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The goal of treatment should be to suppress completely all symp-toms of mania and return the patient to his or her mental status quo ante. Mood, thinking and behavior should normalize. The patient should act and feel like herself or himself. For economic or social reasons, it is sometimes necessary to discharge a patient before total remission of symptoms has occurred. In such cases it is imperative that a patient continues to take medication as pre-scribed and is protected from a recrudescence of manic symp-toms or a rapid slide into acute depression.
The mechanism of action of antimanic drugs is poorly understood. It is not as clear what neural systems are involved in the mechanism of antimanic drugs. That few significant changes in neurotransmit-ter levels have been measured suggests that the site of action may be at the receptor, intracellular level, or second-messenger systems.
For many patients with hypomania, lithium by itself can induce a total remission. For patients with full-blown mania, however, an adjunctive antipsychotic or antianxiety agent may be required to treat intolerable psychosis or excitement.
Lithium is rapidly and completely absorbed after oral ad-ministration. It is not protein bound and does not undergo me-tabolism. Peak plasma levels are achieved within 1.5 to 2 hours for standard preparations or 4 to 4.5 hours for slow-release forms. Lithium’s plasma half-life is 17 to 36 hours. Ninety-five percent of the drug is excreted by the kidneys, with excretion proportion-ate to plasma concentrations. Because lithium is filtered through the proximal tubules, factors that decrease glomerular filtration rates will decrease lithium clearance. Sodium also is filtered through the proximal tubules, so a decrease in plasma sodium can increase lithium reabsorption and lead to increased plasma lithium levels. Conversely, an increase in plasma lithium levels can cause an increase in sodium excretion, depleting plasma so-dium. Many other drugs affect lithium levels (Table 78.1).
Tests that should be done before lithium is started include a complete blood count, electrocardiography, electrolyte determi-nations, and renal and thyroid panels (Table 78.2). Lithium dos-age may be based on a plasma concentration sampled 12 hours after the last dose, or the drug may be gradually titrated to a dose that is tolerated and within the range usually considered “ther-apeutic”. As with any drug, approximately five half-lives must elapse for steady state to be achieved. For an average adult, this takes about 5 days for lithium (longer in the elderly or in patients with impaired renal function). To treat acute mania, plasma concentrations should typically be greater than 0.8 mEq/L, but to avoid toxicity, the level should not usually exceed 1.5 mEq/L. It is important to know what other medications a pa-tient may be taking, because many drugs interact with lithium and can lead to increased or decreased lithium levels and possibly adverse effects (Table 78.2).
To reach therapeutic levels rapidly in healthy younger pa-tients with normal renal and cardiac function, the psychiatrist may prescribe 300 mg of lithium carbonate four times daily from the outset, sampling the first plasma level after 5 days (or sooner should toxic signs become apparent). Thereafter, the dose should be adjusted to achieve a 12-hour plasma concentration between 0.8 and 1.3 mEq/L at steady state.
In a patient with mild hypomanic symptoms, by contrast, it may be wiser to begin with a lower lithium dose, such as 300 mg b.i.d., taking longer to achieve therapeutic levels but, at the same time, minimizing side effects that could trouble the patient and hamper cooperation. Once steady state has been achieved at thera-peutic concentrations and the patient is clinically stable, lithium can be administered to most patients in a once-daily dose, usually at bedtime. Not only is this schedule easier to remember, but it tends to decrease such common side effects as tremor and polyuria.
The most common acute adverse effects from lithium are nausea, vomiting, diarrhea, postural tremor, polydipsia and polyuria (Table 78.2). If troublesome, these can usually be miti-gated by a slower dosage increase or other measures. More severe symptoms and signs, including confusion and ataxia, may herald lithium intoxication and should prompt an immediate blood as-say and, if necessary, temporary discontinuation or dosage re-duction (see Table 78.3).
