19 - Approaches to the Treatment of Manic-Depressive States - Bipolar Disorders
Editors: Shader, Richard I.
Title: Manual of Psychiatric Therapeutics, 3rd Edition
Copyright 2003 Lippincott Williams & Wilkins
> Table of Contents > 19 - Approaches to the Treatment of Manic-Depressive States (Bipolar Disorders)
19
Approaches to the Treatment of Manic-Depressive States (Bipolar Disorders)
Richard I. Shader
Descriptors such as bipolar or manic-depressive evoke the image of patients whose moods regularly alternate between up, excessively happy, or high periods and down, excessively depressed, or low periods. In fact, alternating episodes rarely occur, and manic shifts probably account for less than 15% of all episodes in this diagnostic group. Manic and depressive states have been described for many centuries, but the notion of manic-depressive illness per se was not proposed until the middle of the 19th century by Falret (la folie circulaire) and Baillarger (la folie a double forme). Later, Kraepelin added impetus to its recognition as a distinct disorder when he separated it from schizophrenia by pointing out its episodic course and the importance of abnormal moods, which stood in contrast to the thought disturbance of schizophrenia. In 1957, Leonhard further subdivided manic-depressive illness by separating patients with mania and depression (bipolar) from those with depression or mania alone (monopolar, unipolar).
I. General Diagnostic Considerations
Both subtle and significant changes and controversies have occurred as the diagnostic criteria for manic-depressive illness and bipolar disorder (BD) have evolved into their current iteration in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).
Bipolar I disorders describe those disorders in which at least one manic, hypomanic (with at least one previous manic), or mixed manic and depressive episode clearly is or has been present. Bipolar I disorder presenting solely or even mostly as recurrent manic episodes is extremely rare. This author has seen patients with episodic paranoia, and he believes that they may actually represent this otherwise underrecognized diagnostic subgroup.
Bipolar II disorder describes patients with at least one depressive and one hypomanic episode when no manic episode is or has been present. A diagnosis of BD, not otherwise specified is recommended when the mania, depression, or hypomania appears to be solely secondary to a medical condition, such as multiple sclerosis or hyperthyroidism; to substance use (e.g., amphetamines, cocaine); or to treatment with antidepressants (e.g., monamine oxidase inhibitors), electroconvulsive therapy (ECT), sympathomimetic amines, decongestants, or corticosteroids. Curiously, some patients with secondary presentations (e.g., during prednisone or cocaine use) may be manic in one episode and paranoid in another.
Cyclothymic disorder (CyD) is another currently recognized mood disorder. Its relationship to BD corresponds to the relationship between major depressive disorder (MDD) and dysthymic disorder in many ways (see Chapter 18). Limited data suggest that cyclothymic personality, a diagnostic predecessor of CyD, occurs more often in relatives of BD patients than it does in the relatives of normal control subjects or in patients with MDD. To meet criteria for CyD, patients must have numerous bouts of hypomanic behaviors or symptoms and depressed mood, including anhedonia, for a minimum of 2 years (note: for at least 1 year in youth). Obviously, these descriptive criteria for CyD are both arbitrary and time bound. For example, a patient with muted mood shifts during the year before a consultation likely has CyD, even though the 2-year requirement has not yet been met. Some of these patients may later go on to have full-blown BD. DSM-IV contains a requirement that the symptom intensity or frequency is such that it interferes with functioning or relationships. Many people known for their sustained, optimistic, energetic, and sometimes driven approaches to life would technically qualify as having CyD if this requirement were not present.
The following subsections consider specific types of episodes in BD.
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A. Depressive Episodes
As Chapter 18 noted, the clinical features of a depressive episode (see Table 18.1) are the same in the DSM-IV for both MDD and BD, even though many clinicians recognize differentiating characteristics. Among characteristics of BD are earlier age at onset, shorter episode duration, and a greater likelihood of hypersomnia, rather than the reduced sleep and early morning awakening common to MDD depressive episodes. As is discussed below, treatment response also differs; lithium is more effective in BD depressive episodes than it is in MDD depressive episodes. Depressive episodes of BD most commonly begin in the fall or winter. Most serious postpartum depressions turn out to be episodes of BD.
An important finding from a cohort study conducted in Pittsburgh was a suicide attempt rate of 46.3% during depressive episodes in patients with BD; the comparable rate for patients with manic episodes was 13.4%.
