Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

52. Bipolar Disorder

Shannon J. Drayton and Christine M. Pelic


 Images Bipolar disorder is a cyclic mental illness with recurrent mood episodes that occur over a person’s lifetime. The symptoms, course, severity, and response to treatment differ among individuals.

 Images Bipolar disorder is likely caused by genetic factors, environmental triggers, and the dysregulation of neurotransmitters, neurohormones, and second messenger systems in the brain.

 Images Clinicians should be sure to obtain a detailed history, including potential substance use and medical illness, to avoid a delay in the diagnosis and treatment of bipolar disorder.

 Images The goal of therapy for bipolar disorder should be to improve patient functioning by reducing mood episodes. This is accomplished by maximizing adherence to therapy and limiting adverse effects.

 Images Patients and family members should be educated about bipolar disorder and treatments. Long-term monitoring and adherence to treatment are major factors in obtaining stabilization of the disorder.

 Images Lithium and valproate are the mainstays of treatment for both acute mania and prophylaxis for recurrent manic and depressive episodes. Anticonvulsants (such as lamotrigine, carbamazepine, and oxcarbazepine) and second-generation antipsychotics (such as aripiprazole, olanzapine, risperidone, quetiapine, and ziprasidone) are alternative or adjunctive treatments for bipolar disorder. Anticonvulsants may be more effective than lithium in several mood subtypes (e.g., mixed states and rapid cycling). The use of lithium, valproate, or quetiapine for acute bipolar depression should be considered as a first-line treatment option.

 Images Baseline and followup laboratory tests are required for some medications to monitor for adverse effects.

 Images Some patients can be stabilized on one mood stabilizer, but others may require combination therapies or adjunctive agents during an acute mood episode. If possible, adjunctive agents should be tapered and discontinued when the acute mood episode remits and the patient is stabilized. Adjunctive agents may include benzodiazepines, additional mood stabilizers or antipsychotics, and/or antidepressants.

Images Bipolar disorder is a common, chronic, and often severe cyclic mood disorder characterized by recurrent fluctuations in mood, energy, and behavior.13 It differs from recurrent major depression (or unipolar depression) in that a manic, hypomanic, or mixed episode occurs during the course of the illness.1 Bipolar disorder is a lifelong illness with a variable course and requires both nonpharmacologic and pharmacologic treatments for mood stabilization.1,2


The overall prevalence of bipolar disorder was 4.5% in a U.S. comorbidity study: 1% meeting criteria for bipolar I, 1.1% for bipolar II, and 2.4% of patients with subthreshold recurrent mood cycling (i.e., cyclothymia, bipolar disorder not otherwise specified [NOS]).4 Symptom onset for depression or (hypo)mania in bipolar disorder typically occurs in late adolescence or early adulthood, with greater than two thirds developing symptoms before 18 years of age.5 Bipolar I disorder occurs equally in men and women, whereas bipolar II disorder is more common in women.1,2 Depression and mixed presentations may occur more frequently in women.68


Images The exact etiology of bipolar disorder is unknown. Bipolar disorder is thought to be a complex disease that is influenced by developmental, genetic, neurobiologic, and psychological factors.9 Many theories have been proposed regarding the pathophysiology of mood disorders. Family, twin, and adoption studies report an increased lifetime prevalence risk of having mood disorders among first-degree relatives of patients with bipolar disorder.10,11 Genetic linkage studies suggest multiple gene loci can be involved in the heredity of mood disorders.1214 Neuroimaging studies have found neurochemical, anatomic, and functional abnormalities in bipolar patients.15 Many researchers suspect that altered synaptic and circuit functioning accounts for mood and cognitive changes seen in bipolar disorder, rather than dysfunction of individual neurotransmitters.16 Environmental or psychosocial stressors, immunologic factors, and sleep dysregulation all have been associated with bipolar disorder and can negatively influence the course of illness.1721


Images The essential feature of bipolar spectrum disorders is a history of mania or hypomania that is not caused by any other medical condition, substance, or psychiatric disorder.1,2 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) of the American Psychiatric Association (APA) details the present understanding of mood disorders.1 Bipolar disorder is divided into four subtypes based on the identification of specific mood episodes: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder NOS. See Table 52-1 for a definition of mood disorders by type of episode. Bipolar I and II can further be specified to reflect the most recent mood state (i.e., hypomanic or major depressive episode). See Table 52-2 for the evaluation and diagnostic criteria of mood episodes. Bipolar disorder is a cyclic mood disorder, and patients may sequentially experience different types of episodes with or without a period of normal mood (euthymia) between. Persons with bipolar disorder can have mood fluctuations that continue for months, or after one episode they can sometimes go years without recurrence of any type of mood episode. Comorbid conditions associated with bipolar disorder include, but are not limited to, substance abuse, personality disorders, anxiety disorders, eating disorders, and a higher incidence of several medical conditions.13,2226

TABLE 52-1 Mood Disorders Defined by Episodes


TABLE 52-2 Evaluation and Diagnosis of Mood Episodes



Episodes of mania or depression may be induced or caused by medical illness, medications, or substance intoxication or withdrawal (see Table 52-3 for causes of mania and Table 51-1 for causes of depression).1,2 A complete medical, psychiatric, and medication history; physical examination; and laboratory testing are necessary to rule out any organic causes of mania or depression.2 An accurate diagnosis is important because some psychiatric and neurologic disorders present with manic-like or depressive-like symptoms.2,3 Bipolar disorder commonly co-occurs with substance use disorders and may be difficult to diagnose in the presence of cocaine use.37 When making the diagnosis of new-onset bipolar disorder in a geriatric population, clinicians should be particularly aware of secondary causes of mania and depression that may impact treatment.38

TABLE 52-3 Secondary Causes of Mania


Another disease state that has a similar presentation to bipolar disorder is schizoaffective disorder. This disease is a mix between schizophrenia and bipolar disorder. Patients with schizoaffective disorder have mood episodes, but the distinguishing factor from bipolar disorder is that these patients experience psychosis even between mood episodes during periods of euthymia. Clinicians must rely on family members or others who know the patient well to determine if the patient is psychotic between mood episodes. It can be difficult for clinicians to obtain a full psychiatric history on patients, thus making schizoaffective disorder widely diagnosed. Schizoaffective disorder is treated with mood stabilizers and antipsychotics as maintenance therapy.