Among current anxiolytic agents, benzodiazepines are usually se-lected as adjuncts to treat acute mania because of their safety and efficacy. Benzodiazepines have a wide margin of safety and can be safely administered in even very high doses, suppressing potentially dangerous excitement and allowing patients much needed sleep. When used together with an antipsychotic agent, benzodiazepines counteract the antipsychotic agent’s tendency to provoke extrapy-ramidal reactions and seizures. For lorazepam, 1 to 2 mg can be administered by mouth or intramuscularly as frequently as hourly.
Valproate is available in the USA as valproic acid or divalproex sodium, a compound containing equal parts valproic acid and sodium valproate. Divalproex is better tolerated than valproic acid, has been studied more extensively and is more commonly
used. All valproate preparations are rapidly absorbed after oral administration, reaching peak plasma levels within 2 to 4 hours of ingestion. Food may delay absorption but does not affect bio-availability. Valproate is rapidly distributed and highly bound (90%) to plasma proteins. Its half-life ranges from 9 to 16 hours, depending on whether it is taken alone or with other medications, and it takes 1 to 4 days to attain steady state.
Experts usually rank lithium as the treatment of choice for a patient with classic mania, but divalproex is an accept-able first-line alternative. It may be used singly in patients who cannot tolerate lithium. For patients who do not respond to lithium, there are no secure data on whether divalproex should be added as an adjunct or substituted, but many psychiatrists would choose the former in a patient who appears to respond at least partially to lithium and the latter in patients for whom lithium seems to afford no benefit. Increasingly, psychiatrists are turning to divalproex first for manic patients with organic brain impairment, rapid cycling, mixed or dysphoric mania, or comorbid substance abuse (Bowden et al., 1994; Calabrese et al., 1993).
Before initiating divalproex, the psychiatrist should obtain a comprehensive medical history and insure that a physical exam-ination has been performed, with particular attention to sugges-tions of liver disease or bleeding abnormalities (see Table 78.4).
Baseline liver and hematological functions are measured before treatment, every 1 to 4 weeks for the first 6 months, and then every 3 to 6 months. Evidence of hemorrhage, bruising, or a dis-order of hemostasis–coagulation suggests a reduction of dosage or withdrawal of therapy. The drug should be discontinued im-mediately in the presence of significant hepatic dysfunction.
A typical starting dose for healthy adults is 750 mg/day in divided doses. The dose can then be adjusted to achieve a 12-hour serum valproate concentration between 50 and 125 µg/mL. The time of dosing is determined by possible side effects and, if tolerated, once-a-day dosing can be employed. As with lith-ium, the antimanic response to valproate typically occurs after 1 to 2 weeks.
Adverse effects that appear early in the course of therapy are usually mild and transient, and tend to resolve in time. Gas-trointestinal upset is probably the most common complaint in patients taking valproate and tends to be less of a problem with the enteric-coated divalproex sodium preparation. The adminis-tration of a histamine H2 antagonist such as famotidine (Pepcid) or cimetidine (Tagamet) may alleviate persistent gastrointestinal problems (Stoll et al., 1991). Other common complaints include tremor, sedation, increased appetite and weight, and alopecia. Weight gain is even more of a problem when other drugs are ad-ministered that also promote weight gain, such as lithium, antip-sychotic and other antiepileptics. Less common are ataxia, rashes and hematological dysfunction, such as thrombocytopenia and platelet dysfunction. Platelet count usually recovers with a dosage decrease, but the occurrence of thrombocytopenia or leukopenia may necessitate the discontinuation of valproate. Serum hepatic transaminase elevations are common, dose related, and usually self-limiting and benign. Fatal hepatotoxicity is extremely rare, is usually restricted to young children, and usually develops within the first 6 months of valproate therapy. Other serious problems include pancreatitis and teratogenesis (McElroy et al., 1989). There is also a concern that polycystic ovary syndrome, possibly associated with weight gain, may be a risk for young women who take valproate. If at any point during administration the side ef-fects of valproate become intolerable, the psychiatrist may need to discontinue it and try one of the other treatments described in this section as an alternative. If valproate is tolerated but not totally effective, the psychiatrist might use one of the other treat-ments as an adjunct.