B. Manic Episodes
Table 19.1 lists the clinical features of a manic episode. Manic episodes vary considerably in their intensity both within the same patient over time and among patients. Onset may be rapid and acute (hours to days) or subacute (over a few weeks), and episodes commonly begin in the spring. The durations are also variable; at least 1 week is required by current convention. Before effective therapies were available, some patients had episodes lasting 4 to 13 months, and for approximately four discrete manic episodes to occur within a decade was not unusual. Some episodes appear to occur in response
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to external stressors (e.g., the loss of a significant person in one's life); others seem to develop spontaneously.
TABLE 19.1. DIAGNOSTIC FEATURES OF A MANIC EPISODE | |||
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Up to 50% of acute manic episodes involve some psychotic features. Some data suggest that the earlier the onset of BD, the greater the likelihood is of psychotic features during the course of the disorder. For example, both mood-congruent (e.g., I am the Messiah ) and mood-incongruent (e.g., God made me strike him ) delusions and behaviors may occur. The distinction between congruence and incongruence is often difficult to establish in mania; the idea that God was behind an action, which is a delusion of being controlled, may reflect a sense of being singled out (i.e., exaggerated self-importance). A patient with schizophrenia or MDD with psychosis who says the same thing probably does not feel special in a positive or grandiose sense to God.
Humor is often noted during manic episodes. It is frequently contagious, but it may be caustic or hostile. Manic patients are frequently intrusive, frenetic, or labile in mood. Some are violent; violence is generally seen only during periods of extreme and untreated symptomatology or when the individual misinterprets the intentions of others in a crowded, noisy, or otherwise overstimulating environment.
C. Hypomanic Episodes
Table 19.2 lists the clinical features of a hypomanic episode. Although the intensity of the elevated or irritable mood during a hypomanic episode is by definition less extreme than it is in mania, more lability and volatility may be seen, perhaps as a consequence. Some clinicians believe that patients are more likely to attempt suicide, for example, when they are hypomanic rather than when they are manic. Efforts to initiate any therapeutic intervention during an episode of hypomania are likely to be unsuccessful.
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Most patients like their hypomanic phases (e.g., they enjoy their sense of freedom or their increased productivity or creativity), and their behavior is rarely disruptive enough for others to become involved in trying to bring about treatment.
TABLE 19.2. DIAGNOSTIC FEATURES OF A HYPOMANIC EPISODE | |||
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D. Rapid-Cycling Mania
DSM-IV offers a course-specifying option with rapid cycling for patients having more than three episodes of mood cycling within a year. This modifier can be applied to both bipolar I and bipolar II patients. As the phrase is used in the DSM-IV, with rapid cycling then refers solely to the course and frequency and not to the severity of the moods. Up to 20% of BD patients exhibit rapid cycling; frequency estimates depend in part on whether duration criteria for manic, hypomanic, or depressive episodes are required or whether CyD patients are included. Patients who cycle rapidly probably do not represent a homogeneous subgroup. Some patients have frequent episodes from the very beginning; others cycle more rapidly only after many years of untreated cycling. In at least some patients, antidepressant therapy or the use of psychostimulants may also possibly be a contributing factor.
E. Mixed Mania and Dysphoric Mania
In the DSM-IV, one subcategory under bipolar I disorder is with most recent episode mixed. This refers to patients who meet criteria for both manic and depressive episodes at some time during the day for at least 7 consecutive days. Many clinicians view the diagnosis of mixed mania as overlapping considerably with the unofficial diagnosis of dysphoric mania. One literature review of patients with these diagnoses suggests that dysphoric mania appears in about one-third of BD patients, that a mixed symptom presentation is not limited to any specific stage of BD, and that both shorter and longer term outcomes are less optimistic than they are for unmixed episodes.
II. Genetic, Epidemiologic, Course, and Other Considerations
BD represents about one-fifth of all mood disorders; most patients have their first full episode between 15 and 24 years of age. The Pittsburgh cohort study of 2,308 patients with BD found the mean age at onset to be 19.8 years (median, 17.5 years), a figure close to the commonly stated age of 21 years. The mean age at onset for MDD is about 27 years. The ratio of women to men is approximately equal, although some studies suggest that BD is slightly more common in women. These observations are in contrast to the ratio of 2 or 3 to 1 for women to men in MDD. When BD appears for the first time in a patient over the age of 60, it is likely to be secondary to an eventually identifiable medical condition (e.g., a lesion in the right temporal lobe). Lifetime prevalence rates for BD are estimated at 1.2%; the corresponding figure for MDD is 4.4%. Cross-national data yield lifetime prevalence rates of 0.6% to 3.3% for BD. Some data suggest that the lifetime prevalence rate for bipolar I disorder is slightly higher than that for bipolar II disorder (i.e., 0.8% vs. 0.5%). The 1-year prevalence rate for manic or hypomanic episodes is estimated to be 3.0%.