Images Bipolar disorder is frequently not recognized and treated for many years because of its fluctuating course and episodic mood states.2,3 Patients may have delays in treatment ranging 8 to 13 years from onset of index mood episode until initiation of mood stabilizer.39 This delay confers a risk of poor social functioning, increased hospitalizations, and a greater likelihood of lifetime suicide attempts.40 Onset of illness in early childhood tends to be associated with increased mood episodes, rapid cycling, and comorbid psychiatric conditions as well as a stronger family history of mood disorders.41 Gender differences may influence a patient’s course of illness, tolerability of medication, and response to treatment. Women are more likely to have increased depressive symptoms, older age of onset, better compliance, complex management in pregnancy, and higher association with physical illness such as thyroid abnormalities than men are. In men there may be increased incidence of mania and substance use.42

The kindling theory is used to explain why bipolar disorder progresses over one’s life and why preventative treatment is imperative. Episodes can become longer in duration and more frequent with aging.2Usually there is a period of normal functioning between episodes, but approximately 20% to 30% of patients with bipolar I disorder and 15% with bipolar II disorder have no period of euthymia because of mood lability, residual mood symptoms, or a direct switch to the opposite polarity.1

Rapid cycling (more than four mood episodes per year) is more common in females and occurs in approximately 10% to 20% of bipolar I and II disorder patients.2,3,43,44 Frequent and severe episodes of depression appear to be the most common hallmark of rapid cycling. Use of alcohol, stimulants, antidepressants, sleep deprivation, hypothyroidism, and seasonal changes can play a role in rapid cycling.3,44,45Seasonal patterns of mania in the summer and depression during the winter have been observed. Rapid-cycling patients have a poorer long-term prognosis and often require combination therapies.3

Fluctuations in hormones and neurotransmitters during the luteal phase of the menstrual cycle, postpartum period, and perimenopause (starting ~10 years before menopause) can precipitate mood changes and increase cycling.1,43,46 Women with bipolar I disorder are at greater risk for relapse into mania or depression during the postpartum period.2 If a severe mood episode occurs postpartum, there is an increased risk for recurrences during subsequent postpartum periods.2

Alcohol and substance abuse is common among patients with bipolar disorder and can have a significant impact on the age of onset, course of the illness, and response to treatment.3,22,23 Alcohol and drug abuse or dependence has been reported in 46% and 41% of bipolar patients, respectively.2,22 Patients with substance use disorders are more likely to have an earlier onset of their illness, mixed states, higher rates of relapse, a poorer response to treatment, comorbid personality disorders, increased suicide risk, and more psychiatric hospitalizations.3 Bipolar patients often self-medicate with substances such as alcohol or cocaine during episodes, resulting in further impairment of judgment, poor impulse control, treatment nonadherence, and a worsening of the clinical course.2,3,47

More than one half (55% to 65%) of bipolar I patients have some degree of functional disability after the onset of their illness, and approximately 10% to 20% of bipolar patients have severe impairment in their psychosocial and occupational functioning.2,3,48 In a 1-year longitudinal study in 258 bipolar patients, two thirds had four or more mood episodes a year despite comprehensive pharmacologic treatment, and approximately 33.2% of the year was spent being depressed compared with 10.8% of the time in a manic phase.48

Compared with the general population, individuals with bipolar disorder have a 2.3 times higher mortality rate. Suicide attempts occur in up to 50% of patients with bipolar disorder, and approximately 10% to 19% of individuals with bipolar I disorder commit suicide.13,49 Studies suggest patients with bipolar II disorder have more suicide attempts than bipolar I patients.49

The best predictor for level of functioning during a person’s lifetime is adherence with medication treatment. Medication discontinuation occurs in up to 50% of patients secondary to intolerance of drug-induced side effects.50Failure to recognize the disorder, reluctance to acknowledge it, or poor adherence with treatment are reasons an estimated two thirds of patients with bipolar disorder do not receive appropriate treatment. Nonadherence with pharmacologic treatment and substance abuse are major factors in relapse and hospitalizations.2,3


Desired Outcome

ImagesThe desired outcome in treating bipolar disorder is to effectively resolve acute manic, hypomanic, and depressive episodes, prevent further episodes, maintain good functioning, promote treatment adherence, and minimize side effects.2,3 The general principles and goals for the management of bipolar disorder are found in Table 52-4.

TABLE 52-4 General Principles for the Management of Bipolar Disorder


General Approach to Treatment

Images Treatment of bipolar disorder must be individualized because the clinical presentation, severity, and frequency of episodes vary widely among patients. Treatment approaches should include both nonpharmacologic and pharmacologic strategies.3 Patients and family members should be educated about bipolar disorder (e.g., symptoms, causes, and course) and treatment options. Long-term adherence to treatment is the most important factor in achieving stabilization of the disorder.

Images The treatment of bipolar disorder can vary depending on what type of episode the patient is experiencing. Once diagnosed with bipolar disorder, patients should remain on a mood stabilizer (e.g., lithium, valproate) for their lifetime. During acute episodes, medications can be added and then tapered once the patient is stabilized and euthymic. For example, when treating a patient for mania with psychotic features, the patient should be on a mood stabilizer and an antipsychotic. If the antipsychotic is the patient’s maintenance therapy, the dose should be increased or perhaps the medication should be changed altogether if the patient goes into a manic episode. If treating a patient for a severe depressive episode, a clinician may need to maximize the dose of the mood stabilizer or add another medication (e.g., quetiapine).

Nonpharmacologic Therapy

The basics of nonpharmacologic approaches should address issues of adequate nutrition, sleep, exercise, and stress reduction.3 Sleep deprivation, high stress, and deficiencies in dietary essential amino acids, fatty acids, vitamins, and minerals can exacerbate mood episodes and result in poorer outcomes.3 Mood charting is an effective strategy in detecting early signs and symptoms of mania and depression. Another effective treatment is to combine medications with adjunctive psychoeducational programs, supportive counseling, insight-oriented psychotherapy (individual or group), couples or family therapy, cognitive behavioral therapy, and communication enhancement training.2,3,22,52

Pharmacologic Therapy

Images Pharmacotherapy is crucial for the acute and maintenance treatment of bipolar disorder and includes lithium, valproate, carbamazepine, lamotrigine, first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), and adjunctive agents such as antidepressants and benzodiazepines. General treatment guidelines for the acute treatment of mood episodes in patients with bipolar I disorder are found in Table 52-5.

TABLE 52-5 Algorithm and Guidelines for the Acute Treatment of Mood Episodes in Patients with Bipolar I Disorder


Product information, dosing, and administration of agents used in the treatment of bipolar disorder are found in Table 52-6.

TABLE 52-6 Products, Dosage and Administration, and Clinical Use of Agents Used in the Treatment of Bipolar Disorder



Images The term mood stabilizer is often used to describe the class of medications used in the treatment of bipolar disorder, but this may not be accurate as some medications are more effective for acute mania, some for the depressive episode, and others for the maintenance phase.54 Lithium, valproate (or divalproex sodium), extended-release carbamazepine, aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone are currently approved by the U.S. FDA for the treatment of acute mania in bipolar disorder; only lithium, divalproex sodium, aripiprazole, olanzapine, and lamotrigine are approved for the maintenance treatment of bipolar disorder. Quetiapine is the only monotherapy antipsychotic that is FDA-approved for bipolar depression. Lithium is the drug of choice for bipolar disorder with euphoric mania, whereas valproate has better efficacy for mixed states and irritable/dysphoric mania compared with lithium.2

Combination therapies (e.g., lithium plus valproate or carbamazepine; lithium or valproate plus a SGA) can provide better acute response and long-term prevention of relapse and recurrence than monotherapy in some bipolar patients, particularly those with mixed states or rapid cycling.2,54 The majority of patients hospitalized for an acute episode will be on combination therapy.

