
* Antinuclear antibody: This test is used to rule out lupus.

Infectious screening tests

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.

* HIV test: AIDS causes changes in mental status, including dementia and depression.
* VDRL test: Syphilis, especially in its later stage, alters mental status.

Serum creatinine and BUN

Kidney failure can present as depression. Treatment with lithium can affect urinary clearances, and serum creatinine and BUN can increase. Therefore, carefully and regularly monitor these levels.
Imaging Studies

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

Other Tests

* The reasons for ordering an electroencephalogram (EEG) in patients with bipolar illness are as follows:
o EEG provides a baseline and helps rule out any neurologic problems. Use this test to rule out a seizure disorder and brain tumor.
o 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.
o 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 divalproex.
o Some patients may have seizures when on medications, especially antidepressants. Also, lithium can cause diffuse slowing.
Treatment

For related CME, see Medscape's CME Activity, Advances in Bipolar Disorder Detection and Management.
Medical Care

The treatment of bipolar disorder is directly related to the phase of the episode, eg, 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.

* Inpatient hospital treatment: The indications for hospitalization in a person with bipolar disorder include the following:
o Danger to self: A patient, 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.
o Danger to others: Patients with bipolar disorder can 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 world's 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.
o Total inability to function: Occasionally, depression is so profound that the person cannot function at all. Leaving such a person alone would be dangerous and not therapeutic.
o Totally out of control: This is true especially 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.
o Medical conditions that warrant medication monitoring: 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.
* Partial hospitalization or a day-treatment program
o In general, these patients have severe symptoms but have a level of control and a stable living environment.
o 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 patient's 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.
o First, 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.
o Second, monitor and support the medication. Medications make an incredible difference. The key is to get the benefits and avoid 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.
o Third, develop and maintain the therapeutic alliance. This is one of the many reasons for the practitioner to deal with the patient's ambivalence about the medications. Over time, the strength of the alliance helps keep the patient's symptoms at a minimum and helps the patient remain in the community.
o The fourth aspect involves education. The clinician must help educate both the patient and the family about bipolar illness. They 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. See Patient Education.
o Somatic health issues in individuals with bipolar disorder are ubiquitous, under-recognized, and suboptimally treated.20 Therefore, practitioners must pay attention to patient's 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. These patients often have difficulty obtaining primary physician care.21

Surgical Care

No surgical procedure is indicated. Historically, treatment was attempted with psychosurgery, such as prefrontal lobotomy. Lobotomy is no longer used in the clinical care of patients with bipolar disorder.
Consultations

A consultation with a psychiatric colleague or a psychopharmacologist is always appropriate if the patient does not respond to conventional treatment and medication.
Diet

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.
Activity

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

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. Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. The broad range of antidepressants and electroconvulsive therapy are used for an acute depressive episode (ie, major depression). Finally, another set of medications is chosen for the maintenance and preventive phases of treatment.

Clinical experiences have shown that, if treated with mood-stabilizing drugs, patients with bipolar disorder have fewer episodes of mania and depression. These medications serve to stabilize the patient's mood, as the name implies. They also can dampen extremes of mania or depression.

Atypical antipsychotics 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 documented22 as is the use of long-acting antipsychotics to help with the maintenance phase23 .

Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. These include ziprasidone, quetiapine, risperidone, aripiprazole and olanzapine.

The current consensus is that the most effective treatment for acute mania is a combination of second-generation antipsychotic medications and mood-stabilizing medications.24
Follow-up
Further Inpatient Care

Electroconvulsive therapy (ECT) is useful in a number of instances. ECT 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 contradiction of certain medications necessitates the use of ECT. In a study of 400 patients with acute mania who received ECT, 313 showed significant clinical improvement.
Further Outpatient Care

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.

Fortunately, most patients recover from the first manic episode, but their course beyond that is variable.27
Inpatient & Outpatient Medications

The same medications are applicable in both settings.
Transfer

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 ECT can be administered.
Deterrence/Prevention

Prevention is the key to the long-term treatment of bipolar disorders, as follows:

* First, medications such as lithium serve as mood stabilizers.
* Second, psychoeducation is instituted for the patient and the patient's family. Both the patient and the patient's family must understand and recognize the importance of medication compliance and the early signs of mania and depression. This is critical.

Complications

The complications are suicide, homicide, and addictions. These are discussed in Special Concerns.
Prognosis

* Patients with bipolar I 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 bipolar I 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:
o Poor job history
o Alcohol abuse
o Psychotic features
o Depressive features between periods of mania and depression
o Evidence of depression
o Male sex
* Indicators of a better prognosis include the following:
o Manic phases (short in duration)
o Late age of onset
o Few thoughts of suicide
o Few psychotic symptoms
o Few medical problems

Patient Education

Treatment of patients with bipolar disorder involves initial and ongoing patient education. The 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.28

* An explanation of the biology of the disease must be provided. This decreases feelings of guilt and promotes medication compliance.
* Include information about 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.
* A strong therapeutic alliance remains an essential part of treatment and education.
* 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.
* Inform the patient about relapses within the total context of the disorder.
* Individual stories help patients and families. The National Institute of Mental Health (NIMH) has a story of a person with manic-depressive illness that can help the patient see the struggle and challenge from another perspective.29 Others have written about their family struggles and challenges.30

Important resources for patients and families to gain information on dealing with manic-depressive 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) 443-4279
Fax Back System, Mental Health FAX4U: (301) 443-5158
Email: nimhinfo@nih.gov
* Child & Adolescent Bipolar Foundation
1000 Skokie Blvd, Suite 570
Wilmette, IL 60091
Phone: (847) 256-8525
Email: cabf@bpkids.org
* Depression and Related Affective Disorders Association (DRADA)
2330 West Joppa Rd, Suite 100
Lutherville, MD 21093
Phone: (410) 583-2919
Email: 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 (800) 950-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) 443-5959
Fax: (703) 684-7722

For excellent patient education resources, visit eMedicine's Depression Center. Also, see eMedicine's patient education articles Depression and Bipolar Disorder.
Miscellaneous
Medicolegal Pitfalls

* Involuntary hospitalization for depression: 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.
* Involuntary hospitalization for mania: In the situation of a patient in bipolar/manic phase, often, less clear and dramatic evidence of homicide or suicide is present, 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 their finances, career, and position in the community. This type of self-destructive mania calls for containment with good documentation and family support.

Special Concerns

Several special concerns, including suicide, homicide, and addiction, accompany patients with bipolar disorder.

* 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. Hong's 2003 study demonstrates a genetic link between bipolar disorder and suicidal behavior, especially in white individuals.31
* 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. Also, 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.