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A. Somatic Treatments of Acute Manic and Mixed Episodes

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In general, the primary goal of treatment for patients experiencing a manic or mixed episode is symptom control to allow a return to normal levels of psychosocial functioning. The rapid control of symptoms such as agitation and aggression may be particularly important for the safety of the patient and others.

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1. Lithium

Lithium has been used for the treatment of acute bipolar mania for over 50 years. Five studies have demonstrated that lithium is superior to placebo (176–180). Pooled data from these studies reveal that 87 (70%) of 124 patients displayed at least partial reduction of mania with lithium. However, the use of a crossover design in four of these trials (176–179), nonrandom assignment in two studies (177, 178), and variations in diagnostic criteria and trial duration limit interpretation of the results of all but one trial (180). Nevertheless, in the only placebo-controlled, parallel-design trial in which lithium served as an active comparator to divalproex, lithium and divalproex exerted comparable efficacy (180). In active comparator trials, lithium displayed efficacy comparable to that of carbamazepine (181, 182), risperidone (183), olanzapine (184), and chlorpromazine and other typical antipsychotics (185–190). Among active comparator trials, however, only three (185, 186, 189) were likely to be of sufficient size to detect possible differences in efficacy between treatments. Open studies (191–194) and randomized, active comparator-controlled studies (195–197) indicate that lithium is likely to be effective for treatment of pure or elated mania but is less often effective in the treatment of mixed states.

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a) Side effects

Up to 75% of patients treated with lithium experience some side effects (41, 198). These side effects vary in clinical significance; most are either minor or can be reduced or eliminated by lowering the lithium dose or changing the dosage schedule. For example, Schou (199) reported a 30% reduction in side effects among patients treated with an average lithium level of 0.68 meq/liter compared with those treated with an average level of 0.85 meq/liter. Side effects that appear to be related to peak serum levels (e.g., tremor that peaks within 1 to 2 hours of a dose) may be reduced or eliminated by using a slow-release preparation or changing to a single bedtime dose.

Dose-related side effects of lithium include polyuria, polydipsia, weight gain, cognitive problems (e.g., dulling, impaired memory, poor concentration, confusion, mental slowness), tremor, sedation or lethargy, impaired coordination, gastrointestinal distress (e.g., nausea, vomiting, dyspepsia, diarrhea), hair loss, benign leukocytosis, acne, and edema (200). Side effects that persist despite dosage adjustment may be managed with other medications (e.g., beta-blockers for tremor; diuretics for polyuria, polydipsia, or edema; topical antibiotics or retinoic acid for acne). Gastrointestinal disturbances can be managed by administering lithium with meals or changing lithium preparations (especially to lithium citrate).

Lithium may cause benign ECG changes associated with repolarization. Less commonly, cardiac conduction abnormalities have been associated with lithium treatment. Anecdotal reports have linked lithium with other ECG changes, including the exacerbation of existing arrhythmias and, less commonly, the development of new arrhythmias (201).

The most common renal effect of lithium is impaired concentrating capacity caused by reduced renal response to ADH, manifested as polyuria, polydipsia, or both (202, 203). Although the polyuria associated with early lithium treatment may resolve, persistent polyuria (ranging from mild and well tolerated to severe nephrogenic diabetes insipidus) may occur. Polyuria can frequently be managed by changing to a once-daily bedtime dose. If the polyuria persists, management includes ensuring that fluid intake is adequate and that the lithium dose is as low as possible. If these measures do not ameliorate the problem, then concurrent administration of a thiazide diuretic (e.g., hydrochlorothiazide at a dose of 50 mg/day) may be helpful. The lithium dose will usually need to be decreased (typically by 50%) to account for the increased reabsorption induced by thiazides (198). In addition, potassium levels will need to be monitored, and potassium replacement may be necessary. Amiloride, a potassium-sparing diuretic, is reported to be effective in treating lithium-induced polyuria and polydipsia (203). Its advantages are that it does not alter lithium levels and does not cause potassium depletion. Amiloride may be started at 5 mg b.i.d. and may be increased to 10 mg b.i.d. as needed (204).

Hypothyroidism occurs in 5%–35% of patients treated with lithium. It occurs more frequently in women, tends to appear after 6–18 months of lithium treatment, and may be associated with rapid cycling (41, 80, 198, 205). Lithium-induced hypothyroidism is not a contraindication to continuing lithium and is easily treated by the administration of levothyroxine (198, 205). In addition to the other signs and symptoms of hypothyroidism, patients with bipolar disorder are at risk of developing depression or rapid cycling. If these symptoms occur in the presence of laboratory evidence of suboptimal thyroid functioning, then thyroid supplementation, discontinuation of lithium, or both should be considered (206–208). Hyperparathyroidism has also been noted with lithium treatment (209–211).