Several guidelines and algorithms have been published regarding the treatment of bipolar disorder, and these are generally based on the best available data and clinical consensus of experts. The Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) published updated treatment guidelines in 2009.53 In addition, an international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) has published guidelines for the treatment of acute bipolar depression and mania.55,56 The WFSBP mania and depression guidelines were updated in 2009 and 2010, respectively; maintenance (2003) guidelines have yet to be updated.

Based on the CANMAT and ISBD guidelines and available research, an example treatment algorithm and guidelines for acute mood episodes in adult patients with bipolar I disorder are listed in Table 52-5. Because newer anticonvulsants, SGAs, and combination therapies are under investigation for bipolar disorder, published guidelines, algorithms, and decision trees can quickly become out of date as new scientific knowledge evolves. Selection of treatments for acute mood episodes (e.g., manic or mixed, depressive, or rapid cycling) and for maintenance strategies to prevent relapses of mood episodes should be individualized. Treatment plans should be based on patient-specific characteristics, comorbid psychiatric and medical conditions, and avoidance of drug interactions and adverse effects.2

Specific Pharmacologic Therapies

Lithium Lithium was first used in 1949 as a treatment for mania and was approved in 1972 in the United States for the treatment of acute mania and for maintenance therapy. Despite numerous investigations into the biologic and clinical properties of lithium, there is no unified theory for its mechanism of action.22,5759 Chronic lithium administration may modulate gene expression and have neuroprotective effects. Lithium has unique pharmacokinetics because it is a monovalent cation. It is rapidly absorbed, is widely distributed with no protein binding, is not metabolized, and is excreted unchanged in the urine and in other body fluids.60

Efficacy Lithium was the first established mood stabilizer, and is still considered a first-line agent for acute mania, acute bipolar depression, and maintenance treatment of bipolar I and II disorders.53 Early placebo-controlled studies with lithium reported up to a 78% response rate in aborting an acute manic or hypomanic episode, but more recent studies suggest a slower onset of action and a more moderate effectiveness when compared with other agents.2,3,61 In placebo-controlled studies in bipolar depression, lithium has been found to have efficacy, but there can be a 6- to 8-week delay for its antidepressant effects.2 Lithium is more effective for pure or elated (classic) mania, and can be less effective for mania with psychotic features, mixed episodes, rapid or continuous cycling, alcohol and drug abuse, and in organic-induced mood states.2,3,62

Long-term lithium therapy is more effective in patients with fewer prior episodes, with a history of euthymia or good functioning between episodes, and with a family history of bipolar illness with a positive response to lithium. Lithium produces a prophylactic response in up to two thirds of patients and reduces suicide risk by 8- to 10-fold.2,6163

Clinical Controversy

What is the role of lithium in a patient with suicidality? An observational study demonstrated a reduction in suicide risk in patients on continued lithium treatment. However, this study does not address how and when lithium should be initiated in patients who are currently suicidal. Lithium overdose can be fatal. Therefore, the role of lithium in preventing suicidal behavior during mood episodes is unclear.

Patients maintained on standard serum concentrations of lithium (0.8 to 1 mEq/L [mmol/L]) may have fewer relapses than patients maintained on lower serum concentrations (0.4 to 0.6 mEq/L [mmol/L]).2,3Abrupt discontinuation or noncompliance with lithium therapy can increase the risk of relapse.2,3 Discontinuation-induced refractoriness has been reported in approximately one fifth of patients who previously were stabilized on lithium.2,3

Lithium augmentation of carbamazepine, lamotrigine, and valproate can improve treatment response in bipolar I disorder.2,64 Concomitant use of lithium with valproate or carbamazepine appears to be well tolerated but can increase the risk of sedation, weight gain, GI complaints, and tremor.

Lithium is frequently combined with either FGAs or SGAs for treatment of euphoric acute mania with psychotic features. Case reports of neurotoxicity (e.g., delirium, cerebellar dysfunction, extrapyramidal symptoms, and severe tremors) have been published in elderly patients receiving lithium and FGAs.60 Combining lithium with calcium channel blockers is not recommended because of reports of neurotoxicity and severe bradycardia with verapamil or diltiazem.60 Acute neurotoxicity and delirium have been reported in patients receiving electroconvulsive therapy (ECT) with lithium (even at reduced dosages); therefore, lithium should be withdrawn and discontinued at least 2 days before ECT and should not be resumed until 2 to 3 days after the last treatment.

Adverse Effects Approximately 35% to 93% of patients treated with lithium will experience adverse effects. These are divided into those that occur early in therapy but are generally innocuous and transient, those that occur with long-term therapy and are usually not dose-related, and toxic effects that occur with high serum concentrations.2,60

Initial side effects are often dose-related and are worse at peak serum concentrations (1 to 2 hours postdose).2 Standard approaches for minimizing adverse effects include lowering the dose, taking smaller doses with food, using extended-release products, and trying once-daily dosing at bedtime.2 GI distress (e.g., nausea, vomiting, dyspepsia, and diarrhea) can be minimized by the standard approaches or by adding antacids or antidiarrheal agents.2 Diarrhea can sometimes be managed by switching from tablet or capsule formulation to liquid formulation. Diarrhea produced by lithium is commonly an osmotic diarrhea, and therefore switching to a formulation that clears the gut quickly can ameliorate symptoms. Muscle weakness and lethargy develop in about 30% of patients, but these symptoms are usually transient. Polydipsia with polyuria and nocturia occurs in up to 70% of patients and can be managed by changing to once-daily bedtime dosing.

A fine hand tremor can be evident in up to 50% of patients. Stress, concomitant use of antidepressants or antipsychotics, caffeine, sympathomimetics, and impending toxicity can exacerbate the tremor. Strategies to reduce the tremor include standard approaches (e.g., switch to long-acting preparation, lower dose if possible) or adding a β-adrenergic antagonist (e.g., propranolol 20 to 120 mg/day).

Lithium reduces the kidney’s ability to concentrate urine and can cause a nephrogenic diabetes insipidus characterized by low urine specific gravity and a low osmolality polyuria (urine volumes greater than 3 L/day).2,60 Lithium-induced nephrogenic diabetes insipidus is treated with loop diuretics, thiazide diuretics, or triamterene. If a thiazide diuretic is used (e.g., hydrochlorothiazide 50 mg/day), lithium doses should be decreased by 50%, and potassium levels should be monitored.2 Amiloride, a potassium-sparing diuretic, has weaker natriuretic effects than thiazides and appears to be relatively safe with minimal effect on lithium clearance. Potassium supplements have been suggested as another treatment for lithium-induced polyuria.22 Fluid restriction is not recommended because dehydration increases the risk of lithium toxicity. If edema occurs, treatment approaches include lowering sodium intake or using a diuretic (e.g., spironolactone); close monitoring for lithium toxicity is necessary because these treatments often increase lithium concentrations.

