Bipolar Disorder

BIPOLAR DISORDER

Signs and Symptoms

At the center of the illness is at least one manic or hypomanic episode. A manic episode is a distinct period of unusually elevated, expansive, or irritable mood accompanied by increased goal-directed activity or energy, lasting at least 1 week and present most of the time. During the period of mood disturbance and increased energy or activity, about half of the associated symptoms must be noted and must be different from baseline.

  • Inflated self-esteem or grandiosity.
  • Decreased need for sleep
  • More talkative than usual or pressure to keep talking.
  • Flight of ideas or subjective experience that thoughts are racing.
  • Distractibility (overly rapid shifting of focus)
  • Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (i.e., purposeless non-goal-directed activity).
  • Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

Bipolar I disorder involves manic symptoms while Bipolar II disorder involves only hypomanic episode(s). A hypomanic episode is similar to a manic episode but is of a lower level of intensity. It too is a distinct period of elevated, expansive, or irritable mood and abnormally increased activity or energy, but lasting at least only 4 consecutive days. Hypomanic episodes are defined similarly to manic episodes with one important difference being that they are not severe—that is, they do not entail psychosis, hospitalization, or severe impairment. Similarly, in a hypomanic episode, as in a manic episode, during the period of mood disturbance and increased energy, there are at least three associated symptoms (four if the mood is only irritable): inflated self esteem, decreased need for sleep, more talkative than usual, increase in goal-directed activity or psychomotor agitation, distractibility, racing thoughts or flight of ideas, excessive involvement in pleasurable activities with painful consequences.

Cyclothymic disorder involves manic symptoms and depressive symptoms of at least 2 years that do not meet the criteria of Bipolar I or II or Major Depressive Disorder.

Clinical Course and Prognosis

Bipolar disorder is one of the most disabling mental illnesses, potentially including symptoms of depression, mania, and psychoses (disconnection with reality). Clinical samples suggest that patients with bipolar and related disorders are commonly not able to maintain full-time employment, even if they have at least some college education (Kogan et al. 2004).

Prevalence and Public Health Impact

Bipolar and related disorders, although less common than depressive disorders, may have a lifetime prevalence as high as 4% (1% bipolar I disorder, 1% bipolar II disorder, and 2% bipolar disorder with symptoms that do not meet the criteria for bipolar I or II disorders) (Merikangas et al. 2007). The peak age at onset for bipolar and related disorders is in the late teens to early 20s, with the mean onset age being earliest in bipolar I disorder, intermediate in bipolar II disorder, and latest in major depressive disorder.

Depressive episodes are common in bipolar disorder and are described in Major Depressive Disorder section. When manic or hypomanic episodes coincide with major depressive episodes, we say that they have “mixed features”.

Research

Treatment

The treatment of bipolar disorder involves treatment of both manic or manic symptoms and depressive symptoms. While the occurrence of depressive symptoms are not necessary in meeting the criteria for bipolar disorder, they are actually the most common and disabling symptoms in bipolar disorder.

The foundation of treating bipolar has been the mood stabilizers valproate, lamotrigine, and carbamazepine. They treat mania and lamotrigine treats depressive symptoms as well. In addition, antidepressants, anxiolytics/hypnotics, other anticonvulsants, and other medications are commonly combined with mood stabilizers and SGAs in clinical settings (Ketter 2010).

In the past 10 years, however, second-generation antipsychotics (SGAs) have been increasingly used and many are approved by the FDA for treating symptoms of bipolar disorder.

Lithium

Lithium is an established treatment for acute mania and bipolar maintenance therapy that with chronic treatment appears to decrease suicidal behavior and suicide (Baldessarini et al. 2006; Bauer et al. 2006; Jefferson et al. 1987). As stated in the section on depression, it is also used in major depressive disorder as an augmentation strategy to enhance an antidepressant.

Lithium is especially effective in classic bipolar disorder (euphoric manias, not rapid cycling) but appears less effective in patients with manic episodes with mixed features; patients with rapid cycling (at least four episodes per year); and patients with substance abuse.