Twin studies support a genetic vulnerability or predisposition to BD. No single genetic model is accepted; a multifactorial polygenetic model seems most likely. Concordance rates for BD in monozygotic twins are 65% to 80%, whereas the rates in dizygotic twins are approximately 20%. Family studies also suggest that BD is familial; BD is more common among the first-degree relatives of BD patients than it is among control subjects, but MDD is even more common among these same relatives. Adoption studies are not conclusive. The Pittsburgh cohort study found BD in 54% of family members of patients with BD, whereas 52.1% had relatives with MDD. Some authorities believe that a 2-threshold genetic model is needed to characterize the relationship between MDD and BD.
As is noted above, most serious postpartum depressive and psychotic disturbances are episodes of BD. The risk of a postpartum episode is about 1 per 1,000 deliveries. Infanticide occurs during 3% to 4% of these episodes. Postpartum BD episodes generally respond well to standard interventions, such as lithium, mood-stabilizing anticonvulsants, antipsychotic agents, and ECT.
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It is not uncommon for a period of 3 to 5 years of euthymic functioning to occur between the first and second episodes of BD. This interval usually shortens over time. Concomitant problems with substance misuse or abuse are common in bipolar I patients in the United States.
III. General Treatment Considerations
Most BD patients are treated on an outpatient basis. To accomplish this successfully, involvement of key relatives or reliable and responsible friends is often necessary. Because most BD patients enjoy their highs, they cannot be counted on to seek treatment when their symptomatology begins to escalate. Family members or significant others need to understand the nature and course of BD and its treatment. Anticipating potentially disastrous outcomes and having contingency plans in place whenever possible are essential. For example, if overspending is characteristic of the episodes, limits may need to be placed on bank accounts or credit cards. If hospitalization may be required, a plan for getting the patient to the hospital must already be formulated, because the patient's cooperation is unlikely if he or she has become overexcited and hostile or suicidal. During a manic episode, most patients have little or no insight into either their condition or their negative effects on others; manic denial is almost invariable.
For those patients with access to and an interest in psychotherapy, benefit can be achieved through a cognitive-behavioral approach that pays attention to issues, such as adherence, denial, autonomy or dependency, impact on significant others, and real or symbolic losses. For some, a psychoeducational component that ascertains patients' beliefs about their disorder and that provides clarifications and information about the nature, course, and genetic transmission of BD can be helpful. Family therapy should also include a psychoeducational component, strategies to promote adherence, methods of relapse prevention, and attention to eliciting early signs of pending decompensations. Psychotherapies may be particularly helpful for those BD patients who have episodes that seem to be precipitated by external stresses or that include behaviors that are disruptive to the family. Friends can serve as an early warning system when arrangements have been made in advance. They can also be helpful with regard to issues of treatment and medication compliance.
Hospitalization is often required for patients in the advanced stages of a manic episode. Reducing external stimulation through the use of quiet rooms or even seclusion rooms (see Chapter 25) can be extremely beneficial, particularly in the hours before medications become effective. Physical restraints (see Chapter 26) at times may be indicated to protect the patient from self-injury or from harming others. In implementing these, involving only trained staff and following all guidelines and regulations regarding the use of restraints and seclusion are essential.
IV. Psychopharmacologic Treatments
Although lithium carbonate is the mainstay of the treatment of BD for many, but not all, clinicians, it is not often the best approach to treating an acute manic episode. Although lithium treatment may be initiated, it may not be effective during the acute or dysphoric manic episodes or symptoms, or the symptoms may be too extreme to be able to wait for lithium to take effect. Beginning concomitant use of an antipsychotic agent (e.g., olanzapine, haloperidol, mesoridazine) or a benzodiazepine (e.g., clonazepam, lorazepam) is often necessary to to achieve a more prompt response. Parenteral forms of these five agents are available. Loading doses of valproate are also an option.
When antidepressants are necessary during depressive episodes, a variety of different antidepressants can be added; some antidepressants, like the selective serotonin reuptake inhibitors (SSRIs) and bupropion, are thought to cause fewer switches into mania than do others, such as imipramine and monamine oxidase inhibitors. Among the currently marketed antidepressants, imipramine is associated with more switches into mania than other agents are. Monamine oxidase inhibitors tend to do this somewhat less frequently, and these are considered by some clinicians to be especially useful in the treatment of depressive episodes in
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BD. Short-term treatment is not recommended. Relapses within 12 months are to be expected.
For rapid-cycling patients or those with mixed or dysphoric mania, mood-stabilizing anticonvulsants or clozapine may be preferable to lithium. These agents are considered in the following sections.