Patients on long-term lithium therapy have a 10% to 20% risk of developing morphologic renal changes (e.g., glomerular sclerosis, tubular atrophy, and interstitial nephritis) that is associated with impairment of water resorption and increased serum creatinine concentrations.2 Lithium rarely causes nephrotoxicity if patients are maintained on the lowest effective dose, if once-daily dosing is used, if adequate hydration is maintained, and if toxicity is avoided.22 Lithium should be avoided in patients with preexisting renal disease unless there is frequent monitoring.

Lithium is concentrated in the thyroid gland, interferes with thyroid hormone synthesis, and can induce the formation of thyroid antibodies.60 Up to 30% of patients on maintenance lithium therapy develop transiently elevated thyroid-stimulating hormone concentrations, and 5% to 35% of patients develop a goiter and/or hypothyroidism.2 Lithium-induced hypothyroidism is not dose-related, is observed 10 times more frequently in women (particularly in those with rapid cycling), and usually occurs after 6 to 18 months of therapy.2 Hypothyroidism does not require discontinuation of lithium, because exogenous thyroid hormone (i.e., levothyroxine) can be added to the regimen. When lithium is discontinued, the need for exogenous thyroid hormone should be reassessed, because hypothyroidism can be reversible.

Lithium can cause a variety of benign and reversible cardiac effects, particularly T-wave flattening or inversion (in up to 30% of patients), atrioventricular block, and bradycardia.2,22,60 If a patient has significant preexisting cardiac disease, consultation with a cardiologist and an electrocardiogram is recommended at baseline and during lithium therapy.

Other late-appearing lithium side effects include benign reversible leukocytosis and a variety of dermatologic effects (e.g., acne and acneiform eruptions, exacerbation of psoriasis, pruritic dermatitis).3 Weight gain is common (~20% of patients gain >10 kg [22 lb]) and can be related to fluid retention, the consumption of high-calorie beverages as a result of polydipsia, or a decreased metabolic rate because of hypothyroidism.22,62 Severe neurologic disturbances such as coarse hand tremors, ataxia, slurred speech, myasthenia gravis, extrapyramidal syndrome, pseudotumor cerebri, and papilledema are occasionally observed.

Lithium is an extremely toxic drug if accidentally or intentionally taken in overdose. Lithium toxicity can occur with blood levels greater than 1.5 mEq/L (mmol/L), but elderly patients can have symptoms of toxicity at therapeutic levels.2 Severe lithium intoxication occurs when concentrations are higher than 2 mEq/L (mmol/L), and there is a worsening in several key symptoms: GI (e.g., vomiting, diarrhea, or incontinence), coordination (e.g., severe fine to coarse hand tremor, unstable gait, slurred speech, and muscle twitching), and cognition (e.g., poor concentration, drowsiness, disorientation, apathy, and coma).2Several reports of seizures, cardiac dysrhythmia, permanent neurologic impairments with ataxia and deficits in memory, and kidney damage with reduced glomerular filtration rate have been reported after lithium intoxication.2

Situations that predispose patients to lithium toxicity include sodium restriction, dehydration, vomiting, diarrhea, age greater than 50, heart failure, cirrhosis, and drug interactions that decrease lithium clearance. Heavy exercise, sauna baths, hot weather, and fever can promote sodium loss. Patients should be cautioned to maintain adequate sodium and fluid intake (2.5 to 3 qt [~2.5 to 3 L] per day of fluids) and to avoid the excessive use of coffee, tea, cola, and other caffeine-containing beverages and alcohol.

If lithium toxicity is suspected, the person should go to an emergency room to be monitored, and lithium should be discontinued.2 Gastric lavage and IV fluids may be needed, and the patient should be monitored for fluid balance, renal and electrolyte status, and neurologic changes. When lithium concentrations are above 3.5 to 4 mEq/L (mmol/L), intermittent hemodialysis (12 hours on and 12 hours off) can be started and continued until the lithium concentration is below 1 mEq/L (mmol/L) when taken 12 hours after the last dialysis.

Drug–Drug Interactions Thiazide diuretics, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, angiotensin-converting enzyme inhibitors, and salt-restricted diets can elevate lithium levels.2Neurotoxicity can occur when lithium is combined with carbamazepine, diltiazem, losartan, methyldopa, metronidazole, phenytoin, and verapamil.2,60 Analgesics such as acetaminophen or aspirin and loop diuretics are less likely to interfere with lithium clearance. Caffeine and theophylline can enhance the renal elimination of lithium. Because lithium has no effect on hepatic metabolizing enzymes, it has fewer drug–drug interactions compared with carbamazepine, oxcarbazepine, and valproate.

Dosing and Administration Lithium dosing depends on the patient’s age and weight, tolerance to adverse effects, and the acuity of the illness. Dosing is generally titrated up to achieve steady-state serum lithium concentrations of 0.6 to 1.2 mEq/L (mmol/L).2 Lithium therapy is usually initiated with low to moderate doses (600 mg/day) for prophylaxis and higher doses (900 to 1,200 mg/day) for acute mania, using a two- to three-times daily dosing regimen.2,60Immediate-release lithium preparations should be given in two or three divided daily doses, whereas extended-release products can be given once or twice daily. In clinical practice many clinicians dose the immediate-release and extended-release preparations once daily. It can be best to initially begin a patient on divided dosing, but once stabilized many patients are able to switch to once-daily dosing without decompensating.

Lithium levels are considered to be at steady state at approximately day 5, and serum samples should be drawn 12 hours postdose. Once a desired serum concentration has been achieved, levels should be drawn in 2 weeks and then if stable every 3 to 6 months or as clinically indicated. Maintenance lithium serum concentrations are usually measured every 3 months, but can be adjusted to every 6 months for stabilized patients, and every 1 to 2 months for patients with frequent mood episodes.2 Lithium clearance rates increase by 50% to 100% during pregnancy and return to normal postpartum; thus, lithium levels should be determined monthly during pregnancy and weekly the month before delivery. At delivery, rapid fluid changes can significantly increase lithium levels; thus, a reduction to prepregnancy lithium doses and adequate hydration are recommended.2

The recommended guidelines for baseline and routine laboratory testing for lithium are listed in Table 52-7. The dose should be adjusted based on the steady-state serum concentration drawn 12 hours (±30 minutes) after the last dose.61 A therapeutic trial for outpatients should last a minimum of 4 to 6 weeks with lithium serum concentrations of 0.6 to 1.2 mEq/L (mmol/L). Acutely manic patients can require serum concentrations of 1 to 1.2 mEq/L (mmol/L), and some need up to 1.5 mEq/L (mmol/L) to achieve a therapeutic response. Although serum concentrations less than 0.6 mEq/L (mmol/L) are associated with higher rates of relapse, some patients can do well at 0.4 to 0.7 mEq/L (mmol/L).2 For bipolar prophylaxis in elderly patients, serum concentrations of 0.4 to 0.6 mEq/L (mmol/L) are recommended because of increased sensitivity to adverse effects.2

