Bipolar Disorder

Practice Essentials

Bipolar disorder, which in the ICD-10 is classified as bipolar disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge.^[1]

Signs and symptoms

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.

Manic episodes are feature 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^[2]:

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

Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 consecutive days’ duration. The diagnosis of hypomania requires at least three of the symptoms above. The difference being that in hypomania these symptoms are not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization and are not associated with psychosis.

Major depressive episodes are characterized as, for the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of the symptoms being either a depressed mood or characterized by a loss of pleasure or interest:^[2]

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
Feelings of worthlessness or excessive guilt
Decreased concentration ability or marked indecisiveness
Preoccupation with death or suicide; patient has a plan or has attempted suicide

See Clinical Presentation for more detail.

Diagnosis

Examination of patients with suspected bipolar disorder includes evaluation using the Mental Status Examination as well as assessment of the following:

Appearance
Affect/mood
Thought content
Perception
Suicide/self-destruction
Homicide/violence/aggression
Judgment/insight
Cognition
Physical health

Testing

Although bipolar disorder is diagnosed based on the patient’s history and clinical course, laboratory studies may be necessary to rule out other potential causes of the patient’s signs and symptoms as well as to have baseline results before administering certain medications.

Laboratory tests that may be helpful include the following:

CBC count
ESR levels
Fasting glucose levels
Electrolyte levels
Protein levels
Thyroid hormone levels
Creatinine and blood urea nitrogen levels
Liver and lipid panel
Substance and alcohol screening

Depending on the patient’s presentation, other laboratory tests may be indicated, which may include the following:

Urinary copper levels
Antinuclear antibody testing
HIV testing
VDRL testing

Electrocardiography is important in elderly patients and before antidepressant therapy. Electroencephalography and/or MRI may be appropriate for selected patients.

See Workup for more detail.

Management

The treatment of bipolar disorder is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase, and it may involve a combination of psychotherapy and medication. Always evaluate patients with mania, hypomania, or mixed episode, and those with bipolar depression, for suicidality, homicidality, acute or chronic psychosis, or other unstable or dangerous conditions.^[3]

Pharmacotherapy

Medications used to manage patients with bipolar disorder include the following:

Benzodiazepines - for acute agitation (eg, lorazepam, clonazepam)
Antimanic agents (eg, lithium)
Anticonvulsants (eg, carbamazepine, valproate sodium, valproic acid, divalproex sodium, lamotrigine)
First-generation antipsychotics (eg, inhaled loxapine, haloperidol)
Second-generation antipsychotics (eg, asenapine, ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, olanzapine and fluoxetine, cariprazine, clozapine, paliperidone, lurasidone)
Phenothiazine antipsychotics (eg, chlorpromazine)
Dopamine agonists (eg, pramipexole)

Nonpharmacotherapy

Psychotherapy may help to decrease relapse rates, improve quality of life, and/or increase functioning, or more favorable symptom improvement.^[4]

Electroconvulsive therapy may be useful in selected patients with bipolar disorder.

See Treatment and Medication for more detail.

View Video

What is bipolar disorder? Bipolar disorder, sometimes known as manic depression, is a type of mental disorder where people experience periods of extreme lows, known as depression, as well as periods of extreme highs, or manic episodes. Courtesy of Osmosis.org (https://www.osmosis.org/).

References

Pathophysiology

The pathophysiology of bipolar disorder, or manic-depressive illness (MDI), has not been determined, and no objective biologic markers correspond definitively with the disease state. However, twin, family, and adoption studies all indicate that bipolar disorder has a significant 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, and the heritability of bipolar I disorder (BPI) has recently been estimated at 0.73.^[7]

Genetics

The genetic component of bipolar disorder appears to be complex: The condition is likely to be caused by multiple different common disease alleles, 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.

When the genetics of bipolar disorder were first being studied, less precise tools were available, but they still yielded interesting information. Many loci are now known to be associated with the development of bipolar disorder. These loci are grouped as major affective disorder (MAFD) loci and numbered in the order of their discovery.

MAFD loci

MAFD1 is located at 18p and was originally described in a group of 22 patients with bipolar disorder.^[8]MAFD2 is located at Xq28 and, as such, is associated with an X-linked inheritance pattern. The notion of an X-linked form of bipolar disorder is not a new one, and at least one paper from the pregenetic era discusses this very possibility.^[9]MAFD3 is located at 21q22.13, and the association appears to be with the TRPM2 gene.^{[10, 11]}MAFD4 is located at 16p12 and has been associated with susceptibility to bipolar disease in a cohort of 41 Finnish families.^[12]

MAFD5 is located at 2q22-q24, and MAFD6 is located at 6q23-24. Interestingly, evidence suggests a strong interaction between genes located in these 2 regions. It has been concluded that the candidate gene in the MAFD5 locus shows epistatic interaction with the MAFD6 risk locus.^[13]MAFD7 is located at 22q12.1 and was detected using microsatellite markers in a North American population; a large region on 22q12 was associated with bipolar disorder in this study.^[14]Further study in this region showed a polymorphism in the promoter region of the XBP1 gene, which also showed susceptibility to bipolar disorder in a Japanese cohort.^[15]XBP1 appears to be involved mainly in immune system function; thus,its influence on the susceptibility of bipolar disorder is not understood.

MAFD8 is located at 10q21, and its discovery is the result of a large analysis of over 1.8 million variants in 4387 cases of bipolar disorder.^[16]The association in this study appears to be with the ANK3 gene, which is a gene of marked interest and is therefore discussed at length below.^[16]MAFD9 is located at 12p13.3, and its discovery is the result of the same large analysis as MAFD8. The association in this study appears to be with the CACNA1C gene.^[16]Like ANK3, it remains a gene of interest^[17]and is also mentioned below.

Genome-wide association studies

The first series of genome-wide association studies (GWASs) for bipolar disorder were published in 2007 and 2008,^{[18, 19, 20, 16]}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 4387 cases and 6209 controls.^[16]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 one of the most effective treatments for bipolar disorder.^[21]

Further evidence for association of bipolar disorder to CACNA1C was reported in 2011 in an ever-growing sample (numbering 11,974 bipolar disorder cases and 51,792 controls at the time of the report), providing overwhelming support for this gene as a bipolar susceptibility locus.^[17]

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 GWASs also underscored that bipolar disorder and schizophrenia could indeed share common susceptibility genes on chromosome 6.^[22]

In 2013, the Cross-Disorder Group of the Psychiatric Genomics Consortium published results of their large GWAS study of psychiatric disorders, reporting that specific single-nucleotide polymorphisms (SNPs) are associated with range of childhood- or adult-onset psychiatric disorders.^[23]The study comprised a combined sample of 33,332 persons with schizophrenia, bipolar disorder, major depression, attention deficit disorder and autism spectrum disorders and 27,888 controls of European ancestry.^[23]

Specific expression of common genetic variants at different times during development, or in different regions of the brain, and in concert with other genetic variants could help to explain differences in disease phenotypes. Genetic markers in 4 regions were associated with all 5 disorders, including variants in the CACNA1C gene, another gene for an L-type voltage-gated calcium channel subunit, CACNB2, and markers on chromosomes 3p21 and 10q24.^[23]Although specific variants from CACNA1C showed the strongest association when only samples from individuals with bipolar disorder, major depression and schizophrenia were evaluated, the majority of regions seemed to be associated with all 5 disorders, suggesting that common risk alleles contribute to each phenotype, an effect described as pleiotropy. As noted by the authors, although CACNB2 was not identified in previous GWASs of a combined bipolar and schizophrenia sample, it was one of the main signals detected in an independentGWASs of Han Chinese individuals with bipolar disorder.^[23]

Although the first GWAS of bipolar disorder used a much smaller sample size than subsequent attempts, 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, it still yielded interesting observations that will need to be followed up in the larger samples mentioned earlier.^[18]For example, 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 downregulation of molecules involved in cell death and upregulation of neuroprotective factors.