A. Lithium Salts
Curiously, in 1949, the year Cade reported on the specific value of lithium carbonate in the treatment of mania, the Journal of the American Medical Association published several articles on severe and sometimes fatal lithium poisoning from the use of lithium chloride as a table salt substitute. Fortunately, the significance of Cade's work was recognized by Schou in Denmark. He and his colleagues undertook the further development of lithium carbonate as the earliest cornerstone in the treatment of manic-depressive illness. Their work contributed to its eventual marketing in the United States in 1970 for the treatment of acute mania and to its expanded indication in 1974 for prophylaxis against recurrences of mania. (Note: United States Food and Drug Administration (FDA)-approved indications for lithium salts do not mention depressive episodes.)
The exact mechanisms of lithium's actions in BD are not known. It is a ubiquitous agent that has such diverse effects as (a) altering sodium transport; (b) modest but consistent proserotonergic properties, including sensitization of postsynaptic hippocampal CA3 receptors; (c) augmentation of acetylcholine synthesis and tone in the cortex; (d) reduction of presynaptic (exocytotic) release of norepinephrine and dopamine, perhaps by increasing intraneuronal metabolism of catecholamines; (e) attenuation of circadian rhythms; (f) actions on G-protein coupled second-messenger systems; and (g) reduction of phosphoinositol turnover through the inhibition of the phosphatase that generates inositol from inositol phosphate.
Preparations, pharmacokinetics, and dosing. Lithium carbonate is rapidly absorbed from the gastrointestinal tract, and it reaches peak concentrations in 1 to 6 hours. Absorption is generally complete within 8 hours. Lithium citrate, a formulation that is not always readily available, is absorbed even more rapidly. Lithium concentrates in saliva, the thyroid gland, and bone. It may remain in the bone for years. Although measuring red blood cell concentrations of lithium is by no means routine, these intracellular levels may correlate better with lithium's effects than do serum concentrations. Three percent to 5% of lithium is eliminated in sweat; this irritates the skin of some patients, which may be particularly problematic for patients with psoriasis.
Based on the pharmacokinetics of immediate release forms of lithium, twice-daily dosing has been its traditional pattern of use. However, clinical use data suggest that renal complications are reduced by using single bedtime doses, particularly when higher range dosing is required. Compliance is also improved by implementing this bedtime regimen. Some clinicians prefer sustained-release preparations. In this author's experience, the latter reduce the appearance of gastrointestinal complaints and tremor by reducing peak concentrations; however, their use prolongs the kidney's exposure to the drug. The author prefers sustained-release preparations only for patients requiring 450 to 900 mg of lithium per day.
Table 19.3 describes the brand names, dosage strengths, and forms of lithium carbonate and lithium citrate currently available in the United States. Considerable variability has been observed in serum concentrations produced by various generic preparations; this probably reflects variations in particle size and excipients.
Monitoring. Until the patient is stabilized, a flexible approach to the frequency of determining serum lithium concentrations, such as one that is responsive to the patient's need for dosage adjustments (e.g., the degree of clinical improvement; the presence of side effects; risk situations, such as diarrhea and vomiting), seems appropriate. Once stabilization is achieved,
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intervals of up to 3 months can be considered. Considerable interindividual variation in effective serum concentrations for lithium are seen. The range for most patients during an episode is 0.3 to 1.2 mEq per L. The lower part of this range may be adequate for many elderly patients and for some stabilized patients. For patients who respond at low lithium concentrations (e.g., 0.3 to 0.5 mEq per L), monitoring intervals of 6 to 12 months are sometimes appropriate. For patients requiring sustained concentrations above 1.2 mEq per L, chart documentation should include an indication that the treating clinician is aware that these are higher than typical levels and should provide the reasoning behind using such levels. Obtaining a consultation from an experienced psychopharmacologist may be prudent.TABLE 19.3. SOME FORMS AND BRAND NAMES OF LITHIUM
Lithium carbonatea
Lithium citrateb
Lithotabs
Lithonatec
Eskalith
Lithobidd
Eskalith CReaGeneric forms available in 300 mg uncoated tablets; 150 mg, 300 mg, or 600 mg gelatin capsules; and 125 or 500 mg as powder. The molecular weight of lithium is 73.89 g/mol.
bGeneric syrups available as well; 8 mEq of lithium per 5 mL is equivalent to 300 mg of carbonate.
cCapsules (300 mg).
dSustained-release tablets (300 mg).
eSustained-release tablets (450 mg).Once pre-lithium baseline levels have been established for the following parameters, thyroid functioning (thyroid-stimulating hormone and thyroxine levels, antithyroid antibodies) and renal functioning (e.g., blood urea nitrogen and creatinine levels) should be monitored at least yearly; more frequent monitoring may be indicated depending on the values obtained or the patient's clinical condition. Some physicians believe that a yearly assessment of creatinine clearance is appropriate.
