DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

maternal levels, and are not associated with notable behavioral
effects (Viguera et al., 2007).
Serum Level Monitoring and Dose. Because of the low therapeutic
index for Li + , periodic determination of serum concentrations is
crucial. Li + cannot be used with adequate safety in patients who
cannot be tested regularly. Concentrations considered to be effective
and acceptably safe are between 0.6 and 1.5 mEq/L. The
range of 1.0-1.5 mEq/L is favored for treatment of acutely manic
or hypomanic patients (Sproule, 2002). Somewhat lower values
(0.6-1.0 mEq/L) are considered adequate and are safer for
long-term prophylaxis. Serum concentrations of Li + have been
found to follow a clear dose-effect relationship between 0.4 and
1.0 mEq/L, but with a corresponding dose-dependent rise in
polyuria and tremor as indices of adverse effects. Nonetheless,
patients who maintain trough levels of 0.8-1.0 mEq/L experience
decreased relapse risk compared to those maintained at lower
serum concentrations. There are patients who may do well with
serum levels of 0.5-0.8 mEq/L, but there are no current clinical or
biological predictors to permit a priori identification of these individuals.
Individualization of serum levels is often necessary to
obtain a favorable risk-benefit relationship.
The concentration of Li + in blood usually is measured at a
trough of the daily oscillations that result from repetitive administration
(i.e., from samples obtained 10-12 hours after the last oral dose
of the day). Peaks can be two or three times higher at a steady state.
When the peaks are reached, intoxication may result, even when concentrations
in morning samples of plasma at the daily nadir are in the
acceptable range of 0.6-1 mEq/L. Single daily doses generate relatively
large oscillations of plasma Li + concentration but lower mean trough
levels than with multiple daily dosing, and are associated with a
reduction in the extent and risk for polyuria (Schou et al., 1982);
moreover, single nightly dosing means that peak serum levels occur
during sleep, so complaints regarding CNS adverse effects are minimized.
While relatively uncommon, GI complaints are one compelling
reason for multiple daily dosing or using delayed release Li +
preparations, bearing in mind the increased polyuria risk from these
strategies.
Therapeutic Uses
Drug Treatment of Bipolar Disorder. Treatment with Li +
ideally is conducted in patients with normal cardiac and
renal function. Occasionally, patients with severe systemic
illnesses are treated with Li + , provided that the
indications are compelling, but the need for diuretics,
nonsteroidal anti-inflammatory agents, or other medications
that pose potential kinetic problems often precludes
lithium use in those with multiple medical
problems. Treatment of acute mania and the prevention
of recurrences of bipolar illness in adults or adolescents
are uses approved by the FDA. Li + is the only mood stabilizer
with data on suicide reduction in bipolar patients
(Cipriani et al., 2005 Goodwin et al., 2003; Tondo et
al., 2001), and Li + also has abundant efficacy data for
augmentation in unipolar depressive patients who are
inadequate responders to antidepressant therapy
(Bschor et al., 2002).
Drug Treatment of Mania. The modern treatment of the
manic, depressive, and mixed-mood phases of bipolar
disorder was revolutionized by the introduction of Li +
in 1949, its gradual acceptance worldwide by the
1960s, and late official acceptance in the U.S. in 1970,
initially for acute mania only, and later primarily for
prevention of recurrences of mania. While Li + , valproate,
and carbamazepine have efficacy in acute
mania, in clinical practice these are usually combined
with atypical antipsychotic drugs, even in manic
patients without psychotic features, due to their delayed
onset of action. Li + , carbamazepine, and valproic acid
preparations are only effective with daily dosing that
maintains adequate serum levels, and require serum
level monitoring. Mania patients are often irritable and
poorly cooperative with medication administration and
phlebotomy, thus, atypical antipsychotic drugs may be
the sole initial therapy, and have proven efficacy as
monotherapy (Scherk et al., 2007); moreover, acute IM
forms of olanzapine, ziprasidone, and aripiprazole can
be used to achieve rapid control of psychosis and agitation.
Benzodiazepines are often used adjunctively for
agitation and sleep induction.
Li + is effective in acute mania, but is rarely employed as a
sole treatment for reasons noted above, and because 5-7 days are
required for clinical effect. A 600-mg loading dose of Li + can be
given to hasten the time to steady state, and can also be used to predict
dosage requirements based on the 24-hour serum Li + result, with
a very high correlation coefficient (r = 0.972) (Cooper et al., 1973).
Acutely manic patients may require higher dosages to achieve therapeutic
serum levels, and downward adjustment may be necessary
once the patient is euthymic. When adherence with oral capsules or
tablets is an issue, the liquid Li + citrate can be used. Each 5 mL of
lithium citrate syrup provides 8.12 mEq of Li + , equivalent to 300 mg
of lithium carbonate.
The anticonvulsant sodium valproate provides more rapid
antimanic effects than Li + , with therapeutic benefit seen within 3-5
days. The most common form of valproate in use is divalproex
sodium, preferred over valproic acid due to lower incidence of GI
and other adverse effects. Divalproex is initiated at 25 mg/kg once
daily and titrated to effect or the desired serum concentration. Serum
concentrations of 90-120 μg/mL show the best response in clinical
studies (Bowden et al., 2006). With immediate release forms of valproic
acid and divalproex sodium, 12-hour troughs are used to guide
treatment. With the extended-release divalproex preparation, patients
respond best when the 24-hour trough levels are in the high therapeutic
range (Bowden et al., 2006).
Carbamazepine is effective for acute mania. Immediate
release forms of carbamazepine cannot be loaded or rapidly titrated
over 24 hours as with valproate due to the development of neurological
adverse effects such as dizziness or ataxia, even within the
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
447