Lithium’s usefulness, however, is limited by its adverse effects, which undermine compliance. The prescribing information for lithium include boxed warnings about the toxicity of lithium that can occur at blood levels of the drug close to therapeutic levels. Symptoms can result in the central nervous system, cardiovascular, renal, and gastrointestinal systems. In severe cases, these symptoms may be irreversible. Those most at risk for toxicity include patients with significant renal or cardiovascular disease, those with severe debilitation, those with dehydration, those with sodium depletion, or those taking diuretics or angiotensin-converting enzyme (ACE) inhibitors. However, in medically healthy individuals, at dosages of 900 mg/day or less, lithium is usually well tolerated, and even with low serum levels it may yield benefit in milder forms of bipolar disorders

Lithium can cause common benign as well as rare serious renal adverse effects. Frequent urination is a common benign side effect. Known as nephrogenic diabetes insipidus, the condition involves the kidneys not retaining water as well as at baseline and may occur in as many as 10% of patients with chronic lithium therapy. (Although diabetes is in its name, it does not involve sugar dysregulation, as occurs with the the more common condition diabetes mellitus). Chronic lithium less commonly causes more long-standing and serious renal complications that are apparently more prevalent in cases with repeated lithium toxicity, advanced age, and concurrent nonsteroidal anti-inflammatory drug (NSAID) therapy or chronic medical illness. Patients need to maintain adequate fluid and sodium intake, as fluid and sodium depletion can cause lithium blood levels to rise. Caution is indicated in the setting of protracted sweating, diarrhea, infection, and fever.

Tremor often occurs with lithium treatment and is dose-related. If troublesome, the dose can be lowered or a beta blocker such as propranolol can be prescribed. This medication often relieves the tremor with few side effects.

Weight gain appears to be more of an issue with lithium than with lamotrigine, but less of a problem than with valproate or olanzapine.

Gastrointestinal effects include dyspepsia and diarrhea, but may be relieved by using the extended-release formulation instead of the instant-release formulation.

Dermatological side effects with lithium therapy include acneiform and maculopapular eruptions, psoriasis, and folliculitis. Lithium can also cause thyroid problems.

Lithium can have adverse cardiac effects, ranging from benign electrocardiographic T wave changes to clinically significant sinus node dysfunction or sinoatrial block and irritation to the cardiac ventricular rhythm. Therefore, any cardiac disorders should be reported the the prescribing physician and cardiac symptoms promptly reported.

Like the other mood stabilizers, lithium is a teratogen so female patients should have ensure that they will not become pregnant while being prescribed lithium. (FDA Pregnancy Category D).

Clinical assessments with lithium therapy includes a baseline physical examination and routinely querying patients at baseline and during treatment regarding CNS (sedation, tremor, ataxia), gastrointestinal (nausea, vomiting, diarrhea), metabolic (weight gain), and renal (polyuria, polydipsia) disorders and adverse effects. Laboratory monitoring includes a baseline electrocardiogram (in patients over 40 years of age), and renal (blood urea nitrogen, serum creatinine, and electrolytes) and thyroid (thyroid-stimulating hormone [TSH]) indices, with reevaluation of renal and thyroid indices at 3 and 6 months and then every 6–12 months thereafter, and as clinically indicated (American Psychiatric Association 2002). Serum lithium concentrations are commonly assessed at steady state, which occurs at about 5 days after a dosage change, and then as indicated by inefficacy or adverse effects. More frequent laboratory monitoring is prudent in the medically ill and in patients with abnormal indices.

Valproate

Valproate has shown effectiveness in treating both manic and mixed (concurrently having symptoms of depression and mania/hypomania) episodes, but not in patients under 18 years of age.

The U.S. prescribing information for valproate includes boxed warnings regarding the risks of hepatotoxicity, teratogenicity, and pancreatitis (Physicians’ Desk Reference 2012). Valproate, like the other mood stabilizers, is a teratogen (FDA Pregnancy Category D), and rates of major congenital malformations with valproate exposure could be higher compared with lamotrigine, carbamazepine, or no anticonvulsant exposure. Other warnings include the risks of hyperammonemic encephalopathy in patients with urea cycle disorders, somnolence in older adults, thrombocytopenia, hypothermia, multiorgan hypersensitivity reactions, and suicidality (an anticonvulsant class warning). Valproate therapy has also been associated with polycystic ovarian syndrome.

