Carbamazepine and Oxcarbazepine

For a more detailed discussion of this topic, see Carbamazepine, Ch. 31.14, p. 3073 in Comprehensive Textbook of Psychiatry, 9th Edition.

Carbamazepine (Tegretol) is an iminostilbene drug possessing some structural similarity to the tricyclic antidepressant imipramine (Tofranil). It was approved for use in the United States for the treatment of trigeminal neuralgia in 1968 and for temporal lobe epilepsy (complex partial seizures) in 1974. Interestingly, carbamazepine was first synthesized as a potential antidepressant, but because of its atypical profile in a number of animal models, it was initially developed for use in pain and seizure disorders. It is now recognized in most guidelines as a second-line mood stabilizer useful in the treatment and prevention of both phases of bipolar affective disorder. A long-acting sustained release formulation (Equetro) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute mania in 2002.

An analog of carbamazepine, oxcarbazepine (Trileptal), was marketed as an anti-seizure medication in the United States in 2000, after being used as a treatment for pediatric epilepsy in Europe since 1990. Because of its similarity to carbamazepine, many clinicians began to use it as a treatment for patients with bipolar disorder. Despite some reports that oxcarbazepine has mood-stabilizing properties, this has not been confirmed in large, placebo-controlled trials.

Carbamazepine

Pharmacologic Actions

Absorption of carbamazepine is slow and unpredictable. Food enhances absorption. Peak plasma concentrations are reached 2 to 8 hours after a single dose, and steady-state levels are reached after 2 to 4 days on a steady dosage. It is 70% to 80% protein bound. The half-life of carbamazepine ranges from 18 to 54 hours, with an average of 26 hours. However, with chronic administration, the half-life of carbamazepine decreases to an average of 12 hours. This results from induction of hepatic cytochrome 450 (CYP 450) enzymes by carbamazepine, specifically autoinduction of carbamazepine metabolism. The induction of hepatic enzymes reaches its maximum level after about 3 to 5 weeks of therapy.

The pharmacokinetics of carbamazepine are different for two long-acting preparations of carbamazepine, each of which uses slightly different technology. One formulation, Tegretol XR, requires food to ensure normal gastrointestinal (GI) transit time. The other preparation, Carbatrol, relies on a combination of intermediate, extended-release, and very slow–release beads, making it suitable for bedtime administration.

Carbamazepine is metabolized in the liver, and the 10,11-epoxide metabolite is active as an anticonvulsant. Its activity in the treatment of bipolar disorders is
unknown. Long-term use of carbamazepine is associated with an increased ratio of the epoxide to the parent molecule.

The anticonvulsant effects of carbamazepine are thought to be mediated mainly by binding to voltage-dependent sodium channels in the inactive state and prolonging their inactivation. This secondarily reduces voltage-dependent calcium channel activation and, therefore, synaptic transmission. Additional effects include reduction of currents through N-methyl-D-aspartate (NMDA) glutamate-receptor channels, competitive antagonism of adenosine A₁ receptors, and potentiation of central nervous system (CNS) catecholamine neurotransmission. Whether any or all of these mechanisms also result in mood stabilization is not known.

Therapeutic Indications

Bipolar Disorder

Acute Mania.

The acute antimanic effects of carbamazepine are typically evident within the first several days of treatment. About 50% to 70% of all persons respond within 2 to 3 weeks of initiation. Studies suggest that carbamazepine may be especially effective in persons who are not responsive to lithium, such as persons with dysphoric mania, rapid cycling, or a negative family history of mood disorders. The antimanic effects of carbamazepine can be, and often are, augmented by concomitant administration of lithium (Eskalith), valproic acid (Depakene), thyroid hormones, dopamine receptor antagonists (DRAs), or serotonin–dopamine antagonists (SDAs). Some persons may respond to carbamazepine but not lithium or valproic acid and vice versa.

Prophylaxis.

Carbamazepine is effective in preventing relapses, particularly among patients with bipolar II disorder and schizoaffective disorder, and dysphoric mania.

Acute Depression.

A subgroup of treatment-refractory patients with acute depression responds well to carbamazepine. Patients with more severe episodic and less chronic depression seem to be better responders to carbamazepine. Nevertheless, carbamazepine remains an alternative drug for depressed persons who have not responded to conventional treatments, including electroconvulsive therapy (ECT).

Other Disorders

Carbamazepine helps to control symptoms associated with acute alcohol withdrawal. Although lacking the abuse potential of benzodiazepines in this population, the lack of any advantage of carbamazepine over the benzodiazepines for alcohol withdrawal and the potential risk of adverse effects with carbamazepine limit its use in this role. Carbamazepine has been suggested as a treatment for the paroxysmal recurrent component of posttraumatic stress disorder (PTSD). Uncontrolled studies suggest that carbamazepine is effective in controlling impulsive, aggressive behavior in nonpsychotic persons of all ages, including children and elderly persons. Carbamazepine is also effective in controlling nonacute agitation and aggressive behavior in patients with schizophrenia and schizoaffective disorder. Persons with prominent positive symptoms (e.g., hallucinations) may be likely to respond, as are persons who display impulsive aggressive outbursts.

Precautions and Adverse Reactions

Carbamazepine is relatively well tolerated. Mild GI (nausea, vomiting, gastric distress, constipation, diarrhea, and anorexia) and CNS (ataxia, drowsiness) side effects are the most common. The severity of these adverse effects is reduced if the dosage of carbamazepine is increased slowly and kept at the minimal effective plasma concentration. In contrast to lithium and valproate (other drugs used to manage bipolar disorder), carbamazepine does not appear to cause weight gain. Because of the phenomena of autoinduction, with consequent reductions in carbamazepine concentrations, side effect tolerability may improve over time. Most of the adverse effects of carbamazepine are correlated with plasma concentrations above 9 μg/mL. The rarest but most serious adverse effects of carbamazepine are blood dyscrasias, hepatitis, and serious skin reactions (Table 12-1).

Blood Dyscrasias

The drug’s hematologic effects are not dose related. Severe blood dyscrasias (aplastic anemia, agranulocytosis) occur in about one in 125,000 persons treated with carbamazepine. There does not appear to be a correlation between the degree of benign white blood cell (WBC) suppression (leukopenia), which is seen in 1% to 2% of persons, and the emergence of life-threatening blood dyscrasias. Persons should be warned that the emergence of such symptoms as fever, sore throat, rash, petechiae, bruising, and easy bleeding can potentially herald a serious dyscrasia, and the person should seek medical evaluation immediately. Routine hematologic monitoring in carbamazepine-treated persons is recommended at 3, 6, 9, and 12 months. If there is no significant evidence of bone marrow suppression by that time, many experts would reduce the interval of monitoring. However, even assiduous monitoring may fail to detect severe blood dyscrasias before they cause symptoms.

Hepatitis

Within the first few weeks of therapy, carbamazepine can cause both hepatitis associated with increases in liver enzymes, particularly transaminases, and cholestasis associated with elevated bilirubin and alkaline phosphatase. Mild transaminase elevations warrant observation only, but persistent elevations more than three times the upper limit of normal indicate the need to discontinue the drug. Hepatitis can recur if the drug is reintroduced to the person and can result in death.

Table 12-1 Adverse Events Associated with Carbamazepine

Dosage-Related Adverse Effects	Idiosyncratic Adverse Effects
Double or blurred vision	Agranulocytosis
Vertigo	Stevens-Johnson syndrome
GI disturbances	Aplastic anemia
Task performance impairment	Hepatic failure
Hematologic effects	Rash
	Pancreatitis
GI, gastrointestinal.