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 lithium’s 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 maniclike behavior in mice,^[24]including 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 specifically in the ventral tegmental area of the mouse brain.^[25]This area is rich in D2 receptors. Joseph Coyle hypothesized 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.^[26]

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.^[27]Such promising measures for bipolar disorder include structural brain phenotypes, sleep and activity measures, neurocognitive measures, and gene expression studies.^[28]This collaborative research effort under the aegis of the National Institute of Mental Health (NIMH) has been termed the Bipolar Phenome Project.^[29]

Newer GWASs continue to find additional genes of interest which appear to be associated with an increased risk of bipolar disorder. One study showed an association between bipolar disorder and the NCAN gene.^[30]This gene is expressed in the brain and is involved in the migration of cells within the brain. In a mouse model, it was observed that the NCAN product is most prevalent in the hippocampus. There was no phenotypic defect in NCAN -deficient mice, but subtle effects could not be excluded.^[30]

Although most of the present research does not stratify by sex, a recent study looked at association between estrogen receptor binding site variation with bipolar disorder in females. In particular, the association is with the transglutaminase 2 (TGM2) gene, which is known to be under estrogenic control.^[31]This is further evidence of the heterogeneity of bipolar disorder and also presents evidence to explain the differences in the epidemiology of bipolar disorder between women and men.

Of additional interest, a number of studies suggest that certain large copy number variants (greater than 100 kb) (includes both deletions and duplications) are associated with psychiatric disease, with bipolar disease and schizophrenia being the most commonly associated.^[32]The implication is that possession of one of these copy number variants may modify the phenotype to those who are at risk of psychiatric disease.^[32]

When investigators looked at microarray results for 1001 patients with bipolar disorder and 1033 controls to quantify the risk of deletions throughout the genome for patients with bipolar disorder, they found that 16.2% of patients with bipolar disorder had deletions, whereas 12.3% of controls had deletions. In addition, patients who had bipolar disorder and deletions more frequently had onset of mania before age 18 years.^[4]

Gene expression studies

Gene expression studies are one way of measuring the relative activity or inactivity of genes, and they have already been proven useful for illuminating the pathophysiology of psychiatric disorders, including bipolar disorder. For example, 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-myelin–related genes appear to be decreased in brain tissue from persons with bipolar disorder.^{[33, 34, 35, 36]}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.^{[37, 38]}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.^{[37, 38]}Of note, many widely used psychotropic treatments including those for bipolar disorder share signaling pathways that affect myelination, its plasticity, andrepair;such pathways may promote myelination of neurons.^[39]

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 biologic 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 upregulate the expression of the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains.^[40]These types of studies are also performed on human tissue by exposing cultured monocytes from peripheral blood to lithium and other factors.

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.^[41]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.^[42]

Post et al had previously proposed a mechanism involving electrophysiologic kindling and behavioral sensitization processes, which resonates with the neuronal injury hypothesis.^[24]They asserted that a person who is susceptible to bipolar disorder experiences an increasing number of minor neurologic insults—such as those induced by drugs of abuse, stress-related excessive glucocorticoid stimulation, oxidative or immune-mediated damage—that eventually resulting in mania that further compromises the injured neurons.^[24]Sufficient brain damage might persist to cause mania to recur even with no or minor environmental or behavioral stressors.

Post et al’s 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.

For more information, see the Medscape Reference topic Genetics of Bipolar Disorder.

References

Etiology

A number of factors contribute to bipolar disorder, or manic-depressive illness (MDI), including genetic, biochemical, psychodynamic, and environmental factors.

Genetic factors

Bipolar disorder, especially bipolar type I (BPI) disorder, has a major genetic component, with the involvement of the ANK3,CACNA1C, and CLOCK genes.^{[18, 19, 20, 16, 17, 25, 43]}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. One logitudinal study found that subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of subsequent manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder. High-risk offspring, compared with offspring of parents without bipolar disorder, also had higher rates of ADHD, disruptive behavior disorders, anxiety disorders, and substance use disorders.^[44]

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 disorder, even if they are reared in a home with adopted parents who are not affected. Frey and colleagues’ work supports the genetic contributions in bipolar disorder.^{[45, 46]}

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.^[47]This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum disorders, as Berrettini^[48]previously speculated and that has been confirmed in the recent large-scale GWAS studies mentioned above.^[17]

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.

Duffy et al. described the emergent course of bipolar disorder in offspring of affected parents. They assessed 279 high-risk children and 87 control subjects and found the cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years. The clinical course of the affected parent was associated with that of the affected child. In addition, childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively. Depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively.^[49]

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.

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.

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 of these neurotransmitters in its etiology. Other agents that exacerbate mania include L-dopa, which implicates dopamine and serotonin-reuptake inhibitors, which in turn implicate serotonin.

One study found that as many as a third of all patients with substance use-induced psychosis may go on to develop schizophrenia or bipolar disorder within five years. Researchers studied 6,788 patients who received a diagnosis of substance-induced psychosis over a 20-year period and who did not have any previous record of treatment for schizophrenia spectrum disorders or bipolar disorder. Overall, 32.2% of all patients with substance use-induced psychosis converted to either schizophrenia or bipolar disorder. Cannabis-induced psychosis carried the highest risk of conversion for patients at a rate of 47.4%.^[50]

Evidence is mounting of the contribution of glutamate to both bipolar disorder and major depression. A postmortem study of the frontal lobes of individuals with these disorders revealed that the glutamate levels were increased.^[51]

Calcium channel blockers have been used to treat mania, which may also result from a disruption of intracellular 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 upregulates 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.

Neurophysiologic 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.^[52]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 anatomic alterations in bipolar disorder in brain networks associated with the experience and regulation of emotions.^[52]

White matter hyperintensities(WMH) are more common in individuals with bipolar disorder than in those without, and one study found that WMH burden appears to be associated with familiality and type of BP. The study used MRIs to measure total volume of all WMH in 45 individuals with bipolar disorder (bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II)) and 7 of their unaffected relatives compared to 32 healthy subjects. Results show that BP-I patients had a significantly higher mean total volume of WMH (p < 0.05) than that of healthy subjects. In addition, researchers observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of all participants.^[53]These findings suggest a possible structural marker for bipolar disorder.

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.^[54]

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. For example, pregnancy is a particular stress for women with a manic-depressive illness history and increases the possibility of postpartum psychosis.^[55]

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 who was busy in the spring, summer, and fall became relatively inactive during the winter, except for plowing snow. Consequently, he appeared manic for a good part of the year, and then he would crash and hibernate during the cold months.