Dose-related adverse effects with valproate include gastrointestinal (nausea, vomiting, dyspepsia, diarrhea), hepatic (transaminase elevations), CNS (tremor, sedation, dizziness), and metabolic (weight gain, osteoporosis) problems and hair loss. CNS adverse effects may be lessened by weighting the dose toward bedtime or reducing the dose. The divalproex extended-release and the delayed-release formulation may cause fewer gastrointestinal side effects than valproic acid. Valproate can cause weight gain, which appears to be more problematic than with lithium, but less problematic than with olanzapine.

Valproate inhibits liver enzymes that break down other medications, and thus can increase serum concentrations of other medications

Patients need to be advised of valproate adverse effects and drug interactions. Clinical assessments with valproate therapy include a baseline physical examination and routinely querying patients at baseline and during treatment regarding hepatic and hematological disorders and adverse effects. Laboratory monitoring during valproate therapy commonly includes baseline complete blood count, differential, platelets, and hepatic indices, and reevaluation every 6–12 months and as clinically indicated (American Psychiatric Association 2002). Serum valproate concentrations are typically assessed at steady state and then as clinically indicated by inefficacy or adverse effects.

Lamotrigine

Lamotrigine is approved for bipolar maintenance treatment in adults and is generally well tolerated, particularly in comparison with other treatment options. The most common adverse events in patients with bipolar disorders in clinical trials were headache, benign rash, dizziness, diarrhea, dream abnormality, and pruritus.

The U.S. prescribing information for lamotrigine includes a boxed warning regarding the risk of serious rashes requiring hospitalization, which have included Stevens-Johnson syndrome (Physicians’ Desk Reference 2012). The risk of rash is higher in patients under age 16 years, and may be higher when lamotrigine is coadministered with valproate, when exceeding the recommended initial lamotrigine dose, and when exceeding the recommended lamotrigine dose escalation. Benign rash may be seen in 10% of patients, but because any rash is potentially serious, discontinuation of lamotrigine is required unless the rash is clearly not drug related. Other warnings in the prescribing information include the following risks:

Lamotrigine can cause CNS (headache, somnolence, insomnia, dizziness, tremor) and gastrointestinal (nausea, diarrhea) adverse effects. In most instances these problems lessen or resolve with time or lamotrigine dosage adjustment, but in some patients may require lamotrigine discontinuation. Unlike other mood stabilizers, lamotrigine has not been associated with weight gain.

Lamotrigine dosage is initially titrated very slowly to decrease the risk of rash. When given without valproate, the prescribing information recommends starting lamotrigine at 25 mg/day for 2 weeks, increasing to 50 mg/day for the next 2 weeks, then increasing to 100 mg/day for 1 week, and finally increasing to 200 mg/day in a single daily dose. Dosages exceeding 200 mg/day are not recommended unless concurrent hormonal contraceptives (which decrease serum lamotrigine concentrations) are administered. Even in the absence of hormonal contraceptives, selected patients may benefit from further gradual lamotrigine titration to final dosages as high as 400–500 mg/day.

Carbamazepine

Carbamazepine has demonstrated efficacy for acute manic and mixed episodes in adults, but complexity of use (related to drug interactions and side effects) and lack of a maintenance indication make it less commonly used than other mood stabilizers.

Carbamazepine therapy is associated with common, benign adverse events as well as rare, serious adverse events. The most common dose-related adverse effects with carbamazepine involve CNS (diplopia, blurred vision, fatigue, sedation, dizziness, and ataxia) or gastrointestinal system (nausea, vomiting) problems. Gradual initial dosing and careful attention to potential drug-drug interactions can help attenuate such problems.