A small number of case reports have described exacerbation or first occurrences of psoriasis associated with lithium treatment (212). Some of these patients improved with appropriate dermatologic treatment or when the lithium dose was lowered. In some cases, however, lithium seemed to block the effects of dermatologic treatment, with psoriasis clearing only after lithium was discontinued. In addition, patients occasionally experience severe pustular acne that does not respond well to standard dermatologic treatments and only resolves once the lithium treatment is discontinued (212). This is in contrast to the more common mild to moderate acne that can occur with lithium treatment, which is usually responsive to standard treatments (198).

Approximately 10%–20% of patients receiving long-term lithium treatment (i.e., for more than 10 years) display morphological kidney changes—usually interstitial fibrosis, tubular atrophy, and sometimes glomerular sclerosis. These changes may be associated with impairment of water reabsorption but not with reduction in glomerular filtration rate or development of renal insufficiency (41, 198, 213–216). Although irreversible renal failure caused by lithium has not been unequivocally established, there are a number of case reports of probable lithium-induced renal insufficiency (215, 217, 218). Additionally, several studies have shown that a small percentage of patients treated with lithium may develop rising serum creatinine concentrations after 10 years or more of treatment (215, 218).

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b) Toxicity/overdose

Toxic effects of lithium become more likely as the serum level rises (219). Most patients will experience some toxic effects with levels above 1.5 meq/liter; levels above 2.0 meq/liter are commonly associated with life-threatening side effects. For many patients, the therapeutic range within which beneficial effects outweigh toxic effects is quite narrow, so that small changes in serum level may lead to clinically significant alterations in the beneficial and harmful effects of lithium. Elderly patients may experience toxic effects at lower levels and have a correspondingly narrower therapeutic window (138).

Signs and symptoms of early intoxication (with levels above 1.5 meq/liter) include marked tremor, nausea and diarrhea, blurred vision, vertigo, confusion, and increased deep tendon reflexes. With levels above 2.5 meq/liter, patients may experience more severe neurological complications and eventually experience seizures, coma, cardiac dysrhythmia, and permanent neurological impairment. The magnitude of the serum level and the duration of exposure to a high level of lithium are both correlated with risk of adverse effects (219). Therefore, rapid steps to reduce the serum level are essential. In addition, during treatment for severe intoxication, patients may experience "secondary peaks" during which the serum level rises after a period of relative decline; the clinician must therefore continue to monitor serum levels during treatment for severe intoxication. The patient with lithium intoxication should be treated with supportive care (e.g., maintenance of fluid and electrolyte balance), and steps should be taken to prevent further absorption of the medication (e.g., gastric lavage or, in the alert patient, induction of emesis).

Hemodialysis is the only reliable method of rapidly removing excess lithium from the body and is more effective than peritoneal dialysis for this purpose (220). Criteria for the use of hemodialysis in lithium intoxication are not firmly established, and the decision to dialyze must take into account both the patient's clinical status and the serum lithium level (219, 221). When serum lithium levels are below 2.5 meq/liter, hemodialysis usually is unnecessary. The need for hemodialysis differs in patients who have developed toxicity after an acute overdose compared with those who have developed gradual toxicity or have an acute overdose superimposed on long-term lithium treatment. In acute poisoning, hemodialysis is generally required with serum lithium levels over 6–8 meq/liter, whereas hemodialysis may be needed with serum levels over 4 meq/liter in those who have been on long-term regimens of lithium treatment. Hemodialysis may also be necessary at lower serum levels in patients who are more susceptible to complications because of underlying illnesses (e.g., cardiac disease, renal impairment). Regardless of serum lithium level, hemodialysis is generally indicated in patients with progressive clinical deterioration or severe clinical signs of intoxication such as coma, convulsions, cardiovascular symptoms, or respiratory failure (219, 221). Because serum levels of lithium may rebound after initial hemodialysis, repeat dialysis may be needed (219, 222).

In cases of overdose with sustained-release preparations of lithium, development of toxicity is likely to be delayed, and the duration of toxicity is likely to be prolonged (223, 224). This should be taken into consideration in decisions about the need for initial or repeat hemodialysis (219).

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c) Implementation and dosing

Before beginning lithium treatment, the patient's general medical history should be reviewed, with special reference to those systems that might affect or be affected by lithium therapy (e.g., renal, thyroid, and cardiac functioning). In addition, pregnancy or the presence of a dermatologic disorder must be ascertained. Patient education should address potential side effects of lithium treatment as well as the need to avoid salt-restricted diets or concomitant medications that could elevate serum lithium levels (e.g., diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors). Patients should be cautioned, particularly if nephrogenic diabetes insipidus is present, that lithium toxicity might occur with dehydration from environmental heat, gastrointestinal disturbance, or inadequate fluid intake.