There have been a number of studies linking bipolar disorder and increased amount of sunlight during the day (aka, springtime). In one study, researchers collected data from 5536 patients at 50 sites in 32 countries on six continents; onset of bipolar disorder occurred at 456 locations in 57 countries. Results show a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. The study suggests that a large increase in springtime solar insolation may impact the onset of bipolar disorder, particularly in those patients with a family history of mood disorders.^[56]

Futhermore, another study assessed psychiatric admission of 730 patients and found the admission rate for patients with bipolar disorder was significantly higher during May, June, and July; months with maximum sunlight exposure. These findings suggest photoperiod is a key element in bipolar disorder.^[57]

Pharmacological factors

There is the risk that antidepressant treatment may propel the patient into a manic episode. Researchers investigated the association between antidepressant therapy and the later onset of mania/bipolar disorder. They analyzed the electronic records of 21,012 adults presenting to South London and Maudsley National Health Service (NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare in the United Kingdom, between April 1, 2006 and March 31, 2013 with unipolar depression. The overall incidence rate of mania/bipolar disorder was 10.9 per 1000 person-years. The peak incidence of mania/bipolar disorder was seen in patients aged between 26 and 35 years (12.3 per 1000 person-years). Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder ranging from 13.1 to 19.1 per 1000 person-years. Results suggest that in people with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder. These findings highlight the importance of considering risk factors for mania when treating people with depression.^[58]

References

History

Correct diagnosis of a disorder leads to proper effective treatment. No where is that more relevant than in diagnosing a patient with bipolar disorder, or manic-depressive illness (MDI).

Perform a thorough clinical assessment for patients with a manic, hypomanic, or mixed episode, or those with a bipolar depression episode, including information about the patient’s clinical and psychosocial status, medical and psychiatric comorbidities, current and past medications as well as medication compliance, and substance use.^[3]Obtain a detailed review of symptoms, symptom severity, and their effects on daily functioning in combination with the use of a standard tool.^[3]

The diagnosis of bipolar disorder type I (BPI) requires the presence of a manic episode of at least 1 week’s duration or 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 DSM-5.^[2]The Department of Veterans Affairs and Department of Defense (VA/DOD) recommend using a standardized rating scale such as the Young Mania Rating Scale to assess the severity of a manic episode.^[3]

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 consecutive days’ duration. At least 3 of the following symptoms are also present^[2]:

Grandiosity or inflated self-esteem
Diminished need for sleep
Pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity 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. The episode is not severe enough to cause social or occupational impairment.

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
Feelings of worthlessness or excessive guilt
Decreased concentration ability or marked indecisiveness
Preoccupation with death or suicide; patient has a plan or has attempted suicide

Symptoms cause significant impairment and distress and are 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^[68]and has prompted a revision to the definition of bipolar disorder in DSM-5. With the aim of capturing mixed symptoms more effectively, the “mixed episode” diagnosis has been eliminated in favor of a “mixed features specifier” that could be added to any mood bipolar disorder diagnosis.^[69]Other specifiers include anxious distress, rapid cycling, mood-congruent psychotic features, catatonia, peripartum onset and seasonal pattern.

Of interest, when investigating bipolar mixed states, Swann and colleagues concluded that although controversy exists regarding the definitions and properties of mixed states, the concept of mixed states and their characteristics over a range of clinical definitions and diagnostic methods has remained consistent.^[70]Moreover, “distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.”^[70]

In addition to the well-known differences between manic and hypomanic episodes, other key differences exist between BPI and BPII that may be used to help distinguish between the 2 types of conditions. Data from 1429 bipolar patients included in the National Epidemiological Survey on Alcohol and Related Conditions showed significant differences between BPI and BPII patients in unemployment, a history of a suicide attempt, depressive symptoms (eg, weight gain, feelings of worthlessness), and the presence of specific phobias.^[71]

References

Blood Studies

Complete blood count

A complete blood count (CBC) with differential is used to rule out anemia as a cause of depression in bipolar disorder, or manic-depressive illness (MDI). Treatment, especially with certain anticonvulsants, may depress the bone marrow—hence 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 often indicates an underlying disease process.

Fasting glucose

In some cases, a fasting glucose level is indicated to rule out diabetes. In addition, atypical antipsychotics have been associated with weight gain and problems with blood glucose regulation in patients with diabetes, therefore, a baseline fasting glucose should be obtained.

Electrolytes

Serum electrolyte concentrations are measured to help diagnose electrolyte problems, especially with sodium, that are related to depression. Treatment with lithium can lead to renal problems and electrolyte problems, and 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 is assessed to diagnose hypercalcemia and hypocalcemia associated with mental status changes (eg, hyperparathyroidism). An elevated calcium blood level can cause depression or mania. 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. Such low levels increase the availability of certain medications, because these drugs have less protein to which to bind.

Biomarkers

Researchers and clinicians have long sought biological indicators for mental disorders, particularly for affective disorders. Frye and colleagues took an important first step in this process by analyzing 7.5 ml blood samples from patients diagnosed with unipolar depression (n=52), bipolar II disorder (n=49), and bipolar I disorder (n=46) as well as 141 control subjects. They found six proteins significantly associated with mood disorders including unipolar and bipolar depression. Growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls; MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls; and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. These findings suggest that proteomic panels may be helpful in identifying and distinguishing mood disorders.^[72]

Thyroid hormones

Thyroid tests are performed to rule out hyperthyroidism (mania) and hypothyroidism (depression). Treatment with lithium can cause hypothyroidism, and hypothyroidism may cause rapid cycling of mood, especially in women.

In a study to assess the relationship between bipolar disorder and thyroid dysfunction, Krishna et al found that elevated T3 hormone had a statistically significantly association with bipolar disorder.^[73]In fact, patients with bipolar disorder were 2.55 times more commonly associated with thyroid dysfunction than individuals without bipolar disorder.^[73]

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; however, other signs and symptoms of kidney failure will appear first. Carefully and regularly monitor renal function.

Liver and lipid panel

Antipsychotics agents have also been associated with changes in patients’ lipid profiles, potentially resulting in dyslipidemia (eg, hypertriglyceridemia), as well as liver damage/dysfunction.

Other laboratory tests

Although not a routine screening test in bipolar disorder and unnecessary in patients with normal liver function test results, urine copper level testing may be performed to rule out Wilson disease, which produces mental changes. Wilson disease is a rare condition that is easily missed.

Antinuclear antibody testing is used to rule out lupus.

Testing for human immunodeficiency virus (HIV) may be helpful. Acquired immunodeficiency syndrome (AIDS) causes changes in mental status, including dementia and depression.

Obtaining a Venereal Disease Research Laboratory (VDRL) test may be indicated in selected patients. Syphilis, especially in its later stage, alters mental status.

