Pharmacokinetics The pharmacokinetic properties of mood stabilizers are

summarized in Table 3-2.

Pharmacokinetics PEAK PLASMA

GENERIC NAME TRADE NAME LEVELS (h) HALF-LIFE (h) Carbamazepine

Tegretol and others 1.5–6 25–65 or 8–29 Gabapentin

Neurontin 3 5–7 Lamotrigine

Lamictal 1–5 26 Lithium

Eskalith and others 1–4 18–36 Topiramate

Topamax 2 21 Valproate

Depakote and others 2–4 9–16 Aripiprazole

Ability 3–5 75 ∗ Olanzapine

Zyprexa 6 27 Quetiapine

Seroquel 1.5 7 Risperidone

Risperdal 1 3 ∗∗ Ziprasidone

Geodon 6–8 4–10 ∗ t 1/2 of active metabolite is 94 hours.

∗∗ t 1/2 of active metabolite is 24 hours.

88 HANDBOOK OF PSYCHIATRIC DRUGS LITHIUM

Lithium is available as both immediate release lithium carbonate as well as in two slow-release formulations. The latter are generally better tolerated, produce lower peak levels for a given area under the curve, and allow for once daily administration. In any form, lithium has the following properties:

• Rapid and complete absorption after oral administration. • Low protein binding. • Absence of liver metabolism. • Peak plasma levels achieved within 1.5 to 2 hours for stan-

dard preparations or 4 to 4.5 hours for slow-release forms. • Plasma half-life of 17 to 36 hours. • 95% drug excretion by the kidneys, with excretion propor-

tionate 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 sodium.

ANTICONVULSANTS Valproate is available 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 frequently used. Divalproex is available in immediate, delayed, and extended release forms. Valproate is characterized by the following:

• Rapid absorbtion after oral administration, reaching peak plasma levels within 2 to 4 hours of ingestion.

• Bioavailability unaffected by food, though absorption may

be delayed. • Rapid distribution and high (90%) plasma protein binding. • Half-life between 9 and 16 hours, with 1 to 4 days needed

to attain steady state. Carbamazepine is available in an immediate release and

three extended release forms. It is metabolized by the

MOOD STABILIZERS 89 hepatic cytochrome P450 2D6 system, which it also robustly

induces. As a result of this autoinduction, the rate of metabolism of carbamazepine (and other P450 substrates) usually increases over the first several weeks of treatment (see ‘Drug Interactions’ on page 119). Initial steady state may

be attained within 4 to 5 days, but autoinduction may delay final steady state until 3 to 4 weeks after treatment initiation. This calls for added vigilance on the part of the clinician, as the level of carbamazepine must be monitored and its dose often must be raised during this early phase of treatment. Additional pharmacokinetic properties of carbamazepine include:

• Occurrence of peak plasma levels within 4 to 6 hours after ingestion of the solid dosage form.

• Bioavailability of 85%, which may be reduced when the drug is taken with meals. • Plasma protein binding of 80%.

• A half-life (after 3–4 weeks of treatment) ranging from 5 to

26 hours. • Production of an active metabolite, 10, 11-epoxide, which has

a half-life of about 6 hours. This metabolite, also known as oxcarbazepine, has been utilized as an anticonvulsant itself, and is undergoing clinical testing as a mood stabilizer.

Lamotrigine is primarily metabolized by glucuronic acid conju- gation. Enzyme induces, such as carbamazepine, increase lamotrigine metabolism whereas competitors, such as valproate, markedly decrease its metabolism (see ‘Drug Interactions’ on page 119). Other pharmacokinetic parameters include:

• Complete absorbtion after oral administration. • Bioavailability of 98%, which is unaffected by food. • Peak plasma concentrations occurring between 1 and 2 hours

after administration, but delayed to up to 5 hours in patients also taking valproate.

• Protein binding of approximately 55%, making clinically significant interactions with other protein-bound drugs unlikely.

• Half-life of 12–27 hours, increasing to 59 hours in patients also taking valproate. • Occurrence of steady-state levels in 3 to 10 days.

90 HANDBOOK OF PSYCHIATRIC DRUGS ANTIPSYCHOTICS

The pharmacokinetic characteristics of atypical antipsychotics are described in Chapter 1.

Pharmacokinetics The pharmacokinetic properties of mood stabilizers are