Laboratory measures and other diagnostic tests are generally recommended on the basis of pathophysiological knowledge and anticipated clinical decisions rather than on empirical evidence of their clinical utility. The decision to recommend a test is based on the probability of detecting a finding that would alter treatment as well as the expected benefit of such alterations in treatment. Recommended tests fall into three categories: 1) baseline measures to facilitate subsequent interpretation of laboratory tests (e.g., ECG, CBC); 2) tests to determine conditions requiring different or additional treatments (e.g., pregnancy, thyroid-stimulating hormone level); and 3) tests to determine conditions requiring alteration of the standard dosage regimen of lithium (e.g., creatinine level).

On the basis of these considerations, the following procedures are generally recommended before beginning lithium therapy: a general medical history, a physical examination, BUN and creatinine level measurement, a pregnancy test, thyroid function evaluation, and, for patients over age 40, ECG monitoring with rhythm strip. Some authorities also suggest a CBC.

Lithium is usually started in low, divided doses to minimize side effects (e.g., 300 mg t.i.d. or less, depending on the patient's weight and age), with the dose titrated upward (generally to serum concentrations of 0.5–1.2 meq/liter) according to response and side effects (225). Lithium levels should be checked after each dose increase and before the next. Steady-state levels are likely to be reached approximately 5 days after dose adjustment, but levels may need to be checked sooner if a rapid increase is necessary (e.g., in the treatment of acute mania) or if toxicity is suspected. As levels approach the upper limits of the therapeutic range (i.e., '‰¥1.0 meq/liter), they should be checked at shorter intervals after each dose increase to minimize the risk of toxicity.

Serum concentrations required for prophylaxis may be, in some cases, as high as those required for treatment of the acute episode. A controlled study by Gelenberg et al. (225) found that patients randomly assigned to a "low" lithium level (0.4–0.6 meq/liter) had fewer side effects but more illness episodes than patients in the "standard" lithium group (0.8–1.0 meq/liter). However, the lithium levels of some of the patients in the low-lithium group decreased relatively rapidly from their previous treatment levels, a decrease that could have increased their risk of relapse. Although the prophylactic efficacy of lithium levels between 0.6 and 0.8 meq/liter has not been formally studied, this range is commonly chosen by patients and their psychiatrists (226). Despite the lack of formal study, it is likely that for many patients, increases in maintenance lithium levels will result in a trade-off between greater protection from illness episodes at the cost of an increase in side effects. The "optimal" maintenance level may therefore vary somewhat from patient to patient. Some patients find that a single, daily dose facilitates treatment compliance and reduces or does not change side effects.

The clinical status of patients receiving lithium needs to be monitored especially closely. The frequency of monitoring depends on the individual patient's clinical situation but generally should be no less than every 6 months for stable patients. The optimal frequency of serum level monitoring in an individual patient depends on the stability of lithium levels over time for that patient and the degree to which the patient can be relied upon to notice and report symptoms.

In general, renal function should be tested every 2–3 months during the first 6 months of treatment, and thyroid function should be evaluated once or twice during the first 6 months of lithium treatment. Subsequently, renal and thyroid function may be checked every 6 months to 1 year in stable patients or whenever clinically indicated (e.g., in the presence of breakthrough affective symptoms, changes in side effects, or new medical or psychiatric signs or symptoms) (198, 214).

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2. Divalproex/valproate/valproic acid

Divalproex and its sodium valproate and valproic acid formulations have been studied in four randomized, placebo-controlled trials: two small crossover trials (227, 228) and two parallel-group trials (180, 229). All four studies found significantly greater efficacy for valproate compared with placebo, with response rates ranging from 48% to 53%. Secondary analyses (150, 197) of data from the largest parallel-group trial (180) suggested that patients with prominent depressive symptoms during mania and with multiple prior mood episodes were more likely to respond to acute treatment with divalproex than with lithium. An additional randomized comparison also reported valproate to be more efficacious than lithium among manic patients with mixed symptoms (195). In patients with acute mania, divalproex was comparable in efficacy to haloperidol in an open trial (230) and to olanzapine in a randomized, controlled trial (231) in the reduction of symptoms of mania and psychosis. In contrast, in a second head-to-head comparison trial (232), olanzapine was superior to divalproex in the mean reduction of manic symptoms and in the proportion of patients in remission at the end of the study.

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a) Side effects

Minor side effects of valproate, such as sedation or gastrointestinal distress, are common initially and typically resolve with continued treatment or dose adjustment. In addition, valproate has a wide therapeutic window. Inadvertent overdose is uncommon, and purposeful overdose is less likely to be lethal than it is with lithium. However, in rare instances, valproate can cause life-threatening side effects, and patients must be relied upon to report the often subtle symptoms of these reactions promptly.