Discontinuation. Most patients who respond to lithium tolerate its chronic use (i.e., continuous use for decades) once their individual dosage needs have been established. In patients with recurrent episodes, lithium discontinuation typically (i.e., about 50% of the time) results in the reappearance of symptoms within 6 months. When lithium is discontinued after many years for whatever reason and symptoms recur, it has been observed that some patients may not benefit from reexposure to lithium to the same degree as they did during their earlier treatment with it. These patients may even become less responsive to any other currently available therapies. This lack of effectiveness and possible refractoriness has led some authorities on lithium use to recommend that it not be discontinued in patients who benefit from and are well maintained on continuous lithium treatment. For this reason the author does not recommend lithium holidays. Discontinuation during pregnancy is generally advocated, even though many apparently healthy children have been born to women taking lithium. (Note: Although associated with maternal first trimester use of lithium, Ebstein anomaly, a tricuspid valve malformation, is probably less common than was previously thought. Data also suggest that, in children identified as having this problem, lithium exposure was not a major risk factor.)
The off-label use of lithium to modify premenstrual mood lability and irritability is sometimes successful. Because some SSRIs have
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premenstrual dysphoric disorder as an approved indication, it may be prudent to try an SSRI alone first, before lithium is used adjunctively or by itself. Dosing is usually 300 to 600 mg per day (typically at bedtime) for 10 days before the onset of menstruation. This intermittent usage pattern has not yet been shown to cause treatment refractoriness in premenstrual dysphoric disorder patients.Side effects and toxicity. Some of lithium's more common side effects are nausea, loose stools or diarrhea, thirst, polyuria, metallic taste, headache, and tremor; the latter is responsive to propranolol (20 to 80 mg per day; atenolol at 25 to 50 mg per day is an alternative). Some patients also complain of cognitive dulling. Most of lithium's side effects can be ameliorated by dosage reduction. Because most of lithium's minor side effects are associated with its peak levels, taking the drug after meals or at bedtime or using sustained-release preparations may improve its tolerability. Lithium citrate use is associated with fewer unwanted gastrointestinal effects.
Hypothyroidism is found in 5% to 30% of lithium-treated patients after 6 to 18 months of continuous use. It appears to occur more frequently in women and in rapid-cycling patients. In patients with Hashimoto thyroiditis, lithium may aggravate or cause hypothyroidism. The author regularly screens patients for antithyroid antibodies to identify patients with subclinical Hashimoto thyroiditis.
When lithium reaches toxic concentrations, confusion, restlessness, lethargy, and slurred speech are frequently seen. Stupor and coma may follow. The elderly are particularly susceptible to lithium toxicity. The treatment of lithium toxicity and overdosage is considered in Chapter 3.
Chronic use of lithium is sometimes associated with neurotoxicity. Acute overdosage is a more infrequent cause. Risk factors for neurotoxicity during chronic lithium administration include diabetes insipidus, thyroid dysfunction, impaired renal function, and advanced age. Agents that impair lithium clearance (e.g., aspirin) may also contribute to neurotoxicity.
Drug interactions. Only two interactions will be considered in this section; Chapter 29 reviews some of lithium's important interactions with other drugs. In treatment-resistant depressions, SSRIs are not infrequently combined with lithium; some patients have been reported to show signs of a toxic serotonin syndrome from this combination (see Chapter 3). Of greater concern is the interaction between lithium and the thiazide diuretics (e.g., hydrochlorothiazide). This combination can lead to decreased renal clearance of lithium and increases in serum levels that, if they are high enough, may cause lithium toxicity. Potassium-sparing diuretics (e.g., amiloride, triamterene) are usually safer to use when these agents need to be prescribed together. The safety of loop diuretics (e.g., furosemide) and carbonic anhydrase inhibitors (e.g., acetazolamide) with lithium is ambiguous because contradictory observations have appeared in the literature. A potassium-sparing diuretic alone or in combination with a thiazide diuretic is sometimes added to lithium to reduce lithium-induced polyuria or nephrogenic diabetes insipidus. Another option is switching to a mood-stabilizing anticonvulsant.
B. Mood-Stabilizing Anticonvulsant Agents
The discussion of these agents also covers selected benzodiazepines.