TABLE 52-7 Guidelines for Baseline and Routine Laboratory Tests and Monitoring for Agents Used in Treatment of Bipolar Disorder



Divalproex sodium (also known as sodium valproate) was marketed in 1995 for the acute treatment of mania in adults and is now the most prescribed mood stabilizer in the United States. It is FDA-approved only for the treatment of acute manic or mixed episodes; however, it is commonly used in clinical practice as maintenance monotherapy for bipolar disorder. Limited data support its use in acute bipolar depression. Carbamazepine is commonly used for both acute and maintenance therapy. The only formulation approved in the United States for bipolar disorder is extended-release carbamazepine, although other formulations can be used. Some data support the use of oxcarbazepine, a 10-keto analogue of carbamazepine, in the treatment of bipolar disorder; however, it is not approved for the treatment of bipolar disorder in the United States. Valproate, carbamazepine, and oxcarbazepine all have a wide range of neurologic, GI, electrolyte, and hematologic adverse effects that requires regular assessment and routine blood work.

Lamotrigine is FDA-approved for the maintenance treatment of bipolar I disorder. Lamotrigine add-on or monotherapy has been used for treatment-refractory bipolar depression.64 This medication appears to be most effective in the prevention of relapse of depression and does not appear to have efficacy for treatment of acute depression, mania, mixed states, or rapid cycling in bipolar I.70 Lamotrigine is associated with hypersensitivity reactions and rare life-threatening skin rashes and requires slow dosage titration.2

Valproate Sodium and Valproic Acid The exact mechanism of action of valproic acid is not known. It is a branched-chain fatty acid and was originally used as an organic solvent before it was discovered in the 1960s to have anticonvulsant properties. Valproate has antimigraine, mood-stabilizing, and antiaggressive effects.65 In 1995, the enteric-coated formulation divalproex sodium (sodium valproate) was approved for the acute treatment of mania. Several controlled studies have shown valproate to be as effective as lithium and olanzapine in patients with pure mania, and it can be more effective than lithium in certain subtypes of bipolar disorder (e.g., rapid cycling, mixed states, bipolar disorder with comorbid substance abuse).2,3,22,44,71 Placebo- and lithium-controlled and open studies report that valproate reduces or prevents recurrent manic, depressive, and mixed episodes.2,3,22

Giving lithium, carbamazepine, antipsychotics, or benzodiazepines with valproate can augment its antimanic effects. The addition of valproate to lithium can have synergistic effects in treatment-refractory rapid cycling and mixed states, and the combination has demonstrated efficacy in maintenance therapy for bipolar I disorder.43 Combinations of valproate and carbamazepine can have synergistic effects, but the potential drug interactions make blood level monitoring of both agents essential.22 Adding adjunctive SGAs to valproate can be effective for breakthrough mania or if there is incomplete or partial response to monotherapy. Clozapine, olanzapine, and quetiapine can increase the risk of sedation and weight gain when combined with valproate. The combination of valproate and lamotrigine can be effective, but there is an increased risk of rashes, ataxia, tremor, sedation, and fatigue.65,72

Adverse Effects The most frequent dose-related adverse effects with valproate are GI complaints (anorexia, nausea, indigestion, vomiting, mild diarrhea, and flatulence), fine hand tremors, and sedation.2,22,65The GI complaints are usually transient, but giving the medication with food, using lower initial doses with gradual increases in doses, or switching to divalproex sodium extended-release tablets can minimize them.2,22 Reduction of the dose or the addition of a β-blocker can alleviate tremors, and giving the total daily dose at bedtime can minimize daytime sedation.2,22

Other adverse effects of valproate include ataxia, lethargy, alopecia, changes in the texture or color of hair, pruritus, prolonged bleeding because of inhibition of platelet aggregation, transient increases in liver enzymes, and hyperammonemia.22,65 Increased appetite and weight gain occurs in approximately 50% of patients on long-term valproate therapy. Thrombocytopenia can occur at higher doses, and patients should be monitored for bleeding and bruising. Lowering the valproate dose can restore platelet counts to normal levels.2 Fatal necrotizing hepatitis is a rare idiosyncratic, non–dose-related adverse effect that has occurred in children with epilepsy receiving multiple anticonvulsants.22,65 A life-threatening hemorrhagic pancreatitis has been reported in both children and adults.2,22,65 An in-depth discussion of adverse effects can be found in Chapter 40.

Drug–Drug Interactions A summary of drug–drug interactions for valproate can be found in Chapter 40.

Dosing and Administration For healthy inpatient adults with acute mania, the initial starting dosage of valproate is typically 20 mg/kg/day in divided doses over 12 hours. The daily dose is adjusted by 250 to 500 mg every 1 to 3 days based on clinical response and tolerability. Maximum recommended dosing is 60 mg/kg/day (see Table 52-6).2,22,65 For outpatients who are hypomanic or euthymic, or for elderly patients, the initial starting dose is generally lower (5 to 10 mg/kg/day in divided doses) and gradually titrated to avoid adverse effects. Once an optimal dose has been achieved, the total daily dose can be given twice daily or at bedtime if tolerated.2,22,65 Extended-release divalproex can be administered once daily, but bioavailability can be 15% lower than that of immediate-release products, thus requiring slightly higher doses.2 In clinical practice, patients with bipolar disorder who are stable can be switched between formulations without having to change the dose. This is not the case for patients with seizure disorder.

Recommended baseline and routine laboratory tests for valproate are listed in Table 52-7. Although therapeutic serum concentrations of valproic acid have not been established in bipolar disorder, most clinicians use the anticonvulsant therapeutic serum range of 50 to 125 mcg/mL (347 to 866 μmol/L) taken 12 hours after the last dose.2,22 In one study patients with valproate levels greater than 94.1 mcg/mL (652 μmol/L) had greater efficacy for bipolar mania.73 Patients with cyclothymia or mild bipolar II disorder can have a therapeutic response to lower doses and blood levels, whereas some patients with a more severe form of bipolar disorder can require up to 150 mcg/mL (1,040 μmol/L). Serum valproic acid levels are most useful when assessing for compliance and toxicity.