Common dose-related side effects of valproate include gastrointestinal distress (e.g., anorexia, nausea, dyspepsia, vomiting, diarrhea), benign hepatic transaminase elevations, osteoporosis (233, 234), tremor, and sedation. Patients with past or current hepatic disease may be at greater risk for hepatotoxicity (235). Mild, asymptomatic leukopenia and thrombocytopenia occur less frequently and are reversible upon drug discontinuation. Other side effects that are often bothersome to the patient include hair loss (236, 237), increased appetite, and weight gain. Persistent gastrointestinal distress associated with valproate can be alleviated by dose reduction, change of preparation (use of the divalproex sodium formulation rather than valproic acid), or by administration of a histamine-2 antagonist (e.g., famotidine or cimetidine) (238–242). Tremor can be managed with dose reduction or coadministration of beta-blockers. Cases of mild, asymptomatic leukopenia (total WBC count >3000/mm3 and polymorphonuclear leukocyte count >1500/mm3) are usually reversible upon dose reduction or discontinuation. Similarly, if mild, asymptomatic thrombocytopenia occurs, a decrease in valproate dose will usually restore the platelet count to normal. However, more severe cases of thrombocytopenia have been reported (243).

The relationship between polycystic ovarian syndrome and valproate treatment is unclear (244–246). One uncontrolled report indicated that 80% of women receiving long-term valproate treatment for epilepsy before the age of 20 had polycystic ovaries or hyperandrogenism (247). Other cross-sectional studies have demonstrated higher rates of polycystic ovaries and polycystic ovarian syndrome in women with epilepsy (244–246). However, none of the studies examined whether the polycystic ovarian syndrome began before or after the development of epilepsy or the initiation of valproate therapy (246). Furthermore, women with bipolar disorder may differ from women with epilepsy in their rates of polycystic ovarian syndrome independent of treatment. An accurate assessment of risk will require a longitudinal study of women with bipolar disorder before and after initiation of valproate treatment (246). Consequently, although the risks are unclear, psychiatrists should be aware that polycystic ovarian syndrome may be possible with valproate treatment, and thus patients should be monitored accordingly (244).

Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible hepatic failure, hemorrhagic pancreatitis, and agranulocytosis. Thus, patients taking valproate need to be instructed to contact their psychiatrist or primary care physician immediately if they develop symptoms of these conditions.

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b) Toxicity/overdose

Valproate has a wide therapeutic window, so unintentional overdose is uncommon (248). Signs of overdose include somnolence, heart block, and eventually coma. Deaths have been reported. Overdose can be treated with hemodialysis (249, 250).

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c) Implementation and dosing

Before initiating valproate treatment, a general medical history should be taken, with special attention to hepatic, hematologic, and bleeding abnormalities. Results of liver function tests and hematologic measures should be obtained at baseline to evaluate general medical health.

Data from a number of open trials (230, 251–253) and one randomized controlled trial (254) indicate that divalproex can be administered at a therapeutic initial starting dose of 20–30 mg/kg per day in inpatients. This strategy appears to be well tolerated and may be more rapidly efficacious than more gradual titration from a lower starting dose (254). After a serum valproate level is obtained, the dose is then adjusted downward to achieve a target level between 50 and 125 mcg/ml.

Among outpatients, elderly patients, or patients who are hypomanic or euthymic, valproate may be initiated in low, divided doses to minimize gastrointestinal and neurological toxicity. Valproate should generally be started at 250 mg t.i.d., with the dose increased every few days as side effects allow (204). Depending upon clinical response and side effects, the dose is then titrated upward by 250–500 mg/day every few days, generally to a serum concentration of 50–125 mcg/ml, with a maximum adult daily dose of 60 mg/kg per day (250). Once the patient is stable, valproate regimens can be simplified to enhance convenience and compliance, since many patients do well with once- or twice-a-day dosing.

Extended-release divalproex, a new formulation that allows for once-a-day dosing, has become available. Bioavailability is approximately 15% lower than the immediate-release formulation (hence usually requiring slightly higher doses), and side effect profiles appear to be better than that of the immediate-release formulation (255). Demonstration of efficacy in patients with bipolar disorder is limited to open studies (255–257).

Asymptomatic hepatic enzyme elevations, leukopenia, and thrombocytopenia do not reliably predict life-threatening hepatic or bone marrow failure. In conjunction with careful monitoring of clinical status, educating patients about the signs and symptoms of hepatic and hematologic dysfunction and instructing them to report these symptoms if they occur are essential. Some investigators believe that in otherwise healthy patients with epilepsy receiving long-term valproate treatment, routine monitoring of hematologic and hepatic function is not necessary (258). Nevertheless, most psychiatrists perform clinical assessments, including tests of hematologic and hepatic function, at a minimum of every 6 months for stable patients who are taking valproate (252, 259, 260). Patients who cannot reliably report signs or symptoms of toxicity need to be monitored more frequently.