References

Approach Considerations

Always evaluate patients with mania, hypomania, or mixed episode, and those with bipolar depression, for suicidality, acute or chronic psychosis, or other unstable or dangerous conditions.^[3]

The treatment of bipolar disorder, or manic-depressive illness (MDI), 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.^[75]

It is important to determine whether current medications may be causing the patient’s manic, hypomanic, or mixed manic episode. In such patients, discontinue antidepressants or other mania-inducing agents. However, antidepressants known to have associated discontinuation syndromes should be tapered over several weeks.^[3]

Evaluate and closely monitor patients with bipolar depression for the risk for mood destabilization or switching to mania and for the presence of emergent symptoms following initiation of pharmacotherapy for a depressive episode.^[3]Initiate an antipsychotic agent in patients with bipolar depression with psychotic features, and consider psychosocial interventions (eg, psychoeducation; psychotherapy strategies such as cognitive behavioral therapy [CBT], interpersonal and social rhythm therapy [IPSRT], family focused therapy; chronic care model-based interventions).

The patient’s response to treatment may depend on the number of previous episodes of bipolar disorder. In a report that analyzed pooled data, the importance of early intervention was demonstrated with better treatment responses in individuals who had earlier stages of illness.^[76]Bipolar patients who experienced fewer previous mania episodes (1-5) displayed a twofold increase in the treatment response rate to olanzapine relative to those who had already experienced more than 5 previous episodes.^[76]In patients with depression, the response rates were also significantly higher in patients with fewer episodes, although the findings were only for 2 of the measured responses. In the maintenance studies, groups with fewer previous episodes (1-5 or 6-10) experienced a 40-60% reduction in the risk of relapse to either mania or depression compared to the group that had more than 10 previous episodes.^[76]

If the patient is in a short-term inpatient care unit and has not made significant progress, reevaluate the management strategy. Transfer to a long-term inpatient care unit might also be considered. 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. Additionally, 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, these individuals need education regarding their condition. The schedule must be regular, with great flexibility if they need extra sessions.

The 2010 Veterans Administration/Department of Defense (VA/DoD) clinical practice guideline for management of bipolar disorder recommends reassessing patients who start treatment for acute bipolar mania, hypomania, or mixed episodes every 1-2 weeks for at least 6 weeks.^[3]Patients with severe mania who are not hospitalized should be reassessed every 2-5 days until symptoms improve. An absence of any significant symptoms of mania or depression for 2 months should be considered to be full remission and assessment of symptoms should then be continued periodically to monitor for relapse.^[3]

Evaluate the patient’s response to treatment with the same standardized tool at follow-up visits, after changes in therapy, and with periodic assessments until complete remission has been reached.^[3]The Center for Quality Assessment and Improvement in Mental Health (CQAIMH) provides assessment and screening tools for bipolar disorder and suicide at: http://www.cqaimh.org/stable.html

No surgical care is indicated for bipolar disorder. Historically, treatment was attempted with psychosurgical procedures, such as prefrontal lobotomy. However, lobotomy is no longer used in the clinical care of patients with bipolar disorder.

References

Indications for Inpatient Management

Patients diagnosed with bipolar mania or depression and severe symptoms must be referred for urgent/emergent mental health intervention.^[3]The indications for inpatient treatment in a person with bipolar disorder, or manic-depressive illness (MDI), include the following:

Danger to self
Danger to others
Delirium
Marked psychotic symptoms
Total inability to function
Total loss of control (eg, excessive spending, undertaking a dangerous trip)
Medical conditions that warrant medication monitoring (eg, substance withdrawal/intoxication)

Patients with a possible diagnosis of bipolar depression must also be referred for urgent/emergent mental health intervention if they present with serious delusion, visual/auditory hallucinations, confusion, catatonic behavior, extreme negativism/mutism, and/or inappropriate affect of a bizarre or odd quality.^[3]

A patient with bipolar disorder, especially one in a depressive episode, may present with a significant risk for suicide, especially those with an early onset of symptoms.^[77]Serious suicide attempts and specific ideation with plans constitute clear evidence of the need for constant observation and preventive protection; consider referring these individuals to mental health specialty care.^[3]Occasionally, depression is so profound that the person cannot function at all; thus, the danger to the person may come from other aspects of the disease. For example, a person in extreme mania who foregoes sleep or food may be in a state of serious exhaustion. Leaving such a person alone would be dangerous and not therapeutic.

Goldstein and associates followed the mental health of 413 youths diagnosed with bipolar disorders and found that 76 (18%) attempted suicide at least once within 5 years of study; of these youths, 31 (8% of the overall group and 41% of those who attempted suicide) made many attempts.^[77]The investigators concluded that bipolar disorder with early onset is associated with high suicide attempt rates. Therefore, the patient’s severity of depression at presentation and their family history of depression must be considered when evaluating youths with bipolar disorder and their suicide risk.^[77]

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 world’s misery.

Sometimes, patient’s behaviors are totally out of control, which 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. For example, 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.

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, institutioinal commitment is in order and indicated. In other situations, the depression has led to an inability of the patient to work, eat, and function; hospitalization is also indicated in these cases.

In the situation of a patient in the bipolar/manic phase, although the patient does not show clear and dramatic evidence of homicide or suicide, a pattern of very poor judgment and impairment emerges. Because of their 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.

References

Pharmacologic Therapy

Appropriate medication depends on the stage of the bipolar disorder, or manic-depressive illness (MDI), the patient is experiencing. Thus, a number of drugs are indicated for an acute manic episode, primarily the antipsychotic agents, 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 Table 1, below.) For patients with bipolar disorder in the depressed phase, the Medscape Reference article Depression provides antidepressant guidelines.

Table 1. FDA-Approved Bipolar Treatment Regimens

View Table

See Table

Bauer and colleagues have suggested 2 approaches to treatment options in bipolar patients.^[82]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.^[82]Antidepressants are options for short-term use, but it remains controversial as to whether it is better to administer them in combination with mood-stabilizing agents or as monotherapy. 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.^[82]

One cautionary note of interest: Post and colleagues found that the more different antidepressant trials the patient with bipolar disorder has received, the less responsive they become to treatment.^[83]

Inhaled loxapine (Adasuve) is the first noninjectable therapy approved by the FDA to treat acute agitation associated with schizophrenia and bipolar disorder type I (BPI). The FDA approval was based on 2 phase III studies of 658 individuals; statistically significant reductions in agitation were apparent starting 10 minutes following administration compared with placebo, and these effects were sustained at 2 hours.^{[84, 85]}

Severe mania or mixed episodes

Combined therapy with an antipsychotic agent and another antimanic medication is recommended for patients with severe mania or mixed episodes, with or without psychotic features.^[3]Thus, lithium, a drug commonly used for prophylaxis and treatment of manic episodes, or valproate may be used in combination with antipsychotic agents (eg, severe mania: olanzapine, quetiapine, aripiprazole, risperidone, or possibly ziprasidone; severe mixed episode: aripiprazole, olanzapine, risperidone, haloperidol or possibly quetiapine or ziprasidone).^[3]

Despite the serious side effects associated with clozapine, the Veterans Administration/Department of Defense (VA/DoD) suggest this drug may be added to existing medications if it was successfully used previously for severe mania or mixed episodes or if other antipsychotic agents are unsuccessful.^[3]

Reevaluate nonhospitalized patients being treated for severe mania or mixed episodes every 2-5 days until symptomatic improvement, and adjust medication dosages and regimens as needed.^[3]The therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL. If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached.^[3]