Carbamazepine Carbamazepine, a dibenzazepine derivative, is structurally related to tricyclic antidepressants (TCAs).22 The precise mechanism of action of carbamazepine in affective disorders remains to be elucidated.63Carbamazepine is not a first-line agent for bipolar disorder, and is generally reserved for lithium-refractory patients, rapid cyclers, or mixed states.2,22 It has acute antimanic effects comparable to lithium and chlorpromazine, but its long-term effectiveness is unclear.2,22 One comparison trial in hospitalized manic patients indicated that carbamazepine was less effective and needed more rescue adjunctive medications than valproate.2 Other comparison studies with lithium have reported carbamazepine to be less effective than lithium for maintenance therapy.2 In a double-blind, placebo-controlled, crossover study and in an open study, carbamazepine showed efficacy in the treatment of bipolar depression.2,22 Studies with treatment-refractory patients have reported that carbamazepine has both acute and long-term prophylactic effects.3,22 A gradual loss of efficacy over time (similar to lithium and valproate) has been reported in some patients.3,22

The combination of carbamazepine with lithium, valproate, and antipsychotics is often used for treatment-resistant patients experiencing a manic episode.22 Carbamazepine plus olanzapine was not found to be more effective than carbamazepine alone in the treatment of acute mania or mixed episodes.53 Carbamazepine increases the hepatic metabolism of antidepressants, anticonvulsants, and antipsychotics; thus, dosage increases can be necessary (see Drug–Drug Interactions below).22,66 Calcium channel blockers (e.g., verapamil and diltiazem) increase carbamazepine blood levels; thus, combination therapy should be closely monitored.66 The combination of carbamazepine with nimodipine for treatment-refractory bipolar illness can have potential benefit.74

Adverse Effects A summary of adverse effects for carbamazepine can be found in Chapter 40. Acute overdoses of carbamazepine are potentially lethal, and serum levels above 15 mcg/mL (63 μmol/L) are associated with ataxia, choreiform movements, diplopia, nystagmus, cardiac conduction changes, seizures, and coma.2 Gastric lavage, hemoperfusion, and symptomatic treatment are recommended for the management of carbamazepine toxicity.

Drug–Drug Interactions Carbamazepine significantly induces the hepatic cytochrome P450 isoenzyme 3A4 and to a lesser degree 1A2, 2C9/10, and 2D6, which increases the metabolism of many medications.2,3,66 Women taking oral contraceptives who receive carbamazepine require alternative contraceptive methods.3

Carbamazepine is metabolized to an active 10,11-epoxide metabolite; thus, medications that inhibit 3A4 isoenzymes can result in carbamazepine toxicity (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil).2,3,22,66 When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein-binding sites, thus increasing free levels.3,22 Combining clozapine and carbamazepine is not recommended because of the possibility of bone marrow suppression with both agents.22

Dosing and Administration During an acute manic episode in most hospitalized patients, carbamazepine can be started at 400 to 600 mg/day in divided doses with meals and increased by 200 mg/day every 2 to 4 days up to 10 to 15 mg/kg/day. In outpatients the initial dose of carbamazepine should be lower and titrated gradually in order to avoid adverse effects. In clinical practice many patients are able to tolerate once-daily dosing of carbamazepine once their mood episode has stabilized. The dose of carbamazepine should be gradually increased until response is achieved or there is evidence of toxicity. During the first month of therapy, serum concentrations of carbamazepine may be affected due to autoinduction of cytochrome P450 3A4 enzymes.66

Carbamazepine serum levels are usually obtained every 1 to 2 weeks during the first 2 months, and then every 3 to 6 months during maintenance therapy. Serum levels should be drawn 10 to 12 hours after the dose (trough levels) and at least 4 to 7 days after a dosage change. Although there is no correlation between carbamazepine serum concentration and degree of antimanic or antidepressant response, most clinicians attempt to maintain levels between 6 and 10 mcg/mL (25 and 42 μmol/L) (although some treatment-resistant patients can require serum concentrations of 12 to 14 mcg/mL [51 to 59 μmol/L]). Recommended baseline and routine laboratory tests for carbamazepine are listed in Table 52-7.

Oxcarbazepine Oxcarbazepine, a 10-keto analogue of carbamazepine, blocks voltage-sensitive sodium channels, modulates voltage-activated calcium currents, and increases potassium conductance.67 Initial trials suggested oxcarbazepine has mood-stabilizing effects similar to those of carbamazepine, with the advantages of milder adverse effects, no autoinduction of liver enzymes, and potentially fewer drug interactions.2 There are currently less data supporting the use of oxcarbazepine than carbamazepine in the treatment of bipolar disorder.

Adverse Effects Oxcarbazepine has dose-related adverse effects of dizziness, sedation, headache, ataxia, fatigue, vertigo, abnormal vision, diplopia, nausea, vomiting, and abdominal pain.67 In one study, hyponatremia was reported to occur in patients taking oxcarbazepine and carbamazepine at rates of 29.9% and 13.5%, respectively.75 Severe hyponatremia (sodium less than or equal to 128 mEq/L [mmol/L]) was reported by Dong et al. as 12.4% and 2.8% of patients for oxcarbazepine and carbamazepine, respectively.75 An in-depth discussion of adverse effects can be found in Chapter 40.

Drug–Drug Interactions Oxcarbazepine, a cytochrome P450 2C19 enzyme inhibitor and a 3A3/4 enzyme inducer, has the potential for causing drug interactions.67 It induces the metabolism of oral contraceptives; thus, alternative contraceptive measures are required.3,76

Dosing and Administration Initial dosing is usually 150 to 300 mg twice daily, and daily doses can be increased by 300 to 600 mg every 3 to 6 days up to 1,200 mg/day in divided doses (with or without food).67

Lamotrigine Lamotrigine blocks voltage-sensitive sodium channels, modulates or decreases glutamate and aspartate release, and has antikindling properties.3,64,68,72,77

Efficacy The effectiveness of lamotrigine for the maintenance treatment of bipolar I disorder in adult patients was established in two multicenter, double-blind, placebo-controlled studies.2 Doses of 200 mg/day were more effective than lower doses, and there were no advantages to using 400 mg/day. Lamotrigine has both antidepressant and mood-stabilizing effects; it may have augmenting properties when combined with lithium or valproate, and has low rates of switching patients to mania.72,78 Although lamotrigine is less effective for acute mania compared with standard mood stabilizers, it may be beneficial in the maintenance therapy of treatment-resistant bipolar I and II disorders, in rapid-cycling dysphoric mania, and in mixed states.2,3,72 Lamotrigine seems to be most effective for the prevention of bipolar depression; therefore, clinically it is often used in the treatment of patients with bipolar II. There are case reports of possible lamotrigine-induced mania when added to lithium, carbamazepine, and valproate.79In each of the cases reported, the patients had depressive mood symptoms or rapid mood changes requiring additional therapy.79

Adverse Effects Common adverse effects include headache, nausea, dizziness, ataxia, diplopia, drowsiness, tremor, rash, and pruritus.68,72 Approximately 10% of patients in premarketing clinical trials developed a maculopapular rash and required discontinuation of therapy.68,72 Although most rashes are self-limiting and resolve with continued treatment, some cases progressed to life-threatening conditions such as Stevens-Johnson syndrome. The incidence of rash appears to be greatest with coadministration of valproate, with higher than recommended initial doses, and with rapid dose escalation.68 Patients should be warned about the rash, and the need for discontinuing lamotrigine if the rash is diffuse, involves mucosal membranes, and is accompanied by a fever or sore throat. For an in-depth discussion of the adverse effects of lamotrigine, see Chapter 40.