Psychiatrists should be alert to the potential for interactions between valproate and other medications (261). For example, valproate displaces highly protein-bound drugs from their protein binding sites. In addition, valproate inhibits lamotrigine metabolism and more than doubles its elimination half-life by competing for glucuronidation enzyme sites in the liver (262, 263). Consequently, in patients treated with valproate, lamotrigine must be initiated at a dose that is less than half that used in patients who are not receiving concomitant valproate.

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3. Carbamazepine

Many controlled trials of carbamazepine have been conducted in the treatment of acute bipolar mania, but interpretation of the results of a number of these studies is difficult because of the confounding effects of other medications administered as part of study protocols (264). Carbamazepine was superior to placebo in one randomized, crossover trial (265). Carbamazepine was less effective and associated with more need for adjunctive "rescue medication" than valproate in a randomized, blind, parallel-group trial of 30 hospitalized manic patients (266). Carbamazepine was comparable to lithium in two randomized comparison trials (181, 182) and comparable to chlorpromazine in two other randomized trials (267, 268).

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a) Side effects

Up to 50% of patients receiving carbamazepine experience side effects, and the drug is associated with potentially serious adverse reactions (258, 269, 270).

The most common dose-related side effects of carbamazepine include neurological symptoms, such as diplopia, blurred vision, fatigue, nausea, and ataxia. These effects are usually transient and often reversible with dose reduction. Elderly patients, however, may be more sensitive to side effects. Less frequent side effects include skin rashes (271), mild leukopenia, mild thrombocytopenia, hyponatremia, and (less commonly) hypo-osmolality. Mild liver enzyme elevations occur in 5%–15% of patients. Mild asymptomatic leukopenia is not related to serious idiopathic blood dyscrasias and usually resolves spontaneously with continuation of carbamazepine treatment or with dose reduction. In the event of asymptomatic leukopenia, thrombocytopenia, or elevated liver enzymes, the carbamazepine dose can be reduced or, in the case of severe changes, discontinued. Hyponatremia may be related to water retention caused by carbamazepine's antidiuretic effect (272). Hyponatremia occurs in 6%–31% of patients, is rare in children but probably more common in the elderly, occasionally develops many months after the initiation of carbamazepine treatment, and sometimes necessitates carbamazepine discontinuation. In addition, carbamazepine may decrease total and free thyroxine levels and increase free cortisol levels, but these effects are rarely clinically significant. Weight gain is also a common side effect of carbamazepine.

Rare, idiosyncratic, but serious and potentially fatal side effects of carbamazepine include agranulocytosis, aplastic anemia, thrombocytopenia, hepatic failure, exfoliative dermatitis (e.g., Stevens-Johnson syndrome), and pancreatitis (243, 258, 273–275). Although these side effects usually occur within 3–6 months of carbamazepine initiation, they have also occurred after more extended periods of treatment. Routine blood monitoring does not reliably predict blood dyscrasias, hepatic failure, or exfoliative dermatitis. Thus, in addition to careful monitoring of clinical status, it is essential to educate patients about the signs and symptoms of hepatic, hematologic, or dermatologic reactions and instruct them to report symptoms if they occur. Other rare side effects include systemic hypersensitivity reactions, cardiac conduction disturbances, psychiatric symptoms (including sporadic cases of psychosis), and, very rarely, renal effects (including renal failure, oliguria, hematuria, and proteinuria).

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b) Toxicity/overdose

Carbamazepine may be fatal in overdose; deaths have been reported with ingestions of more than 6 g. Signs of impending carbamazepine toxicity include dizziness, ataxia, sedation, and diplopia. Acute intoxication can result in hyperirritability, stupor, or coma. The most common symptoms of carbamazepine overdose are nystagmus, ophthalmoplegia, cerebellar and extrapyramidal signs, impaired consciousness, convulsions, and respiratory dysfunction. Cardiac symptoms may include tachycardia, arrhythmia, conduction disturbances, and hypotension. Gastrointestinal and anticholinergic symptoms may also occur. Management of carbamazepine intoxication includes symptomatic treatment, gastric lavage, and hemoperfusion.

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c) Implementation and dosing

A pretreatment evaluation for carbamazepine should include a general medical history and physical examination, with special emphasis on prior history of blood dyscrasias or liver disease. Most authorities recommend that the minimum baseline evaluation include a CBC with differential and platelet count, a liver profile (evaluation of LDH, SGOT, SGPT, bilirubin, and alkaline phosphatase), and renal function tests (204). Serum electrolyte levels may also be obtained, especially in the elderly, who may be at higher risk for hyponatremia.