The U.S. prescribing information for carbamazepine includes boxed warnings regarding the risks of serious dermatological reactions in patients with the genetic HLA-B*1502 allele (Asians should be genetically tested and, if HLA-B*1502 positive, should not be treated with carbamazepine unless benefit clearly outweighs risk), aplastic anemia (16/million patient-years), and agranulocytosis (48/million patient-years) (Physicians’ Desk Reference 2012). Other warnings in the prescribing information include the risks of teratogenicity, increased intraocular pressure due to mild anticholinergic activity, and suicidality (an anticonvulsant class warning). Carbamazepine can cause hematological (benign leukopenia, benign thrombocytopenia), dermatological (benign rash), electrolyte (asymptomatic hyponatremia), and hepatic (benign transaminase elevations) problems. Much less commonly, carbamazepine can cause analogous serious problems. Rash presenting with systemic illness or involving the eyes, mouth, or bladder (dysuria) constitutes a medical emergency; in this situation, carbamazepine should be immediately discontinued and the patient assessed emergently.

Although carbamazepine can cause modest TSH increases, frank hypothyroidism is very uncommon. Carbamazepine may affect cardiac conduction and should be used with caution in patients with cardiac disorders. Carbamazepine appears less likely than lithium or valproate to cause weight gain. Carbamazepine-induced hyponatremia is often tolerated in young physically well individuals, but can cause obtundation and other serious sequelae in medically frail older adult patients. Carbamazepine, like the other mood stabilizers, is a teratogen (FDA Pregnancy Category D).

In acute settings, such as the inpatient treatment of mania, carbamazepine therapy is commonly initiated at 200–400 mg/day and increased as necessary and tolerated by 200 mg/day every 2–4 days. Euthymic or depressed patients tend to tolerate aggressive initiation less well than manic patients. In less acute situations, such as the initiation of prophylaxis or adjunctive use, carbamazepine is often started at 100–200 mg/day and increased as necessary and tolerated by 200 mg/day every 4–7 days. Even this gradual initiation may cause adverse effects. Starting with 50 mg (half of a chewable 100-mg tablet) at bedtime and increasing by 50 mg every 4 days can yield a better-tolerated initiation. Because of autoinduction, doses after 2–4 weeks of therapy may need to be twice as high as in the first week to yield comparable serum levels. Target dosages are commonly between 600 and 1,200 mg/day, yielding serum levels from 6 to 12 μg/mL (20–60 mM/L), with the higher portion of the range used acutely and lower dosages used in prophylaxis or adjunctive therapy.

Carbamazepine has multiple problematic drug-drug interactions (in excess of those seen with lithium or valproate). These interactions are predominantly related to it being a potent hepatic inducer that can decrease serum concentrations and efficacy of psychotropic (including valproate, lamotrigine, most SGAs, and multiple antidepressants and anxiolytics) and nonpsychotropic medications, and to the ability of certain enzyme inhibitors to increase carbamazepine serum concentrations and cause toxicity. Detailed reviews of carbamazepine drug-drug interactions may be found in articles by Ketter et al. 1991a, Ketter et al. 1991b).

Patients need to be advised of carbamazepine adverse effects and drug interactions. Clinical assessments with carbamazepine therapy include a baseline physical examination and routinely querying patients at baseline and during treatment regarding hepatic and hematological disorders and adverse effects. In the past, recommended laboratory monitoring during carbamazepine therapy has included baseline complete blood count, differential, platelets, hepatic indices, and serum sodium, with reevaluation at 2, 4, 6, and 8 weeks, and then every 3 months and as clinically indicated (American Psychiatric Association 2002). In contemporary clinical practice, somewhat less focus is placed on scheduled monitoring, and clinically indicated (e.g., when a patient becomes ill with a fever) monitoring is emphasized. Patients who have abnormal or marginal indices at any point merit careful scheduled and clinically indicated monitoring. Serum carbamazepine concentrations are typically assessed at steady state, and then as indicated by inefficacy or adverse effects.