Mania/hypomania or mixed episodes

Initiate lithium, valproate, carbamazepine, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone in patients with mania.^[3]In patients with mixed episodes, initiate therapy with valproate, carbamazepine, aripiprazole, olanzapine, risperidone, or ziprasidone. Consider clozapine, haloperidol, or oxcarbazepine in patients with mania or mixed episodes, and consider lithium or quetiapine in those with mixed episodes.^[3]

Researchers have demonstrated a link between a locus on chromosome 21 and patient response to lithium. The study found that a single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response. Carriers of the SNPs had significantly lower rates of disease relapse than carriers of the alternate alleles.^[86]

It is not recommended that topiramate, lamotrigine, and gabapentin be used to treat patients with mania or mixed episodes.^[3]

Bipolar depression

The American Psychiatric Association's (APA) 2005 guideline watch for the treatment of patients with bipolar disorder noted that medications having the strongest evidence for efficacy for the acute treatment of depression in BPI are the olanzapine-fluoxetine combination, quetiapine, and lamotrigine.^[59]Furthermore, there is some evidence that pramipexole may be helpful as an adjunctive agent, although only modest evidence exists for the efficacy of an antidepressant with adjunctive mood stabilizer. Antidepressants in the absence of a mood stabilizer are not recommended by the APA for BPI patients.^[59]

Monotherapy

The VA/DoD considers first-line monotherapy in adult patients with bipolar depression to include quetiapine, lamotrigine, or lithium.^[3]Cautiously consider olanzapine monotherapy due to its adverse effects. Second-line pharmacotherapy includes the combination of olanzapine/fluoxetine owing to its side-effect profile of weight gain, diabetes risk, and hypertriglyceridemia.^[3]

Although the VA/DoD found insufficient evidence for or against the use of valproate, carbamazepine, topiramate, risperidone, ziprasidone, or clozapine for managing bipolar depression, it did advise against aripiprazole monotherapy in patients with acute bipolar depression, except in cases in which there was^[3]: (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

A post hoc analysis of older adults (aged >55 years) showed lurasidone was significantly more effective than placebo as monotherapy. Adjunctive therapy with lurasidone was not associated with significant improvement. Both monotherapy and adjunctive therapy with lurasidone were safe and well tolerated in this older adult population.^[87]

Combination therapy

In patients whose bipolar depression is unresponsive to monotherapy, consider the combination of lithium with lamotrigine.^[3]Alternatively, consider short-term augmentation of antidepressant agents with a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), bupropion, and monoamine oxidase inhibitor (MAOI); patients using this treatment strategy must be closely monitored for triggering of manic symptoms.^[3]

As in severe mania or severe mixed episodes, consider adding clozapine for augmentation, and closely monitor the patient for metabolic or other adverse effects.^[3]Because of the known complications involved with clozapine, it is recommended that a psychiatric consultation be initiated.

The VA/DoD found insufficient evidence for or against the use of augmentation with aripiprazole, olanzapine, risperidone, haloperidol, oxcarbazepine, topiramate, ziprasidone, valproate, or carbamazepine in bipolar depression.^[3]However, the VA/DoD advised against the use of gabapentin and tricyclic antidepressant agents (TCAs) for monotherapy or augmentation in patients with acute bipolar depression, except in cases in which there was^[3]: (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

Dosing or medication adjustments

Switch to another effective treatment for patient intolerance to side effects. For patients that switch into mania or hypomania or enter a mixed manic state, follow the recommendations discussed above in Mania/hypomania or mixed episodes.

Reevaluate patients every 1-2 weeks for a minimum of 6 weeks. As noted earlier, the therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL.^[3]If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached.^[3]

In patients with a partial treatment response (no response 2-4 weeks after initiation of an adequate medication dose), consider augmenting the medication with additional agents as discussed under Combination therapy,discontinuing the current drug (tapered withdrawal with monitoring for antidepressant syndrome and mood destabilization) and switching to another effective agent, or electroconvulsive therapy (ECT) if multiple trials of switching medications/augmentation strategies have been unsuccessful.^[3]

Other considerations

A study by Bauer et al suggested that lithium may also have a neuroprotective role.^[88]However, this agent 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.^[89]

Atypical antipsychotics are increasingly being used for the treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (i.e. major depression). However, ECT may also be considered for patients with severe mania or treatment-resistant mania, those who prefer ECT, and pregnant women with severe mania.^[3]Ansari and Osser developed a very useful algorithm for the Harvard South Shore Program to treat a bipolar patient in a depressed phase through “an organized, sequential, and evidence-supported approach.”^[90]Finally, another set of medications is chosen for the maintenance and preventive phases of treatment.

Diazgranados and colleagues reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of the N -methyl-D -aspartate (NMDA) antagonist ketamine was administered.^[91]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. However, it is important to note that the benefit of such treatment disappeared after 4 days.

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.^[92]

Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.^[93]These medications not only serve to stabilize the patient’s 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.^[94]

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.

In the treatment of depression associated with bipolar disorder type II, Swartz and associates reported that 95% of relevant trials were published later than 2005.^[95]They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. However, mixed support was noted for lamotrigine.^[95]

Maintenance

The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,^[96]as is the use of long-acting antipsychotics to help with the maintenance phase. The APA’s 2005 guideline watch for the treatment of patients with bipolar disorder considered both lamotrigine and lithium to have substantial utility in the maintenance treatment of patients with bipolar disorder.^[59]

Popovic et al suggested the use of a Polarity Index to guide the choice of maintenance therapy in bipolar patients.^[97]Based on results from randomized, placebo-controlled trials, the investigators indicated that this index may provide a measure of the relative preventive antimanic versus antidepressive efficacy of drugs that are used to treat bipolar disorder.^[97]They defined a Polarity Index value greater than 1.0 as having a relative greater antimanic prophylactic efficacy, whereas a value less than 1.0 would have a relative greater antidepressive efficacy. The following are this study’s polarity indices results for maintenance drugs in bipolar disorder^[97]:

Risperidone: 12.09
Aripiprazole: 4.38
Ziprasidone: 3.91
Olanzapine: 2.98
Lithium: 1.39
Quetiapine: 1.14
Lamotrigine: 0.40

Note that Popovic et al indicated the respective polarity indices for valproate and oxcarbazepine were potentially unreliable owing to the failure of their maintenance trials.^[97]

There have been concerns that ziprasidone may have adverse effects on body weight, fasting lipids, and fasting glucose. When Pappadopulos et al looked at a comprehensive set of analyses of metabolic alternations in patients on this medication, they found no significant differences between the ziprasidone and placebo groups in levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies.^[98]

In July 2017, the FDA approved aripiprazole extended-release injectable suspension (Abilify Maintena) for maintenance monotherapy of bipolar I disorder (BP-I) in adults. Approval was based on a 52-week, Phase 3, double-blind, placebo-controlled, randomized withdrawal study that enrolled patients experiencing a manic episode at screening and met the DSM-IV-TR criteria for BP-I. The primary endpoint showed once monthly aripiprazole IM significantly delayed recurrence time of any mood episode in adults having a manic episode at screening compared with placebo (P < 0.0001). Significant differences were observed between treatment arms in delaying time to recurrence of both manic and mixed episodes. No substantial differences, however, were seen for depressive mood episodes.^[99]