Although doses can range from 200 to 1800 mg/day, the relationships among dose, serum concentration, response, and side effects are variable. Therefore, the dose should be titrated upward according to response and side effects. In patients over the age of 12, carbamazepine is usually begun at a total daily dose of 200–600 mg, given in three to four divided doses. In hospitalized patients with acute mania, the dose may be increased in increments of 200 mg/day up to 800–1000 mg/day (unless side effects develop), with slower increases thereafter as indicated. In less acutely ill outpatients, dose adjustments should be slower, since rapid increases may cause patients to develop nausea and vomiting or mild neurological symptoms such as drowsiness, dizziness, ataxia, clumsiness, or diplopia. Should such side effects occur, the dose can be decreased temporarily and then increased again more slowly once these side effects have passed.

While therapeutic serum levels of carbamazepine have not been established for patients with bipolar disorder, serum concentrations established for treatment of seizure disorders (4–12 mcg/ml) are generally applied. Trough levels are most meaningful for establishing an effective level for a given patient and are conveniently drawn before the first morning dose. Serum levels should be determined 5 days after a dose change or sooner if toxicity or noncompliance is suspected. Maintenance doses average about 1000 mg/day but may range from 200–1600 mg/day in routine clinical practice (204). Doses higher than 1600 mg/day are not recommended.

CBCs, platelet measurements, and liver function tests should be performed every 2 weeks during the first 2 months of carbamazepine treatment. Thereafter, if results of laboratory tests remain normal and no symptoms of bone marrow suppression or hepatitis appear, blood counts and liver function tests should be performed at least every 3 months (204). More frequent monitoring is necessary in patients with laboratory findings, signs, or symptoms consistent with hematologic or hepatic abnormalities. Life-threatening reactions, however, are not always detected by routine monitoring. The psychiatrist should educate patients about signs and symptoms of hepatic, hematologic, or dermatologic reactions and instruct patients to report these symptoms if they occur. More frequent clinical and laboratory assessments are needed for those patients who cannot reliably report symptoms.

Psychiatrists should be aware that carbamazepine is able to induce drug metabolism, including its own, through cytochrome P-450 oxidation and conjugation (261, 263, 276). This enzymatic induction may decrease levels of concomitantly administered medications such as valproate, lamotrigine, oral contraceptives, protease inhibitors, benzodiazepines, and many antipsychotic and antidepressant medications. In addition, carbamazepine has an active epoxide metabolite and is metabolized primarily through a single enzyme, cytochrome P-450 isoenzyme 3A3/4, making drug-drug interactions even more likely. Consequently, carbamazepine levels may be increased by medications that inhibit the cytochrome P-450 isoenzyme 3A3/4, such as fluoxetine, fluvoxamine, cimetidine, and some antibiotics and calcium channel blockers. Thus, in patients treated with carbamazepine, more frequent clinical and laboratory assessments may be needed with addition or dose adjustments of other medications.

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4. Other anticonvulsants

Oxcarbazepine, the 10-keto analog of carbamazepine, was comparable in efficacy to lithium and haloperidol in two small trials (277, 278). However, these studies lacked sufficient power to detect possible drug-drug differences. While direct comparisons with carbamazepine in studies of bipolar disorder are lacking, studies of epilepsy suggest that oxcarbazepine may have a lower rate of severe side effects (279) and be well tolerated overall (280), although it has been associated with clinically significant hyponatremia (281). Moreover, unlike carbamazepine, oxcarbazepine does not induce its own metabolism (282). However, it may still decrease plasma concentrations of oral contraceptives and dihydropyridine calcium channel blockers, requiring medication change or dose adjustment. (For a more complete review, see the bipolar disorder treatment algorithm of the Texas Medication Algorithm Project [283].)

Three controlled studies, all with methodological limitations, have evaluated lamotrigine in the treatment of bipolar mania. In the first trial, 28 patients with bipolar I or bipolar II disorder were assessed in a double-blind, randomized, crossover series of three 6-week monotherapy trials of lamotrigine, gabapentin, or placebo (284). The response rate for manic symptom improvement, as measured by the Clinical Global Impression Scale for Bipolar Illness, did not differ significantly among the three treatment groups. However, the low mean Young Mania Rating Scale scores at baseline, the crossover design, and the small number of subjects may have limited the findings. In the second study, 16 outpatients with mania, hypomania, or mixed episodes who were inadequately responsive to or unable to tolerate lithium were randomly assigned to lamotrigine or placebo as mono- or adjunctive therapy (285). There were no significant differences between lamotrigine and placebo groups on changes in Young Mania Rating Scale scores or response rates. Limitations of this study included the small study group size and high (50%) placebo response rate. In the third study, 30 inpatients were randomly assigned to lamotrigine or lithium for 4 weeks (286). Both treatment groups displayed significant and comparable reductions in manic symptoms from baseline to endpoint. Limitations of this study included lack of a placebo group, small patient group size, and use of relatively low lithium levels (mean plasma concentration of 0.7 meq/liter at study endpoint). Adverse events and implementation and dosing issues associated with lamotrigine treatment are described in detail in Section V.B.2.c.