Drug–Drug Interactions Valproate decreases the clearance of lamotrigine (i.e., more than doubles the half-life), and lamotrigine must be administered at a reduced dosage (approximately half the standard dose).68 For an in-depth discussion of drug–drug interactions with lamotrigine, see Chapter 40.

Dosing and Administration For the maintenance treatment of bipolar disorder, the usual dosage range of lamotrigine is 50 to 300 mg/day. The target dose is generally 200 mg/day (100 mg/day in combination with valproate and 400 mg/day in combination with carbamazepine).68,72 For patients not taking medications that affect lamotrigine’s clearance, the dose is 25 mg/day for the first 2 weeks of therapy, 50 mg/day for weeks 3 and 4, 100 mg/day for week 5, and 200 mg/day for week 6 and beyond.2,68,72 Patients who stop lamotrigine therapy for more than a few days should be restarted on the recommended dosage escalation titration schedule.


FGAs that block dopamine-2 (DA2) receptors and SGAs that block both DA2 and serotonin 2A (5-HT2A) receptors are used to decrease dopamine (DA) activity in the treatment of mania and mixed states. FGAs and SGAs such as aripiprazole, asenapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or adjunctive therapy in the treatment of acute mania.80Controlled studies in acute mania with lithium or valproate plus an antipsychotic suggest greater efficacy with combination therapies compared with that with any of these agents alone.2,80 FGAs (e.g., chlorpromazine and haloperidol) are effective in up to 70% of patients with acute mania, particularly those with psychosis and psychomotor agitation. SGAs have demonstrated similar efficacy for the treatment of acute mania associated with agitation, aggression, and psychosis.2,80

Treating acute bipolar depression is very challenging, and some antipsychotics may play a useful role. Four large randomized controlled trials support use of quetiapine as a monotherapy treatment option for bipolar depression.53Data also support use of combined fluoxetine/olanzapine in treating bipolar depression.

Long-term safety of antipsychotics as monotherapy or as an adjunctive therapy for bipolar maintenance treatment still needs to be evaluated.2,53,80 Risks versus benefits must be weighed due to the long-term adverse effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, and tardive dyskinesia) antipsychotics may cause.80,81 Aripiprazole, olanzapine, and risperidone long-acting injection are effective monotherapy options for maintenance treatment in bipolar disorder.53 Some data reported in abstract form support quetiapine for maintenance treatment. First-generation depot antipsychotics (e.g., haloperidol decanoate, fluphenazine decanoate) can have a place in maintenance treatment of bipolar disorder in patients who are noncompliant or treatment-resistant.2

Clozapine monotherapy has acute and long-term mood-stabilizing effects in refractory bipolar disorder, including conditions with mixed mania and rapid cycling, but requires regular white blood cell monitoring for agranulocytosis.2,22,80

Clinical Controversy

What is the role of SGAs in bipolar disorder?

The use of SGAs in bipolar disorder does not come without risk. Metabolic side effects should be considered when weighing risks and benefits of various acute and chronic treatment options. The optimal management of weight gain and its consequences on physical and mental health is important. Clinicians must make prescribing decisions in collaboration with patients concerning the treatment of bipolar disorder, weighing the risks of antipsychotics versus traditional mood stabilizers (e.g., lithium or valproate).

Adverse Effects A summary of adverse effects for antipsychotics can be found in Chapter 50.

Drug–Drug Interactions A summary of drug interactions with antipsychotics can be found in Chapter 50.

Dosing and Administration For acute mania, higher initial doses of antipsychotics can be required (e.g., olanzapine 20 mg/day in hospitalized patients). Once acute mania is controlled (usually within 7 to 28 days), the antipsychotic can be gradually tapered and discontinued, and the patient maintained on the mood stabilizer monotherapy.


Images Recommendations for baseline and routine laboratory testing for patients receiving carbamazepine, lamotrigine, lithium, oxcarbazepine, SGAs, and valproate are found in Table 52-7.

Alternative Medication Treatments

Images Benzodiazepines Weighing the risk-to-benefit ratio, high-potency benzodiazepines such as clonazepam and lorazepam are commonly used as an alternative to or in combination with antipsychotics when patients are experiencing acute mania, agitation, anxiety, panic, and insomnia, or cannot take mood stabilizers (e.g., during the first trimester of pregnancy).2,3,82,83 Lorazepam is available for intramuscular injection and is useful in the acute management of agitation. Benzodiazepines cause minimal adverse effects compared with antipsychotics, and at higher doses, rapidly sedate agitated patients.3 They can cause CNS depression, sedation, cognitive and motor impairment, dependence, and withdrawal reactions. When no longer required, benzodiazepines should be gradually tapered and discontinued to avoid withdrawal symptoms.

Antidepressants For many years antidepressants were recommended as adjunctive therapy for acute bipolar depression. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) suggest that adjunctive antidepressants may be no better than placebo for acute bipolar depression when combined with mood stabilizers.84 Controversy exists concerning the use of antidepressants, and many clinicians consider them third line in treating acute bipolar depression, except in patients with no history of severe and/or recent mania or potentially in bipolar II patients.85 The concern of mood switching (i.e., rapidly switching from depression to mania or hypomania) with the use of antidepressants is valid, although not common. Data show that the rate of mood switch with selective serotonin reuptake inhibitors (SSRIs) is around 3.8%, similar to placebo, when combined with mood stabilizers. The rate of mood switch with dual-acting agents (e.g., TCAs or venlafaxine) is higher, and thus these agents should be used with caution.85,86 It is very important that before initiating therapy with an antidepressant, the patient should be on a therapeutic dosage or blood level of a primary mood stabilizer.2Patients who have a history of mania after a depressive episode or who have frequent cycling should be treated cautiously with antidepressants.2,3 In general, the antidepressant should be gradually withdrawn 2 to 6 months after remission, and the patient maintained on a mood-stabilizing agent.87,88 For more information, see Chapter 51 for comparisons among antidepressants.

Calcium Channel Antagonists Calcium channel antagonists inactivate voltage-sensitive calcium channels, thus inhibiting neurotransmitter synthesis and release and neuronal signal transmission.22,77 Verapamil, a nondihydropyridine, has demonstrated mood-stabilizing properties in some studies, but negative results were found in other trials.2,3,22,89 Nimodipine, a dihydropyridine, can be more effective than verapamil for rapid-cycling bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good penetration into the brain.2,3,22,45,77,89 Calcium channel blockers are generally well tolerated, and the most common adverse effects are bradycardia and hypotension. These are seldom used in everyday clinical practice.