According to a multiple treatments meta-analysis of treatments for acute mania, the most efficacious treatments are haloperidol, risperidone, and olanzapine, significantly outperforming primary mood stabilizers and other antipsychotic medications.^[100]In several randomized, double-blind, controlled studies, olanzapine monotherapy was significantly more effective in treating manic or mixed episodes than haloperidol^[101]or divalproex monotherapy.^[102]The adjunctive use of olanzapine with divalproex or lithium,^[103]or of risperidone with divalproex or lithium, was also significantly more effective than divalproex or lithium alone.^{[104, 105]}

As outlined in the APA’s 2002 clinical practice guideline,^[106]benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. With the increased risk of substance use disorder in patients with bipolar disorder, long-term use of benzodiazepines is generally discouraged. Additionally, the guideline stated 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, and their discussion is beyond the scope of this article (see the Medscape Reference article Pediatric Bipolar Affective Disorder). However, Hamrin and Iennaco developed guidelines and recommendations for medications and management approaches after an extensive literature review using research findings on medication effectiveness in this population.^[107]

There is evidence that risperidone may be the best first-line treatment for childhood mania, as shown in a randomized controlled trial with patients aged 6 to 15 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) diagnosis of BPI (manic or mixed phase).^[108]Specifically, risperidone was significantly more effective than lithium or divalproex sodium for the initial treatment of childhood mania; however, use of risperidone had the potential for serious metabolic side effects.^[108]

Caution in polyantipsychotic therapy in bipolar disorder

In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis.^[109]

In a study that 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 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), Brooks et al concluded that although polytherapy was fairly common in bipolar disorder, it was also associated with increased side effects (eg, dry mouth, sexual dysfunction, and constipation) and increased health service use (almost threefold) but not with improved clinical status or function.^[110]Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.^[110]

References

Complications

The main complications of bipolar disorder, or manic-depressive illness (MDI), are suicide, homicide, and addictions.

Previously or currently 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 et al’s study demonstrated a genetic link between bipolar disorder and suicidal behavior, especially in white individuals.^[113]According to a more recent study, men with bipolar disorder are at higher risk for suicide.^[114]

The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study, a 2-year prospective, observational study, suggested the following characteristics found in patients with bipolar disorder who are suicidal may help identify subjects at risk for suicidal behavior^[115]:

Female sex
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 (5-item Hamilton Depression Rating Scale [HAMD-5] total score)
Current benzodiazepine use
Higher overall symptom severity (Clinical Global Impression-Bipolar Disorder [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, and they can turn dramatically violent. In addition, these individuals 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.^[116]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. Bipolar disorder type I (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.^[117]

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.^[118]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.^[119]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. Leibenluft’s 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.