In light of the less well-substantiated evidence for the efficacy of carbamazepine, we place this anticonvulsant fourth in the antimania algorithm – behind lithium, valproate, and olanzap-ine. The decision to move on to carbamazepine – and whether to use it alone or in addition to lithium, valproate, or olanzapine – hinges on the same treatment considerations listed earlier. If a patient has been treated with one or more of these agents in a previous manic episode, that experience may guide treatment of a current episode.
Carbamazepine’s absorption and metabolism are variable. Peak plasma levels occur within 4 to 6 hours after ingestion of the solid dosage form. Bioavailability is estimated at 85% but may be less when the drug is taken with meals. Eighty percent of plasma carbamazepine is protein bound, and its half-life ranges from 5 to 26 hours (after 3–4 weeks of treatment). Carbamazepine’s active metabolite, 10,11-epoxide, has a half-life of about 6 hours.
Carbamazepine is metabolized by the hepatic cytochrome P450 2D6 system. It causes an induction of the cytochrome P450 enzymes, often resulting in an increased rate of its own metabolism over several weeks, as well as that of other drugs metabolized by the P450 system (Table 78.5). Because of enzyme induction, the dose of carbamazepine often must be raised after 2 to 4 months of treatment. Steady state may be attained within 4 to 5 days, but when clearance increases as a result of autoinduction, steady state may not be achieved for 3 to 4 weeks. Concomitant administration of drugs that inhibit P450 (see Table 78.6) will increase plasma levels of carbamazepine. Conversely, drugs that induce P450 enzymes – such as phenobarbital, phenytoin, or primidone – can decrease carbamazepine levels. Before carbamazepine is started, baseline blood and platelet counts, urinalysis, and liver and kidney function tests are in order (see Table 78.4). Although earlier guidelines called for routine monitoring of some or all of these indices, and some psychiatrists still obtain blood counts once or twice during the first few months of treatment and when plasma concentrations are sampled, a more general consensus at present is to instruct patients and family members to contact the psychiatrist immediately if petechiae, pallor, weakness, fever, or infection occur, at which time the psychiatrist should order relevant tests.
Used as a monotherapy, the typical starting dose for carbamazepine is 200 to 400 mg/day in three or four divided doses, increased to 800 to 1000 mg/day by the end of the first week. If clinical improvement is insufficient by the end of the second week, and the patient has not had intolerable side effects to the drug, increases to as high as 1600 mg/day may be considered. Although there are no good studies of the correlation between blood level and clinical response, a common target range for ma-nia is 4 to 15 ng/mL. If carbamazepine is combined with lithium
or neuroleptics, lower doses and blood levels of carbamazepine are often used. If valproate and carbamazepine are administered simultaneously, blood levels of each should be monitored care-fully because of complex interactions between the two agents.
When the dose of carbamazepine is built up rapidly, side effects are more likely. The most common effects in the first cou-ple of weeks are drowsiness, dizziness, ataxia, diplopia, nausea, blurred vision and fatigue (Table 78.6). These tend to diminish in time or to respond to a temporary reduction in dose. Less com-mon reactions include gastrointestinal upset, hyponatremia and a variety of skin reactions, some of which are severe enough to require discontinuation of carbamazepine. About 10% of patients experience transient leukopenia, but unless infection develops, carbamazepine may be continued. More serious hematopoietic re-actions, including aplastic anemia and agranulocytosis, are rare.
Since carbamazepine and valproate are efficacious for acute ma-nia, new antiepileptic medications are often tested for mania. Lamotrigine, which appears useful in maintenance, bipolar de-pression and rapid-cycling (see below), has not shown efficacy in acute mania, with the exception of one recent double-blind trial (Berk, 1999; Anand et al., 1999; Bowden et al., 2000).
When an acutely manic patient is unresponsive to or intolerant of medication, or if medication presents other risks (e.g., during preg-nancy), ECT should be seriously considered and may be lifesaving. Although there are no coherent theories about why ECT is effective in acute mania, it has been used for more than half a century, and there are widespread clinical impressions of its safety and efficacy.
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