Two controlled studies have evaluated the efficacy of gabapentin in the treatment of bipolar manic symptoms. In the first study (284), there were no significant differences in efficacy between gabapentin monotherapy and placebo in improvement in manic symptoms. The second controlled trial (287) compared gabapentin with placebo added to lithium, valproate, or both in 114 outpatients with manic, hypomanic, or mixed symptoms. Both treatment groups displayed a decrease in Young Mania Rating Scale scores from baseline to endpoint, but this decrease was significantly greater in the placebo group.

Finally, one small placebo-controlled trial also suggested efficacy for the anticonvulsant phenytoin in the treatment of mania when added to haloperidol treatment (288).

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5. Olanzapine

Olanzapine was superior to placebo in the treatment of acute bipolar mania in two large, multicenter randomized controlled trials. In the first trial (289), olanzapine versus placebo differences did not reach statistical significance until the third week of treatment. In the second study (290), significant reductions in manic symptoms were apparent in olanzapine-treated patients compared with those receiving placebo at the first assessment point (after 1 week). These differences were probably due to differences in initial starting dose, since the initial olanzapine dose was 10 mg/day in the first study and 15 mg/day in the second trial. In a secondary analysis of data from the second trial, in which sufficient proportions of patients with mixed episodes or rapid cycling were included for comparison, olanzapine response was comparable in patients with or without these features (291). In other randomized, controlled trials, olanzapine exerted comparable efficacy to lithium (184), divalproex (231), and haloperidol (292) in the reduction of manic symptoms. Olanzapine was superior to divalproex in a randomized comparison trial (232). Last, olanzapine was superior to placebo as adjunctive therapy to lithium or divalproex in a randomized, controlled acute treatment trial (292).

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a) Side effects

In short-term, placebo-controlled clinical trials, somnolence was the most common side effect associated with olanzapine. Other common side effects included constipation, dry mouth, increased appetite, and weight gain (291). Especially during initial dose titration, olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope. Syncope was reported in 0.6% of olanzapine-treated patients in phase II and III trials.

In clinical trials, seizures occurred in 0.9% of olanzapine-treated patients. Although confounding factors may have contributed to seizures in many instances, olanzapine should be used cautiously in patients with a history of seizure disorder or in clinical conditions associated with lowered seizure threshold. Transient elevations in plasma prolactin concentrations were also observed in short-term trials (293). These elevations typically remained within the normal physiological range and decreased with continued treatment. Clinically significant hepatic transaminase elevations ('‰¥3 times the upper limit of the normal range) were observed in 2% of olanzapine-treated patients.

In long-term studies, 56% of olanzapine-treated patients gained >7% of their baseline weight. In retrospective analyses of patients followed for a median of 2.54 years, the mean and median weight gains were 6.26 kg and 5.9 kg, respectively (294). Weight gain did not appear to be dose related, occurred most rapidly within the first 39 weeks of treatment, was greatest in patients with the lowest baseline body mass index, and was not correlated with increases in serum glucose. Increases in serum glucose in olanzapine-treated patients did not differ significantly from those in patients treated with haloperidol (294). Weight gain and hyperglycemia in patients treated with atypical antipsychotics have been reviewed in detail elsewhere (295, 296).

In short-term trials, there were no significant differences in the incidence of dystonic reactions, parkinsonism, akathisia, or dyskinetic events among patients receiving placebo or olanzapine (291). Also, extrapyramidal side effects with olanzapine were substantially less than those seen with conventional antipsychotic medications such as haloperidol (297). In a 1-year haloperidol-controlled trial, the incidence of dyskinetic movements among olanzapine-treated patients with schizophrenia was 0.6% compared with 7.5% in patients receiving haloperidol (298). This incidence rate is confounded by prior treatment with typical antipsychotics and the rate of spontaneous dyskinesia in patients with schizophrenia. In 98 patients with bipolar disorder who received olanzapine for 1 year, some in combination with lithium or fluoxetine, no patients developed dyskinetic movements (291).

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b) Implementation and dosing

In the two placebo-controlled studies of olanzapine in patients with bipolar mania, the mean final dose was approximately 15 mg/day. In the first study in which olanzapine was initiated at 10 mg/day and then titrated according to response and side effects, olanzapine did not differentiate from placebo until the third week of the trial (289). The second trial used a starting dose of 15 mg/day and found a significant difference in efficacy in favor of olanzapine at 1 week (the time of the first rating) (290). Taken together, the results of these trials suggest that for inpatients with acute mania, a starting dose of 15 mg/day may be more rapidly efficacious. For outpatients, lower starting doses of 5–10 mg/day may be indicated (299).

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6. Other antipsychotics

Only one randomized, placebo-controlled study of typical antipsychotic medications has been reported in the treatment of acute bipolar mania (300). In this study, chlorpromazine was superior to placebo in global improvement of manic symptoms. Typical antipsychotics were comparable to lithium in reducing manic and psychotic symptoms in acute treatment comparison trials (185–190).