Valproate. A divalproex sodium delayed release tablet formulation has FDA approval for the treatment of mania associated with BD. An extended release version (500 mg) that is currently approved for use in migraine headaches is used by some clinicians to support adherence. A carboxylic acid derivative, valproate enhances -aminobutyric acid (GABA) activity, increases potassium conductance, and appears to block N-methyl-D-aspartate receptor-mediated (i.e., calcium channel) depolarization. Cross-tolerance between valproate and carbamazepine is seen
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on amygdala-kindled seizures, even though valproate has little affinity for peripheral-type benzodiazepine receptors. Some data suggest that valproate may desensitize GABA autoreceptors. How these and other actions of valproate contribute to its antimanic effects is not known.Valproate is reasonably effective in acute mania, and it sustains its antimanic effectiveness during chronic administration. Valproate also appears to work well in rapid-cycling patients and in patients with mixed or dysphoric mania. Table 19.4 lists the forms of valproate currently marketed in the United States. Concentration-response relationships for valproate are not strong; a range of 50 to 125 g per mL is often cited for the serum concentration of valproic acid. Starting doses depend on the severity, and they can range from 500 to 1,500 mg per day (divided doses). Longer term use is typically in the range of 1,000 to 2,000 mg per day. For acutely manic patients, some clinicians advocate beginning with a loading dose of 30 mg per kg per day and decreasing to 20 mg per kg per day once improvement is noted.
Common side effects include nausea, anorexia, and other gastrointestinal effects; sedation; propranolol-responsive tremor; and ataxia. The enteric-coated divalproex sodium formulation is preferred by many clinicians because it may produce fewer gastrointestinal side effects. Reversible asymptomatic liver transaminase elevation is not uncommon; rare cases of idiosyncratic hepatic toxicity have been fatal. Increased appetite and accelerated hair loss are seen in some patients; some data suggest that concomitant daily use of a multivitamin preparation containing selenium and zinc may be beneficial. Acute pancreatitis can occur; the development of polycystic ovaries has also been noted.
Some clinicians choose valproate formulations instead of carbamazepine because valproate use is associated with fewer drug interactions.
Carbamazepine. This agent, an iminostilbene, resembles tricyclic antidepressants in its structure but it has a carbamyl side chain that conveys anticonvulsant effects. These appear to be mediated at least in part through its GABA-linked calcium channel blocking at the so-called peripheral or
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GABAB-benzodiazepine receptor and via its 2-adrenergic receptor agonist properties (see section IV.D.1), as well as by way of its membrane-stabilizing effects. Carbamazepine appears to act preferentially in limbic brain areas. Although its mood-stabilizing and antimanic properties are not FDA approved, carbamazepine use in BD is somewhat common, especially as a prophylactic agent for lithium nonresponders and in rapid-cycling patients. Carbamazepine is sometimes used concurrently with lithium and other agents. Onset of action is variable, and it may take from 3 to 15 days.TABLE 19.4. VALPROATE PREPARATIONS
Brand Name, Form (Strengths) Preparation Time to Peak Serum Concentration (h)a Depakene, capsules (250 mg) Valproic acid 1 2 Depakene, syrup (250 mg/5 mL) Sodium valproate 1 2 Depakote, delayed-release tablets (125, 250, 500 mg)b Divalproex sodium 3 8 Depakote, sprinkle capsules (125 mg) Divalproex sodium coated particles in capsules c Depakote ER, extended released (500 mg) Divalproex sodium Depacon, injectable (100 mg/mL i.v. use) Sodium valproate Abbreviation: i.v., intravenous. aMeasured in serum as valproic acid.
bThis is the only formulation specifically marketed for the treatment of manic symptoms in bipolar disorder.
cCompared with divalproex sodium tablets, sprinkle capsules have earlier onset and slower rate of absorption, with slightly lower peak serum concentrations.
dMarketed for migraine headache prophylaxis.Although a concentration-response range has not been established for the use of carbamazepine in BD, plasma levels in the range of 4 to 12 g per mL appear to be appropriate for many patients. These levels are typically achieved with dosages between 100 and 1,600 mg per day; this wide and variable range reflects carbamazepine's nonlinear kinetics (i.e., induction of its own oxidative metabolism). Orally administered, carbamazepine is slowly absorbed, and it has poor water solubility. Carbamazepine use is not infrequently associated with benign neutropenia; very rare and sometimes fatal cases of agranulocytosis and aplastic anemia have occurred. Earlier concerns about its hematopoietic toxicity arose when it was coprescribed with other antiepileptic agents. Therefore, regular monitoring of both plasma levels and complete blood counts is recommended. Carbamazepine's most common unwanted effects include ataxia, headache, lightheadedness, rash, and sedation.