References

What is bipolar affective disorder (manic-depressive illness)?How is mania in bipolar affective disorder (manic-depressive illness) characterized?How is hypomania diagnosed in bipolar affective disorder (manic-depressive illness)?How are major depressive episodes diagnosed in bipolar affective disorder (manic-depressive illness)?What is included in the Mental Status Exam for bipolar affective disorder (manic-depressive illness)?Which lab tests are performed in the evaluation of bipolar affective disorder (manic-depressive illness)?What is the role of electrocardiography in the evaluation of bipolar affective disorder (manic-depressive illness)?What is the focus of treatment for bipolar affective disorder (manic-depressive illness)?Which medications are used in the treatment of bipolar affective disorder (manic-depressive illness?)What are the nondrug treatment options for bipolar affective disorder (manic-depressive illness)?What is bipolar affective disorder (manic-depressive illness)?How is bipolar affective disorder (manic-depressive illness) characterized?What are the symptoms of mania in bipolar affective disorder (manic-depressive illness)?How are unipolar (major depressive) disorder and bipolar affective disorder (manic-depressive illness) differentiated?How is bipolar affective disorder defined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, (DSM-5)?What is the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of genetics in the pathogenesis of bipolar affective disorder (manic-depressive illness)?What is the role of the major affective disorder (MAFD) loci in the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of the ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) genes in the pathogenesis of bipolar affective disorder (manic-depressive illness)?Why is the CACNA1C gene associated with bipolar affective disorder (manic-depressive illness)?What is the evidence of common susceptibility genes for bipolar affective disorder (manic-depressive illness) and schizophrenia?What is the evidence of single-nucleotide polymorphisms (SNPs) as etiologic factors in bipolar affective disorder (manic-depressive illness)?How are differences in bipolar affective disorder (manic-depressive illness) phenotypes explained?What is association of the DGKH gene and lithium regulation in bipolar affective disorder (manic-depressive illness)?What is the role of glycogen synthase kinase 3-beta (GSK3?) in the pathophysiology of bipolar affective disorder (manic-depressive illness)?What are endophenotypes in bipolar affective disorder (manic-depressive illness)?What is the role of the NCAN gene in the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of estrogen receptor binding site variation in the pathophysiology of bipolar affective disorder (manic-depressive illness) in females?What is the association between large copy number genetic variants and bipolar affective disorder (manic-depressive illness)?How does deletions throughout the genome increase the risk for bipolar affective disorder (manic-depressive illness)?What have gene expression studies increase understanding of the pathophysiology of bipolar affective disorder (manic-depressive illness)?What findings on gene expression and neuroimaging studies suggest bipolar affective disorder (manic-depressive illness) and schizophrenia share a biologic etiology?What findings of gene expression in rat brains have increased understanding of the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of hippocampal neurons in the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of neuroplasticity and cellular resiliency in the pathophysiology of bipolar affective disorder (manic-depressive illness)?What is the role of electrophysiologic kindling and behavioral sensitization processes in the pathophysiology of bipolar affective disorder (manic-depressive illness)?Which factors contribute to the etiology of bipolar affective disorder (manic-depressive illness)?What is the genetic component to the etiology of bipolar affective disorder (manic-depressive illness)?What are the risk factors for the development of bipolar disorder type I (BPI)?What has been learned from twin studies about the etiology of bipolar disorder type I (BPI)?What has been learned from adoption studies about the etiology of bipolar disorder type I (BPI)?What is etiologic relationship between schizophrenia spectrum disorders and bipolar affective disorder (manic-depressive illness)?What findings from gene expression studies support a shared etiologic factors for bipolar affective disorder (manic-depressive illness), major depression, and schizophrenia?What is the role of biochemical pathways in the etiology of bipolar affective disorder (manic-depressive illness)?What is the catecholamine hypothesis of the etiology of bipolar affective disorder (manic-depressive illness?)Which drugs are implicated in the etiology of bipolar affective disorder (manic-depressive illness)?What is the etiologic relationship between substance-induced psychosis and bipolar affective disorder (manic-depressive illness [manic-depressive illness])?What is the role of glutamate in the etiology of bipolar affective disorder (manic-depressive illness)?What is the role of calcium regulation in the etiology of bipolar affective disorder (manic-depressive illness)?Which biochemical factors may contribute to the etiology of bipolar affective disorder (manic-depressive illness)?What is the role of neurophysiologic factors in the etiology of bipolar affective disorder (manic-depressive illness)?What is the role of white matter hypersensitivities (WMH) in the etiology of bipolar affective disorder (manic-depressive illness)?What is the role of psychodynamic factors in the etiology of bipolar affective disorder (manic-depressive illness)?Which personality disturbances are associated with bipolar affective disorder (manic-depressive illness)?What is the role of environmental factors in the etiology of bipolar affective disorder (manic-depressive illness)?What is the role of pharmacological factors in the etiology of bipolar affective disorder (manic-depressive illness)?What is the prevalence of bipolar affective disorder (manic-depressive illness) in the US?What is the global prevalence of bipolar affective disorder (manic-depressive illness)?In what age groups is the onset of bipolar affective disorder (manic-depressive illness) most likely?How does the incidence of bipolar affective disorder (manic-depressive illness) vary by sex?What are the morbidity and mortality rates for bipolar affective disorder (manic-depressive illness)?Which factors are associated with a worse prognosis for bipolar affective disorder (manic-depressive illness)?Which factors are associated with a better prognosis for bipolar affective disorder (manic-depressive illness)?What is the role of patient education in the treatment of bipolar affective disorder (manic-depressive illness)?What is the focus of patient education in bipolar affective disorder (manic-depressive illness)?Why is patient education on the biology of bipolar affective disorder (manic-depressive illness) important?Why is patient education on the stressors in bipolar affective disorder (manic-depressive illness) important?How is sharing individual stories of patients with bipolar affective disorder (manic-depressive illness) important?What are the important sources of information for patients and families about bipolar affective disorder (manic-depressive illness)?What is improved with a correct diagnosis of bipolar affective disorder (manic-depressive illness)?What should be the focus of history in suspected bipolar affective disorder (manic-depressive illness)?What is required for the diagnosis of bipolar disorder type I (BPI)?Which symptoms must be present for the diagnosis of manic episodes in bipolar affective disorder (manic-depressive illness)?Which symptoms must be present for the diagnosis of hypomanic episodes in bipolar affective disorder (manic-depressive illness)?Which symptoms must be present for the diagnosis of major depressive episodes in cases of bipolar affective disorder (manic-depressive illness)?When is the DSM-5 mixed features specifier used in the diagnosis of bipolar disorder?How is bipolar affective disorder (manic-depressive illness) characterized?Which symptoms must be present for the diagnosis of manic episodes in bipolar affective disorder (manic-depressive illness)?Which symptoms must be present for the diagnosis of hypomanic episodes in bipolar affective disorder (manic-depressive illness)?Which symptoms must be present for the diagnosis of major depressive episodes in cases of bipolar affective disorder (manic-depressive illness)?How is bipolar affective disorder (manic-depressive illness) diagnosed?Which conditions should be included in the differential diagnoses of bipolar affective disorder (manic-depressive illness)?What are the differential diagnoses for Bipolar Disorder?What is the role of lab studies in the evaluation of bipolar affective disorder (manic-depressive illness)?Why should encephalitis be included in the differential diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of complete blood count (CBC) in the diagnosis of bipolar affective disorder (manic-depressive illness)?How does lithium affect lab test findings in the evaluation of bipolar affective disorder (manic-depressive illness)?What is the role of erythrocyte sedimentation rate in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of fasting glucose in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of electrolyte measurement in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of serum calcium assessment in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the significance of low protein levels in bipolar affective disorder (manic-depressive illness)?What is the role of biomarkers in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of thyroid tests in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of creatinine and blood urea nitrogen (BUN) levels in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of the liver and lipid panel in the diagnosis of bipolar affective disorder (manic-depressive illness)?Which lab tests may be indicated in the diagnosis of bipolar affective disorder (manic-depressive illness)?Why should alcohol and substance abuse be included in the differential diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of a substance screen in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of MRI in the diagnosis of bipolar affective disorder (manic-depressive illness)?What is the role of ECG in the management of bipolar affective disorder (manic-depressive illness)?When is EEG indicated for bipolar affective disorder (manic-depressive illness)?What factors affect treatment response in bipolar affective disorder (manic-depressive illness)?How is the response to treatment in bipolar affective disorder (manic-depressive illness) evaluated?Which dangerous conditions should be evaluated for in patients with bipolar affective disorder (manic-depressive illness)?How is treatment for bipolar affective disorder (manic-depressive illness) directed?How should medications be evaluated prior to treatment for bipolar affective disorder (manic-depressive illness)?What monitoring in needed following initiation of medication for the treatment of bipolar affective disorder (manic-depressive illness)?What are treatment options for bipolar affective disorder (manic-depressive illness) nonresponsive to medications?What is the role of outpatient monitoring in bipolar affective disorder (manic-depressive illness)?What are the Veterans Administration/Department of Defense (VA/DoD) clinical practice treatment guidelines for bipolar affective disorder (manic-depressive illness)?What is the role of surgery in the treatment of bipolar affective disorder (manic-depressive illness)?What are the indications for inpatient treatment in bipolar affective disorder (manic-depressive illness)?When is urgent or emergency mental health intervention indicated in bipolar affective disorder (manic-depressive illness)?How is the risk of suicide managed in bipolar affective disorder (manic-depressive illness)?Which factors increase the likelihood of suicide in patients with bipolar affective disorder (manic-depressive illness)?How might a patient with bipolar affective disorder (manic-depressive illness) be a threat to others?Which behaviors during a manic episode are indications for hospitalization in bipolar affective disorder (manic-depressive illness)?What comorbid medical conditions may require monitoring in patients with bipolar affective disorder (manic-depressive illness)?During which phase of bipolar affective disorder (manic-depressive illness) might a patient be both suicidal and homicidal?What are indications for hospitalization during a manic phase of bipolar affective disorder (manic-depressive illness)?When is partial hospitalization or day treatment indicated for bipolar affective disorder (manic-depressive illness)?What are the major goals of outpatient treatment for bipolar affective disorder (manic-depressive illness)?What are the benefits of psychotherapy in the treatment of bipolar affective disorder (manic-depressive illness)?What are somatic health issues associated with bipolar affective disorder (manic-depressive illness)?What are Collaborative Chronic Care Models (CCMs) for the treatment of bipolar affective disorder (manic-depressive illness)?Which pharmacologic treatment regimens are used in the treatment of bipolar affective disorder (manic-depressive illness)?What are the medication treatment options for bipolar affective disorder (manic-depressive illness)?Why should multiple antidepressant trials be avoided in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of inhaled loxapine in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of combined therapy in the treatment of bipolar affective disorder (manic-depressive illness)?What are the treatment regimens for nonhospitalized patients with bipolar affective disorder (manic-depressive illness)?What are the pharmacologic treatments for mania/hypomania or mixed episodes in bipolar affective disorder (manic-depressive illness)?Which medications are recommended by the American Psychiatric Association's (APA) for the acute treatment of depression in bipolar disorder type I (BPI)?What are the VA/DoD guidelines for monotherapy in the treatment of bipolar affective disorder (manic-depressive illness)?What are the VA/DoD guidelines for combination therapies in the treatment of bipolar affective disorder (manic-depressive illness)?What is the importance of dosing or medication adjustments in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of lithium in the treatment bipolar affective disorder (manic-depressive illness)?What is the role of atypical antipsychotics in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of ketamine in the treatment of bipolar affective disorder (manic-depressive illness)?What is the efficacy of antidepressants for the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of mood-stabilizing drugs in the treatment of bipolar affective disorder (manic-depressive illness)?Which atypical antipsychotics are used in the treatment of bipolar affective disorder (manic-depressive illness)?What are the pharmacologic treatment options for depression in bipolar disorder type II (BPII)?What is the role of mood stabilizers and antipsychotic medications in maintaining therapy for bipolar affective disorder (manic-depressive illness)?What is the Polarity Index and how is it used in the treatment of bipolar affective disorder (manic-depressive illness)?What are the adverse effects of ziprasidone in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of aripiprazole in the treatment of bipolar affective disorder (manic-depressive illness)?What are the most efficacious treatments for bipolar affective disorder (manic-depressive illness)?What is the efficacy of benzodiazepines in the treatment of bipolar affective disorder (manic-depressive illness)?What guidelines are available for the treatment of children and adolescents with bipolar affective disorder (manic-depressive illness)?What is the role of risperidone in the treatment of bipolar affective disorder (manic-depressive illness) in children?What is the risk of lamotrigine in the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of second-generation antipsychotic (SGA) polytherapy for the treatment of bipolar affective disorder (manic-depressive illness)?What is the role of electroconvulsive therapy (ECT) in the treatment of bipolar affective disorder (manic-depressive illness)?When is electroconvulsive therapy (ECT) indicated for the treatment of bipolar affective disorder (manic-depressive illness)?When is electroconvulsive therapy (ECT) recommended by the VA/DoD for primary treatment of bipolar affective disorder (manic-depressive illness)?What are the dietary restrictions for patients with bipolar affective disorder (manic-depressive illness)?What are the activity restrictions for patients with bipolar affective disorder (manic-depressive illness)?What are the main complications of bipolar affective disorder (manic-depressive illness)?What is the risk of suicide in patients with bipolar affective disorder (manic-depressive illness)?Which factors may increase the risk for suicidal behaviors in bipolar affective disorder (manic-depressive illness)?What are behaviors of patients at risk for homicidal behavior in bipolar affective disorder (manic-depressive illness)?What are the complications associated with addiction in patients with bipolar affective disorder (manic-depressive illness)?What are the increased risks in patients with dual diagnosis of substance abuse and bipolar affective disorder (manic-depressive illness)?How does bipolar affective disorder (manic-depressive illness) affect quality of life (QOL)?How common is progression to bipolar affective disorder (manic-depressive illness) in patients with hypomania?What is the risk of bipolar affective disorder (manic-depressive illness) in children and adolescents with severe emotional lability?What is the risk for bipolar affective disorder (manic-depressive illness) in children with severe mood dysregulation?What is the role of prevention in the management of bipolar affective disorder (manic-depressive illness)?What is included in long-term monitoring of affective disorder (manic-depressive illness)?How frequently should patients with bipolar affective disorder (manic-depressive illness) be monitored?What are the long-term treatment and prophylactic regimens for bipolar affective disorder (manic-depressive illness)?How are medications selected for the treatment of bipolar affective disorder (manic-depressive illness)?Which medications in the drug class Antiparkinson Agents, Dopamine Agonists are used in the treatment of Bipolar Disorder?Which medications in the drug class Antipsychotics, Phenothiazine are used in the treatment of Bipolar Disorder?Which medications in the drug class Antipsychotics, 1st Generation are used in the treatment of Bipolar Disorder?Which medications in the drug class Antipsychotics, 2nd Generation are used in the treatment of Bipolar Disorder?Which medications in the drug class Anticonvulsants are used in the treatment of Bipolar Disorder?Which medications in the drug class Mood stabilizers are used in the treatment of Bipolar Disorder?Which medications in the drug class Anxiolytics, Benzodiazepines are used in the treatment of Bipolar Disorder?

