Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 29: Psychopharmacological Treatment

Laboratory Interferences Circulating levels of thyroxine and triiodothyronine are asso- ciated with a decrease in thyroid-stimulating hormone and may be associated with treatment. Carbamazepine is also associated with an increase in total serum cholesterol, pri- marily by increasing high-density lipoproteins. The thyroid and cholesterol effects are not clinically significant. Carba- mazepine may interfere with the dexamethasone (Decadron) suppression test and may also cause false-positive pregnancy test results. Dosing and Administration The target dose for antimanic activity is 1,200 mg a day, although this varies considerably. Immediate-release carbam- azepine needs to be taken three or four times a day, which leads to lapses in compliance. Extended-release formulations are thus preferred because they can be taken once or twice a day. One form of extended-release carbamazepine, Carbatrol, comes as 100-, 200-, and 300-mg capsules. Another form, Equetro, is identical to Carbatrol and is marketed as a treatment for bipolar disorder. These capsules contain tiny beads with three different types of coatings so they dissolve at different times. Capsules should not be crushed or chewed. The contents can be sprin- kled over food, however, without affecting the extended-release qualities. This formulation can be taken either with or without meals. The entire daily dose can be given at bedtime. The rate of absorption is faster when it is given with a high-fat meal. Another extended-release form of carbamazepine, Tegretol XR, uses a different drug-delivery system than Carbatrol. It is avail- able in 100-, 200-, and 300-mg tablets. Preexisting hematologic, hepatic, and cardiac diseases can be relative contraindications for carbamazepine treatment. Per- sons with hepatic disease require only one third to one half the usual dosage; the clinician should be cautious about raising the dosage in such persons and should do so only slowly and gradually. The laboratory examination should include a com- plete blood count with platelet count, liver function tests, serum electrolytes, and an electrocardiogram in persons older than 40 years of age or with a preexisting cardiac disease. An electro- encephalogram is not necessary before the initiation of treat- ment, but it may be helpful in some cases for the documentation of objective changes correlated with clinical improvement. Table 29.13-3 presents a brief user’s guide to carbamazepine in bipolar disorder. Routine Laboratory Monitoring Serum levels for antimanic efficacy have not been established. The anticonvulsant blood concentration range for carbamaze- pine is 4 to 12 m g/mL, and this range should be reached before determining that carbamazepine is not effective in the treatment of a mood disorder. A clinically insignificant suppression of the WBC count commonly occurs during carbamazepine treat- ment. This benign decrease can be reversed by adding lithium, which enhances colony-stimulating factor. Potential serious hematologic effects of carbamazepine, such as pancytope- nia, agranulocytosis, and aplastic anemia, occur in about 1 in 125,000 patients. Complete laboratory blood assessments may

Table 29.13-3 Carbamazepine in Bipolar Illness: A Brief User’s Guide

be performed every 2 weeks for the first 2 months of treatment and quarterly thereafter, but the FDA has revised the package insert for carbamazepine to suggest that blood monitoring be performed at the discretion of the physician. Patients should be informed that fever, sore throat, rash, petechiae, bruising, or unusual bleeding may indicate a hematologic problem and should prompt immediate notification of a physician. This approach is probably more effective than is frequent blood monitoring during long-term treatment. It has also been sug- gested that liver and renal function tests be conducted quarterly, although the benefit of conducting tests this frequently has been questioned. It seems reasonable, however, to assess hematologic status, along with liver and renal functions whenever a routine examination of the person is being conducted. A monitoring protocol is listed in Table 29.13-4. Carbamazepine treatment should be discontinued and a con- sult with a hematologist should be obtained if the following lab- oratory values are found: total WBC count below 3,000/mm 3 , erythrocytes below4.0 × 10 6 /mm 3 , neutrophils below1,500/mm 3 , hematocrit less than 32 percent, hemoglobin less than 11 g/ 100 mL, platelet count below 100,000/mm 3 , reticulocyte count below 0.3 percent, and a serum iron concentration below 150 mg/100 mL.  1. Start with low (200 mg) bedtime dose in depression or euthymia; higher doses (600–800 mg/day in divided doses) in manic inpatients.  2. All bedtime dosing is reasonable with carbamazepine extended-release preparation.  3. Titrate slowly to the individual’s response or side effects threshold.  4. Hepatic enzyme CYP450 (3A4) induction and autoinduction occur in 2 to 3 weeks; slightly higher doses may be needed or tolerated at that time.  5. Warn regarding benign rash, which occurs in 5%–10% of those taking the drug; progression to rare, severe rash is unpredictable, so the drug should be discontinued if any rash develops.  6. Benign white blood cell count decreases occur regularly (usually inconsequential).  7. Rarely, agranulocytosis and aplastic anemia may develop (several per million new exposures); warn regarding appearance of fever, sore throat, petechiae, and bleeding gums and to check with physician to obtain an immediate complete blood cell count.  8. Use adequate birth control methods, including higher dosage forms of estrogen (as carbamazepine lowers estrogen levels).  9. Avoid carbamazepine in pregnancy (spina bifida occurs in 0.5%; other severe adverse outcomes occur in about 8%). 10. Some people will respond well to carbamazepine and not other mood stabilizers (lithium) or anticonvulsants (valproic acid). 11. Combination treatment often required to maintain remission and prevent loss of effect via tolerance. 12. Major drug interactions associated with increases in carbamazepine and potential toxicity from 3A4 enzyme inhibition include calcium channel blockers (isradipine and verapamil); erythromycin and related macrolide antibiotics; and valproate.