Carbamazepine is an inducer of cytochrome P-450 (CYP) 2D6 (see Chapter 29) hepatic microsomal enzymes (e.g., it will probably lower levels of haloperidol), but the principal pathway (CYP 3A4) in its own metabolism is likely inhibited by CYP 3A family-metabolized drugs, such as verapamil, ritonavir, ketoconazole, erythromycin, or nefazodone. Its major active metabolite is a 10,11-epoxide; increased amounts of this metabolite contribute significantly to carbamazepine's toxicity. Increased levels of this metabolite occur, for example, with coadministration of phenobarbital (i.e., from enzyme induction). Valproate, by inhibiting an epoxide hydroxylase, also increases the levels of this carbamazepine metabolite.
Other anticonvulsants. Modest support is found for the use of two additional agents in BD. Lamotrigine, which shares some mechanisms of action with carbamazepine (e.g., blockade of neuronal sodium channels, decreased release of excitatory amino acids), can be of benefit for the depressed phase in some patients with BD. Its antidepressant effects are more consistent than its antimanic effects. Topiramate appears to have a degree of antimanic effects, and it may reduce cycle frequency. Topiramate blocks AMPA glutamate receptors, and it is a carbonic anhydrase inhibitor; this latter property may contribute to the formation of renal calculi. The bulk of present evidence does not support benefits from the use of gabapentin in BD; dosage could be a factor.
Clonazepam and lorazepam. Although all benzodiazepines are GABAA agonists and have sedative and anticonvulsant properties, clonazepam and lorazepam enjoy greater popularity in the treatment of manic symptomatology. Both are relatively free from drug interactions other than potentiated sedation, and neither has active metabolites. Benzodiazepines are often preferred for the treatment of secondary mania (i.e., from medical conditions, medications, or abusable substances) and for patients who develop extrapyramidal side effects from the use of antipsychotic agents. Clonazepam's half-life (t1/2 ) (18 to 50 hours) and duration of action are somewhat longer than those of lorazepam (t1/2 = 8 to 24 hours). Clonazepam reaches peak blood levels somewhat faster than lorazepam (1 to 2 vs. 1 to 6 hours). Oral dosage ranges for clonazepam and lorazepam are 1.5 to 20 and 2 to 10 mg per day, respectively. Both agents act more rapidly than lithium does, and they are sometimes combined with lithium or other antimanic
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agents. Lorazepam is also used intramuscularly (1 to 5 mg every 2 hours), either alone or in combination with haloperidol (1 to 5 mg). The most common side effect of lorazepam or clonazepam is sedation; because of its longer duration of action, clonazepam use is more likely to be associated with unwanted daytime drowsiness. Anterograde memory impairment is not uncommon from both agents at the higher dosage ranges that are used to treat manic excitement (see Chapter 14).
C. Antipsychotic Agents
Olanzapine and haloperidol. All classes of antipsychotic agents have been used in acute mania; their efficacy is thought to be related to their dopamine-2 receptor antagonism.
Olanzapine has specific FDA approval for use in acute manic episodes associated with BD. Initial dosing is usually in the range of 5 to 15 mg per day (maximum recommended dose of 20 mg per day). Short-term use (i.e., up to 3 to 4 weeks) is generally recommended. Olanzapine's clearance is increased by activities (e.g., cigarette smoking) or agents (e.g., omeprazole) that induce CYP 1A2. A tablet that dissolves in the mouth without additional fluids is also available (Zydis). Either can be used with lithium to treat the patient before lithium becomes effective.
Although haloperidol is not FDA approved for this use, it is used in some settings for the treatment of manic symptomatology. Haloperidol is given either orally or intramuscularly (2 to 40 mg per day), and it has a half-life of about 18 hours. Intramuscular haloperidol dosing (1 to 5 mg every 2 to 6 hours) is sometimes used with lithium. Haloperidol is sometimes combined with lorazepam when greater sedation is required. Extrapyramidal side effects are problematic with haloperidol (see also Chapter 20). The markedly reduced likelihood of extrapyramidal side effects associated with olanzapine, its FDA approval for the short-term treatment of acute manic episodes associated with BD, and its availability in oral (10 to 20 mg per day) and intramuscular (2.5 to 15 mg per day) forms are key factors in its increasing usage. Drowsiness and weight gain are more common with olanzapine than they are with haloperidol.