References

Generic Name	Trade Name	Manic	Mixed	Maintenance	Depression
Valproate	Depakote	X	X
Carbamazepine extended release	Equetro	X	X
Lamotrigine	Lamictal			X
Lithium		X		X
Aripiprazole	Abilify	X	X	X
Ziprasidone	Geodon	X	X	X
Risperidone	Risperdal	X	X	X
Asenapine	Saphris	X	X	X
Quetiapine	Seroquel	X	X	X	X
Chlorpromazine	Thorazine	X
Cariprazine	Vraylar	X	X	X	X
Olanzapine	Zyprexa	X	X	X	X^*
Olanzapine/fluoxetine combination	Symbyax				X
Lurasidone	Latuda				X
FDA = United States Food and Drug Administration. In combination with fluoxetine Source:* Prescribing information for individual drugs; Gutman DA, Nemeroff C.Medscape Education. Atypical antipsychotics in bipolar disorder.Available at: http://www.medscape.org/viewarticle/554128. Accessed: June 27, 2007.^[81]

Bipolar Disorder

Practice Essentials

Signs and symptoms

Diagnosis

Management

What is bipolar disorder? Bipolar disorder, sometimes known as manic depression, is a type of mental disorder where people experience periods of extreme lows, known as depression, as well as periods of extreme highs, or manic episodes. Courtesy of Osmosis.org (https://www.osmosis.org/).

Background

Pathophysiology

Genetics

Etiology

Genetic factors

Biochemical factors

Neurophysiologic factors

Psychodynamic factors

Environmental factors

Pharmacological factors

Epidemiology

United States statistics

International statistics

Age-related differences in incidence

Sex-related differences in incidence

Prognosis

Patient Education

History

Physical Examination

Approach Considerations

Blood Studies

Complete blood count

Erythrocyte sedimentation rate

Fasting glucose

Electrolytes

Proteins

Biomarkers

Thyroid hormones

Creatinine and blood urea nitrogen

Liver and lipid panel

Other laboratory tests

Substance and Alcohol Screening

Magnetic Resonance Imaging

Electrocardiography

Electroencephalography

Approach Considerations

Indications for Inpatient Management

Considerations for Partial Hospitalization or Day Treatment

Considerations of Outpatient Treatment

Pharmacologic Therapy

See Table

Severe mania or mixed episodes

Mania/hypomania or mixed episodes

Bipolar depression

Other considerations

Maintenance

Caution in polyantipsychotic therapy in bipolar disorder

Electroconvulsive Therapy

Dietary and Activity Measures

Complications

Prevention and Long-Term Monitoring

Medication Summary

Lorazepam (Ativan)

Clonazepam (Klonopin)

Class Summary

Lithium carbonate (Lithobid)

Class Summary

Carbamazepine (Equetro, Epitol, Carbatrol, Tegretol, Tegretol XR)

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

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Topiramate (Topamax, Qudexy XR, Trokendi XR, Topamax Sprinkle)

Class Summary

Asenapine (Saphris)

Ziprasidone (Geodon)

Quetiapine (Seroquel, Seroquel XR)

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

Aripiprazole (Abilify, Abilify Maintena, Aristada)

Olanzapine (Zyprexa, Zyprexa Zydis)

Olanzapine and fluoxetine (Symbyax)

Clozapine (Clozaril, FazaClo ODT, Versacloz)

Paliperidone (Invegaj, Invega Sustenna, Invega Trinza)

Cariprazine (Vraylar)

Lurasidone (Latuda)

Class Summary