Mr. P, age 35 with schizophrenia and seizure disorder, has been maintained on risperidone, 6 mg qhs, and phenytoin, 300 mg qhs. For clinical reasons, the treating neurologist changes the anticonvulsant to divalproex. One week later, Mr. P presents to the emergency room complaining of jaw and neck stiffness.
Ms. K, age 43 with a history of schizoaffective disorder, bipolar type, and erratic medication adherence, is being treated with quetiapine, 600 mg at bedtime, and carbamazepine, 1,000 mg/d. Between appointments she stops taking carbamazepine, believing it is causing her to hear voices from her television. Two weeks later, the manager of Ms. K’s independent living facility tells the psychiatrist that the patient appears excessively sedated and has fallen twice in the past few days.
Mrs. T, a 39-year-old state hospital resident with schizoaffective disorder, bipolar type, has been treated with clozapine, 250 mg bid for 6 months; her most recent trough serum level was 492 ng/mL. She smokes 15 cigarettes/d. Two weeks after the hospital institutes a no-smoking policy, Mrs. T complains of excessive drooling and lightheadedness. Her trough clozapine level is now 875 ng/mL.
Discontinuing a medication that has enzyme-inducing effects presents a hidden problem for patients receiving antipsychotic pharmacotherapy. Certain hepatic enzymes responsible for antipsychotic metabolism—as well those involved in intercellular drug transport—are induced by medication or environmental exposures.1,2 Adding a medication that induces these enzymes to the regimen of a patient receiving antipsychotic therapy can result in markedly reduced serum antipsychotic levels, and discontinuing an inducing agent can result in increased antipsychotic levels.
Drug-drug interactions (DDIs) are a substantial contributor to adverse drug reactions (Box).3-7 Antipsychotic prescribing information highlights potential DDIs from the use of enzyme inhibitors and inducers but identifies only effects caused by adding a second agent. The prescriber remains the sole line of defense for monitoring for DDIs when discontinuing a medication that has inducing or inhibiting effects.
Most psychiatrists are aware that certain medications have clinically significant effects on cytochrome P450 (CYP) activity and of the potential for CYP inhibitors to generate DDIs. Clinicians often are aware of antidepressant medications’ CYP-inhibiting effects, know that levels of other medications will change when discontinuing a potent P450 inhibitor, and understand the need to increase dosages of medications influenced by such agents.8
However, few studies have evaluated the effects of enzyme induction on antipsychotic drug levels,9,10 and the literature rarely discusses changes in serum drug levels after loss of enzyme or drug transport induction.11 If unrecognized, these changes may have significant clinical consequences.
Drug interactions: A common cause of nonadherence
Drug-drug interactions (DDIs) are a common and often preventable cause of morbidity and mortality. National surveillance data showed 700,000 emergency room visits related to adverse drug reactions (ADRs) in the 2 years from January 2004 through 2005.3 ADRs are particularly concerning for psychiatrists managing polypharmacy regimens for patients with severe mental disorders such as schizophrenia.
Literature on DDIs with antipsychotics focuses primarily on kinetic interactions that generate supratherapeutic drug levels.4,5 Because development of side effects is associated with reduced adherence, these kinetic interactions may increase the risk of adverse effects and lead to patients stopping the antipsychotic treatment.6,7
Two induction pathways
The primary mechanism underlying clinically significant DDIs occurs during CYP-mediated phase I metabolism. Molecules undergo oxidative conversion into metabolites that can be conjugated by phase II enzymes, generating more soluble forms that facilitate excretion.
The workhorse of human CYP metabolism is 3A4 (Table 1),12,13 which comprises 30% of hepatic activity and 70% of gut cytochrome activity.14 CYP 1A2 is responsible for 10% to 15% of CYP activity.
Both CYP 3A4 and 1A2 are inducible. A wide variety of medications induce 3A4 activity. The list of 1A2 inducers is shorter; the most common are aryl hydrocarbons from cigarette smoke and proton pump inhibitors.
CYP 2D6 accounts for 20% of hepatic cytochrome activity but is not inducible. CYP 2D6 is well known to psychiatrists because some selective serotonin reuptake inhibitors (SSRIs) and the non-SSRI antidepressant bupropion are potent inhibitors of this enzyme.15,16
P-glycoprotein (PGP) induction. Transmembrane shuttles such as P-glycoprotein (PGP) are an important component of drug disposition. PGP belongs to the family of ATP binding cassette (ABC) transporters that bring molecules across cellular barriers.17,18 It was first described in cancer cells that developed multiple drug resistance (MDR) and is often referred to as MDR1.19 PGP is encoded on human chromosome 7 and expressed in normal tissues, particularly in areas where cells seek to limit drug influx, such as those lining the luminal surface of the small and large intestine and those lining the blood-brain barrier and blood-testis barrier. The expression of PGP in hepatic cells promotes drug clearance by enhancing biliary drug excretion.