Antidepressant and Antimanic Medications: Carbamazepine
Carbamazepine is an anticonvulsant drug structurally related to the TCAs. As with the TCAs, its absorption and metabolism are variable. Carbamazepine is rapidly absorbed, with peak plasma levels occurring within 4-6 hours. Eighty percent of plasma carbamazepine is protein-bound, and its half-life ranges from 13 to 17 hours. Carbamazepine is metabolized by the hepatic CYP2D6 system. It induces the CYP enzymes, causing an increase in the rate of its own metabolism over time as well as that of other drugs metabolized by the CYP system. This often results in having to raise the total dose within 2-4 months of treatment initiation.
Concomitant administration of carbamazepine with oral contraceptives, warfarin, theophylline, doxycycline, haloperidol, TCAs, or valproic acid leads to decreased plasma levels of these other drugs. Concomitant administration of drugs that inhibit the CYP system will increase plasma levels of carbamazepine. These drugs include fluoxetine, cimetidine, erythromycin, isoniazid, and calcium channel blockers and propoxyphene. Concomitant administration of phenobarbital, phenytoin, and primidone causes a decrease in carbamazepine levels through induction of the CYP enzymes.
Since 1978, findings from more than 19 studies (almost all of them small case series or open trials) evaluating the effectiveness of carbamazepine in the treatment of mania have been published. The majority of these trials have shown carbamazepine to be equal in efficacy to lithium and neuroleptics and more effective than placebo. However, the number of patients in each study was small, the diagnoses were heterogeneous or unspecified, concomitant medications were used, and study designs were unclear. A large-scale comparison with placebo and lithium has not been performed. Nor have direct comparisons with valproic acid been performed. Some studies suggest that compared with lithium, carbamazepine may have a faster onset of action, similar to the onset of the antimanic effects of antipsychotics (Post et al. 1987). Carbamazepine may be more effective than lithium in patients with dysphoric mania or rapid cycling.
Plasma blood-level monitoring of carbamazepine was first instituted to maximize its anticonvulsant effects, and these recommendations appear to be relevant to the treatment of mania, although definitive studies have not been carried out. Usual therapeutic total dosages of carbamazepine range from 400 mg to 1,200 mg/day, and therapeutic plasma levels range from 4 to 12 μg/mL.
Carbamazepine frequently causes lethargy, sedation, nausea, tremor, ataxia, and visual disturbances during the acute-treatment phase (Zajecka 1993). Some patients can develop mild leukopenia or thrombocytopenia during this phase and usually do not progress. Carbamazepine has been reported to cause a severe form of aplastic anemia or agranulocytosis that is estimated to occur with an incidence of about 2-5 per 100,000, which is 11 times the incidence in the general population. Although more than 80% of these reactions occur during the first 3 months of therapy, some cases have been reported as late as 5 years after initiation of therapy treatment. If the white blood cell count drops below 3,000 cells/mm3, the medication should be discontinued.
Carbamazepine has also been associated with fetal anomalies, including a risk of spina bifida (1%), low birthweight, and small head circumference. It has also been shown to have effects on cardiac conduction, slowing atrioventricular conduction. Other reported side effects include inappropriate secretion of antidiuretic hormone with concomitant hyponatremia; decreased thyroid hormone levels without changes in levels of thyroid-stimulating hormone; severe dermatological reactions such as Stevens-Johnson syndrome; and hepatitis.
Because of the cardiac, hematologic, endocrine, and renal side effects associated with carbamazepine, patients should have had a recent physical examination, complete blood count (CBC) with platelet count, liver function tests, thyroid function tests, and renal indices before initiation of treatment. The CBC and liver function should be monitored every 2-3 weeks during the initial 3-4 months of treatment, and all baseline tests should be repeated at a minimum of yearly intervals thereafter. Any change in the tests listed above should warrant closer evaluation and follow-up. Carbamazepine shares with the TCAs the risk of hypertensive crisis when coadministered with MAOIs, and so this combination should not be routinely used. If carbamazepine has a role, it is more likely as an adjunct in patients with rapid cycling and patients with dysphoric mania or mixed states.
Revision date: June 18, 2011
Last revised: by Andrew G. Epstein, M.D.