Among the atypical antipsychotic agents, risperidone and ziprasidone have also been studied in the treatment of acute bipolar mania with randomized, placebo-controlled trials. As an adjunct to treatment with lithium or divalproex, risperidone was comparable to haloperidol and superior to placebo (301). Ziprasidone was also superior to placebo in a large, multicenter monotherapy trial, with significant differences in favor of ziprasidone apparent at the time of the first rating, day 2 of treatment (302). While no placebo-controlled trials exist for the use of clozapine in the treatment of bipolar disorder, one randomized 1-year trial in patients with refractory bipolar or schizoaffective disorder showed greater clinical improvement with the addition of clozapine than with treatment as usual (303). An open trial of clozapine in the treatment of refractory mania was also associated with improvement in manic symptoms (304, 305). In general, these trials have used dose ranges similar to those used in schizophrenia trials, with similar rates of adverse events.

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7. Combination therapy

Controlled trials of lithium plus an antipsychotic and of valproate plus an antipsychotic suggest greater efficacy or more rapid onset of action with these combinations than with any of these agents alone. All of these studies involved patients who were currently being treated but who experienced breakthrough episodes of mania or incomplete response to monotherapy. The studies compared combination therapies: an antipsychotic combined with either valproate or placebo (306); lithium or valproate combined with either olanzapine or placebo (290); lithium or valproate combined with either risperidone or placebo (301); or lithium, valproate, or carbamazepine combined with either risperidone or placebo (307). This last trial supported combination therapy only when the carbamazepine-treated group was excluded.

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8. ECT

Three prospective studies have assessed clinical outcomes of treatment of acute mania with ECT. In a prospective, randomized controlled trial (308), patients who received ECT followed by lithium maintenance treatment exhibited greater improvement after 8 weeks than did patients who received lithium as both acute and maintenance treatment. Clinical outcomes with ECT were also found to be superior to outcomes with a combination of lithium and haloperidol (309). In a third study (310), 30 manic patients were all treated with chlorpromazine but were randomly assigned to receive a course of either six ECT sessions or six sham ECT sessions. Patients treated with sham ECT did significantly worse than those treated with real ECT. Although all of these studies had small study group sizes, the results were consistent with other earlier retrospective comparisons of outcome in mania (311, 312) and with earlier naturalistic case series (see Mukherjee et al. [309] and the APA Task Force Report on ECT [110] for reviews).

Although there are no prospective, randomized controlled studies of the use of ECT in the treatment of mixed states, in the aforementioned trial of ECT for treatment of mania (308), the strongest predictor of clinical response was the baseline rating of depressive symptoms. Case reports also suggest that ECT may be efficacious in treatment of mixed states (313–315).

Information on side effects and implementation of ECT can be found in the APA Task Force Report on ECT (110).

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9. Novel treatments

A number of new agents are under active investigation as potential treatments for patients with acute bipolar mania, but data regarding their efficacy from randomized controlled trials are not yet available. These agents include the atypical antipsychotics quetiapine and aripiprazole; the antiepileptics zonisamide, acamprosate, and levetiracetam; and omega-3 fatty acids (316).

Two other medication classes, benzodiazepines and calcium channel blockers, have been studied in randomized controlled trials for treatment of acute bipolar mania. Among the benzodiazepines, clonazepam and lorazepam have been studied alone and in combination with lithium (317–322). Interpretation of many of these studies is confounded by small study group sizes, short treatment durations, concomitant antipsychotic use, and difficulties in distinguishing putative antimanic effects from nonspecific sedative effects. Taken together, however, these studies suggest that the sedative effects of benzodiazepines may make them effective treatment adjuncts while awaiting the effects of a primary antimanic agent to become evident. The fact that lorazepam, unlike other benzodiazepines, is well absorbed after intramuscular injection has made it particularly useful for the management of agitation. However, intramuscular olanzapine was superior to intramuscular lorazepam in ameliorating agitation in patients with bipolar mania (322).

Two randomized, controlled trials found little support for the efficacy of the calcium channel antagonist verapamil in the treatment of acute mania. In the first study, verapamil was compared with lithium in 40 patients hospitalized for an acute manic episode (323). The mean reduction in manic symptoms was significantly greater in the group of patients receiving lithium compared with the verapamil-treated group. The second trial, a 3-week double-blind study involving 32 patients with acute mania (324), showed no significant differences in efficacy between verapamil and placebo. These studies indicate that lithium was superior to verapamil and that verapamil, in turn, was not superior to placebo as an antimanic agent. In contrast, in a crossover trial involving 12 patients with refractory ultrarapid-cycling bipolar disorder (325), the calcium channel antagonist nimodipine was superior to placebo in ameliorating mood cycling.

References

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