Second-Generation Antipsychotics

Based on their efficacy profiles and lower risks of extrapyramidal symptoms and tardive dyskinesia, SGAs have displaced first-generation antipsychotics in the management of bipolar and related disorders. Multiple SGAs have FDA indications for monotherapy and adjunctive (combined with lithium or valproate) therapy for acute mania and bipolar maintenance in adults. In addition, risperidone, aripiprazole, olanzapine, and quetiapine have pediatric mania monotherapy indications. Aripiprazole also has a pediatric mania adjunctive (to lithium or valproate) indication and a pediatric bipolar maintenance monotherapy indication. Olanzapine (combined with fluoxetine) and quetiapine monotherapy have acute bipolar depression indications in adults. Although (as of early 2013) cariprazine and lurasidone lack FDA indications for bipolar disorders, controlled trials suggest their efficacy in acute mania and bipolar depression, respectively, and clozapine may be effective in treatment-refractory patients. Short-acting injectable formulations of SGAs such as olanzapine, ziprasidone, and aripiprazole appear useful in the treatment of agitation, and a long-acting injectable (LAI, depot) formulation of risperidone may prove useful in patients with bipolar disorders who have poor medication compliance. Olanzapine LAI, although approved for the treatment of schizophrenia, is not approved for the treatment of bipolar and related disorders.

Second-generation antipsychotics compared with mood stabilizers entail more safety and tolerability challenges that can attenuate their efficacy benefits (e.g., weight gain with olanzapine, extrapyramidal symptoms with risperidone, sedation with quetiapine, and akathisia with ziprasidone and aripiprazole). The U.S. prescribing information includes multiple warnings and precautions for these agents (Physicians’ Desk Reference 2012). Indeed, the six SGAs (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and asenapine) with FDA indications for bipolar disorders (as well as lurasidone, which as of early 2013 was approved for schizophrenia but not yet for bipolar depression) have in common 12 such warnings and precautions:

Increased mortality in elderly patients with dementia-related psychosis; this is a boxed warning, with a reminder that SGAs are not approved for dementia-related psychosis

Neuroleptic malignant syndrome; the drug should be discontinued and the patient should be monitored closely

Tardive dyskinesia; the drug should be discontinued if clinically appropriate

Hyperglycemia and diabetes mellitus; the patient should be monitored for hyperglycemia symptoms such as polydipsia, polyuria, polyphagia, and weakness, and glucose should be monitored if there is a diabetes risk

Orthostatic hypotension with or without syncope; the drug should be used with caution if the patient has cardiovascular or cerebrovascular disease

Leukopenia, neutropenia, and agranulocytosis; the patient should be monitored if there is prior or baseline leukopenia, and the drug should be discontinued if there is a decrease in white blood cells in the absence of other causative factors

Seizures; the drug should be used with caution if the patient has a seizure disorder or seizure risk

Potential for cognitive and motor impairment; the patient should use caution when operating machinery

Body temperature regulation (pyrexia, feeling hot); caution should be used when prescribing the drug to a patient who may be doing strenuous exercise, may be exposed to extreme heat, may become dehydrated, or is taking an anticholinergic medication)

Suicide (risk related to bipolar disorders and schizophrenia); high-risk patients should be closely supervised

Dysphagia; the drug should be used with caution if there is a risk of aspiration pneumonia

Use in patients with concomitant illness; the drug should be used with caution if the patient has cardiovascular or another systemic disease

The presence or absence of additional warnings and precautions indicates within-class safety and tolerability differences between individual SGAs. For example, to date, the U.S. prescribing information includes four additional warnings and precautions for all of the above SGAs, with exceptions as noted:

Weight gain (ziprasidone excepted); the patient’s weight should be monitored

Hyperprolactinemia (aripiprazole excepted); includes risk of galactorrhea, amenorrhea, gynecomastia, and impotence

Hyperlipidemia/dyslipidemia (ziprasidone and asenapine excepted); the patient’s lipids should be monitored

Cerebrovascular accidents, including stroke, in elderly patients with dementia-related psychosis (quetiapine and ziprasidone excepted); SGAs are not approved for dementia-related psychosis

Other, less widespread warnings and precautions distinguishing individual SGAs from one another are noted in the following subsections on specific drugs.