Pharmacology of carbamazepine (Tegretol)

Carbamazepine chemical structure

An underappreciated medication

Carbamazepine is an underappreciated drug.  Its lack of weight gain should put it at the fore of mood stabilizer options in groups concerned about weight, such as young women.  Since lamotrigine is less effective in the long-term for manic episode prevention than for depression, and since it is acutely ineffective for mixed or manic symptoms, carbamazepine would seem to have an important niche in the young woman with predominantly mixed episode symptoms, or with a history of more severe mania than depression.  In such persons, I frequently see lamotrigine used with little benefit, and often carbamazepine is never even tried.

Use the slow release form, not the standard generic agent

It is our strong clinical experience that slow-release carbamazepine ER has fewer nuisance side effects, described below, than generic carbamazepine.  PL believes that this agent is underappreciated, at least in the US, because of side effects experienced with its standard generic form.  The slow-release agent, now generic and easily obtainable, is much better tolerated. 

Best clinical uses

Carbamazepine is most useful in such younger individuals who do not have many medical morbidities and are not taking other medications, thus obviating the drug interaction complications.   Further, if a patient with bipolar disorder does not respond well to carbamazepine in monotherapy, or in combination with lithium, I tend to avoid continuing combinations with antipsychotics or anticonvulsants, due to the undercutting effect of carbamazepine‚Äôs hepatic enzyme induction on the blood levels of those other agents.   In a study of risperidone added to mood stabilizers, for instance, the combination with carbamazepine was not better than placebo, although the combinations with lithium or valproate were better than placebo.  In such settings of polypharmacy, carbamazepine is usually best left out of the mix. 

Formulations, mechanisms, dosing, and pharmacokinetics

Carbamazepine is available in generic form, in standard trade formulation (Tegretol), and in a generic extended release form (Carbamazepine ER).    Standard carbamazepine has a half-life of about 6 hours, thus requiring at least twice daily dosing (unlike valproate and lithium), even with the extended release formulation. In the outpatient setting, I begin with 200 mg at night, then increase by 200 mg/d intervals every 5-7 days until either it is intolerable or therapeutic range doses are achieved.  In the inpatient setting, it is effective to begin with 400 mg at night, increase by 200-400 mg/d intervals every 1-2 days.     The psychotropic mechanism of action of carbamazepine is unclear.  Unlike valproate and lithium, it does not appear to affect many second messenger systems (like protein kinase C), but it does affect the second messenger cyclic AMP.  Carbamazepine usually requires doses around 800 mg/d (range 600-1000 mg/d) in BID dosing for an effective serum level of about 8 (range 4-12). This serum level has been established for acute mania, as well as epilepsy.

Drug interactions

Perhaps the most important pharmacological effect of carbamazepine is its strong induction of the hepatic cytochrome P450 enzyme system.  Hence, carbamazepine reduces efficacy or blood levels of many other medications.  This effect is a major problem in treating patients with other medical conditions, such as the elderly.  It is also a major problem in treating bipolar disorder, since most such patients are treated with multiple psychotropic medications. 

Carbamazepine‚Äôs 9,10-epoxide metabolite can be neurotoxic (producing delirium or confusion), and may be produced in greater amount in combination treatment with valproate.  Consequently, the valproate-carbamazepine, though safely used in many patients, should be avoided on a routine basis.

Side effects

Carbamazepine has important nuisance side effects as well as serious medical risks.  Among its associated side effects, which are dose-related, are sedation, double vision (diplopia), ataxia, and dizziness.  As an important advantage, carbamazepine does not cause appreciable weight gain in most patients, unlike lithium and valproate.

Medical risks

Carbamazepine is associated with liver function test abnormalities, like valproate, and occasionally, hepatic failure.  It is also associated with rare agranulocytosis (1 in 575,000 cases), and rare Stevens-Johnson syndrome (1 in 10,000 cases).  Benign reversible leukopenia can also occur, as can hyponatremia (with associated seizure risk).  Non-serious rash is also common.     

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