Mesoridazine. Mesoridazine (75 to 300 mg per day) is an option used by some clinicians; it is also the principal active product of thioridazine metabolism. In contrast to thioridazine, mesoridazine can also be given intramuscularly (12.5 to 50 mg every 6 hours). Its half-life is highly variable, ranging from 1 to 3 days. As with haloperidol and olanzapine, mesoridazine is often combined with lithium in the initial days of treatment. Extrapyramidal side effects are rare, and the pigmentary retinopathy observed with high-dose thioridazine is not reported with comparable doses of mesoridazine; mesoridazine is twice as potent as thioridazine. Prolongation of the cardiac QT interval and an associated risk for ventricular tachyarrhythmias limit the value of both thioridazine and mesoridazine in current practice.
Risperidone. This agent has also been reported to be useful for the treatment of acute manic symptomatology in BD patients, and many clinicians suggest its use. Unfortunately, adequate trials have not yet been published.
Pimozide. Pimozide (2 to 20 mg per day) is an unusual antipsychotic agent that also has calcium channel blocking properties. Some clinicians, particularly in Europe, have found it useful for treating acute mania; this is not an FDA-approved indication. Sedation and anticholinergic side effects are common, and dose-dependent prolongation of the QTc interval and other electrocardiographic changes should be expected. Cardiac arrhythmias that have included rare instances of fatal tachydysrhythmias have been reported. Pretreatment and follow-up electrocardiograms are essential to good patient care; these may be difficult to obtain in the acutely manic patient. Because a warning about associated hepatic injury was added to pimozide's product labeling,
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pimozide use in BP is now rare. Pimozide reaches peak blood levels slowly, and it has a long elimination half-life of 1.5 to 2.5 days (see also Chapters 4 and 7).Clozapine. This atypical antipsychotic agent has shown effectiveness, typically in the range of 250 to 800 mg per day, in case and small series reports describing the treatment of patients with dysphoric mania (note: this is not an FDA-approved indication). It has a relatively short half-life that averages about 8 hours. Some patients do well on clozapine alone, whereas others require concomitant medications (e.g., valproate, lithium). Close monitoring for granulocytopenia is essential; this need is magnified when combination therapies are used because many of the possible adjunctive agents have their own effects on the hematopoietic system (see also Chapter 20).
D. Cardiovascular Agents with Mood-Stabilizing Properties
Clonidine. This 2-adrenergic receptor partial agonist is sometimes helpful in manic patients through its reduction of central sympathetic outflow (note: this is not an FDA-approved indication for its use) (see also Chapter 10). It also has peripheral presynaptic 2-adrenergic agonist activity, and clonidine lowers blood pressure by reducing norepinephrine release. It is rapidly absorbed orally, and it quickly reaches adequate central nervous system concentrations. The dosage range is 0.2 to 1.2 mg per day. At higher doses, decreases in blood pressure are observed. In addition to hypotension, dry mouth and drowsiness are common unwanted effects. Any depressive symptoms that are present may worsen with its use. Clonidine should be used only when standard approaches have failed; close monitoring of the patient is essential.
Calcium channel blocking agents. Verapamil (240 to 400 mg per day) and diltiazem (150 to 300 mg per day) may have some effectiveness in reducing manic symptomatology (note: these are not FDA-approved indications for their use). Supporting their possible usefulness is the observation that cerebrospinal fluid levels of calcium are low during manic episodes and high during depressive episodes. Verapamil has weak anticonvulsant properties, and both agents increase synaptic calcium levels. Neither is a first-line treatment for mania; their use should be considered only when standard treatments have not been effective. Verapamil use has been associated with increased depression and anxiety in some patients.
V. Electroconvulsive Therapy
ECT is discussed in Chapter 24. Although most clinicians and patients prefer pharmacotherapies, considerable data exists that supports the greater efficacy of ECT as compared with lithium in the earliest days of severely manic decompensations. Chapter 24 notes the possibly unique role for ECT as a comparatively safe and effective treatment for BD episodes during pregnancy.
VI. Comment
Patients with bipolar I disorders are somewhat less prevalent than those with some of the other major mental disorders; their impact, however, is far from inconsequential. On the positive side, many of these patients are exceptionally creative and energetic, and they have made singular contributions to society in areas such as the arts, politics, sciences, and business. On the negative side, the costs to society of squandered talents and dollars, lost days from work, family disruptions, suicides, hospitalizations, and the like from the large numbers of untreated patients are enormous. No more than one-fourth of these patients receive adequate treatment at the present time. Much work has to be done to find ways to engage these patients in treatment and to improve their compliance. More consistently effective and safer agents are also needed. Finally, the roles of kindling phenomena and sensitization the effects of untreated or inadequately treated episodes or discontinuations of treatment on subsequent episode severity, frequency and duration, and treatment refractoriness must be better understood.
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VII. Treatment Algorithms
Appendix VII contains useful information about algorithms for BD.
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