Newer Anticonvulsants Third-generation anticonvulsants have been investigated for treating bipolar disorder with the hope that a different mechanism of action would be beneficial for mood stabilization. Gabapentin, levetiracetam, tiagabine, topiramate, and zonisamide have negative or limited positive data supporting their use in bipolar disorder. Topiramate has been used as an add-on weight-reduction medication, but there are no randomized controlled trials supporting its use in bipolar disorder.90

Special Population

The approach for treating bipolar disorder in special populations (e.g., comorbid medical or psychiatric disorders, pregnancy) can vary among clinicians. Patients with comorbid medical conditions or concomitant substance abuse, those older than 65 or younger than 18 years of age, and pregnant patients can require different treatment approaches. Women have a high risk of relapse postpartum; therefore, prophylaxis with mood stabilizers is recommended immediately postpartum to decrease the risk of relapse.91

Prophylactic medications such as lithium or valproate can prevent postpartum episodes in women with bipolar disorder.2 Pharmacotherapy during pregnancy is complicated, and the risk-to-benefit ratio must be weighed. Infants whose mothers took lithium during the first trimester of pregnancy may have a lower incidence of cardiovascular defects (particularly Ebstein’s anomaly) than was previously thought.2,22Current estimates of this malformation when given lithium during the first trimester are estimated between 1:1,000 and 1:2,000.91 Lithium freely crosses the placenta and is found in equal concentrations in maternal and fetal blood.60 When lithium is used during pregnancy, it should be tapered down to the lowest effective dose necessary to decrease the risk of relapse. Lithium can cause “floppy” infant syndrome (e.g., low Apgar scores, lethargy, hypotonia, bradycardia, cyanosis, shallow respiration, and poor sucking), hypothyroidism, and nontoxic goiters. Milk concentrations of lithium range from 30% to 50% of the mother’s serum concentration, and serum concentrations in the nursing infant are 10% to 50% of the mother’s; thus, breastfeeding is usually discouraged.2,92 If using lithium during pregnancy, dose adjustments and close monitoring of serum levels will be needed due to changes in glomerular filtration rates and renal perfusion rates during pregnancy and immediately after delivery.93

Neural tube defects cause the most concern for clinicians treating pregnant patients during their first trimester. Data from the North American Antiepileptic Drug Pregnancy Registry show the risk of neural tube defects is about 1 in 1,500 for nonexposed babies.94 Carbamazepine’s risk of neural tube defects is estimated to be 0.5% to 1%.77 Carbamazepine is excreted in breast milk (the milk-to-maternal plasma ratio of carbamazepine is ~0.4).3 Craniofacial abnormalities, developmental delays, microcephaly, and other abnormalities are also of concern when using anticonvulsants. For pregnant patients treated with lamotrigine, major malformation rates are similar to those in the general population (2.9% vs. 2% to 3%, respectively), but data for lamotrigine are limited compared with those for some older anticonvulsants.93 The International Lamotrigine Pregnancy Register reports 12 major congenital malformations from 414 first-trimester exposures.93 Valproate is usually not recommended during the first trimester of pregnancy because the risk of neural tube birth defects is about 1 in 20 exposed babies.94 Australian registry data in patients with epilepsy show dose-related teratogenicity with doses greater than 1,100 mg/day of valproate.95 Administration of folate can reduce the risk of neural tube defects; therefore, the risks versus benefits of using valproate during pregnancy must be discussed with the patient.22Women of childbearing age on valproic acid and pregnant women should receive folic acid supplementation. Valproic acid is excreted into human breast milk in low concentrations (less than 1% to 10% of the mother’s serum level), so is considered to be compatible with breastfeeding.3 One case report of thrombocytopenia and anemia from valproate exposure has been reported in a nursing infant. If the mother receives valproate during breastfeeding, mother and infant should have identical laboratory monitoring.

Caution should be used when prescribing antipsychotics during pregnancy. There are far more data on the use of FGAs than those on the use of SGAs during pregnancy. Some data are available for haloperidol and low-dose chlorpromazine, and these data show no elevated rate of physical malformations during first-trimester exposure.96 Higher doses of chlorpromazine used in treating psychiatric illness may be associated with neonatal withdrawal and extrapyramidal symptoms.96 Data on other FGAs are limited. Data on the SGAs are more limited, but do not show an overall increased risk of fetal abnormalities.96Most of the data are for olanzapine, risperidone, and quetiapine.96There are limited reports with clozapine, aripiprazole, and ziprasidone.96 There is still a paucity of human data with antipsychotics, and therefore risk-to-benefit ratio must be weighed.

There are few controlled studies in children and adolescents with bipolar disorder; thus, little is known about the long-term efficacy and safety of specific agents or for combination therapies in this population.10,97 Lithium, valproic acid, and carbamazepine are all used in pediatric bipolar disorder. Data are limited, supporting their use with only six double-blind studies completed in the pediatric population.98 Lithium is the only medication approved as a mood stabilizer for children older than 12 years of age.99 Aripiprazole and risperidone are FDA-approved for bipolar mania in patients aged 13 to 17 years.100 Quetiapine is approved as monotherapy or adjunct to lithium or divalproex in patients aged 10 to 17 years during a manic episode.100 It did not show efficacy in a small pilot study of adolescent bipolar depression.101 Olanzapine is approved for use in patients with manic or mixed episodes aged 13 to 17 years.100 Ziprasidone has support of an FDA advisory panel for pediatric acute mania, but it does not yet have FDA approval.102 Long-term data are still needed for all of these agents. Published guidelines for treatment of bipolar disorder in children and adolescents include the Practice Parameters for the Assessment and Treatment of Children and Adolescents with Bipolar Disorder by the American Academy of Child and Adolescent Psychiatry.10

Patients with bipolar illness are more likely to have medical comorbidities than the general population (64.3% vs. 48.3%).103 As people age, medical comorbidities tend to increase, which complicates the management of bipolar disorder in elderly patients. Renal clearance decreases, and elimination half-life nearly doubles for lithium in elderly patients.104 Half-life of valproate has been reported to increase with aging.105 Patients with dementia can have increased sensitivity to the side effects of mood stabilizers and antipsychotics. No prospective, randomized, placebo-controlled trials have been published examining efficacy of lithium or valproate in elderly patients.106

Personalized Pharmacotherapy

New information is quickly evolving in the area of pharmacogenetics and pharmacogenomics that may help clinicians individualize treatment for patients with bipolar disorder. Genetic testing is available to determine if patients are poor or rapid metabolizers of cytochrome P450 2D6 and 2C19, thus helping predict potential response as well as adverse effects. The use of carbamazepine requires genetic testing for the human leukocyte antigen (HLA) allele, HLA-B 1502, in patients of Asian ancestry to help detect a higher risk of Stevens-Johnson syndrome and toxic epidermal necrolysis.


The establishment and maintenance of a therapeutic alliance between the patient and clinician is essential in monitoring a patient’s psychiatric status and safety; enhancing treatment adherence; promoting good nutrition, sleep, and exercise; identifying stressors; recognizing new mood episodes; and minimizing adverse reactions and drug interactions.2 Patients who have a partial response or nonresponse to established bipolar therapies should be reassessed for an accurate diagnosis, concomitant medical or psychiatric conditions, and medications or substances that exacerbate mood symptoms. Nonadherence to medication treatment, delusional symptoms, alcohol or substance abuse, rapid cycling, or mixed states are often associated with poorer treatment outcomes.




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