Ziprasidone Carbamazepine

Among these choices, bnspirone is preferred if the patient is also experiencing anxiety. If the patient is depressed and agitated, a SSRI should be tried first. Second line choices inclnde carbamazepine (Tegretol) or one of the atypical antipsychot-ics—ziprasidone (Geodon), risperidone (Risperdal), olanzapine (Zyprexa), quetiap-ine (Seroquel), or aripiprazole (Abilify) can be tried. If psychotic symptoms are present, one of the atypical antipsychotics should be tried first. 

Drugs that can decrease carbamazepine serum levels include charcoal, cisplatin, doxorubicin, felbamate, hydantoins, rifampin, phenobarbital, primidone, theophylline. The serum levels of oral contraceptives, haloperidol, bupropion, anticoagulants, felbamate, valproic acid, felodipine, tricyclic antidepressants, acetaminophen, ziprasidone, voriconazole, topiramate, tiagabine, olanzapine, and lamotrigine can be lowered by carbamazepine. 

Drugs that inhibit CYP 3A4 reduce metabolism of ziprasidone concurrent treatment with ketoconazole increased blood levels of ziprasidone by approximately 40%. Carbamazepine (and possibly other enzyme inducers) may decrease ziprasidone levels by approximately 35%. Effects of ziprasidone on metabolism of other drugs have not been reported. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Drugs can not only be substrates for a cytochrome P450 enzyme or an inhibitor of a P450 enzyme, they can also be inducers of a cytochrome P450 enzyme and thereby increase the activity of that enzyme. This was discussed in Chapter 6 for CYP450 3A4, and the induction of 3A4 activity by the anticonvulsant and mood stabilizer carbamazepine was given as an example (Fig. 6—19). Since mood stabilizers may be frequently mixed with atypical antipsychotics, it is possible that carbamazepine may be added to the regimen of a patient previously stabilized on clozapine, quetiapine, ziprasidone, or sertindole. If so, the doses of these atypical antipsychotics may need to be increased over time to compensate for the induction of 3A4 by carbamazepine. 

FIGURE 11—51. The enzyme CYP450 3A4 can be induced by the anticonvulsant and mood stabilizer carbamazepine. If this agent is stopped in a patient who is receiving an atypical antipsychotic that is a substrate for this same enzyme (i.e., clozapine, quetiapine, ziprasidone, or sertindole), the doses of these antipsychotics may need to be reduced because the autoinduction of 3A4 by carbamazepine will reverse over time once it is discontinued. 

Pfizer, the marketing authorization holder of ziprasidone, has promoted several pharmacokinetic studies. Oral contraceptives (ethinylestradiol 30 pg/day plus levonorgestrel 150 pg/day) (34), lithium 900 mg/day (35), ketoconazole 400 mg/day (36), and carbamazepine (100-400 mg/day)... 

Miceli JJ, Anziano RJ, Robarge L, Hansen RA, Laurent A. The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers. Br J Clin Pharmacol 2000 49(Suppl. 1) 65S-70S. 

The effect of steady-state carbamazepine administration on the steady-state pharmacokinetics of ziprasidone has been studied in 25 healthy young adults, in a randomized, placebo-controlled study (112). Carbamazepine caused small reductions in ziprasidone AUCo i2 and Cmax (36% and 27% respectively). The authors concluded that carbamazepine had increased ziprasidone clearance by induction of CYP3A4. 

Antidepressants mirtazapine, nefazodone, sertraline Neuroleptics thioridazine, haloperidol, clozapine, quetiapine, risperidone, sertindole, ziprasidone Mood stabilizers carbamazepine, gabapentin, lamotrigine... 

Low doses of carbamazepine do not appear to affect the pharmacokinetics of ziprasidone. 

In a randomised study, healthy subjects were given ziprasidone 20 mg twice daily with either placebo (10 subjects), or carbamazepine 200 mg twice daily for 5 doses (9 subjects). It was found that the AUCo i2 and maximum serum levels of ziprasidone were reduced by 36% and 27%, re-... 

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