Drug Interactions

Essential Concepts

All antipsychotics are metabolized to varying degrees by the hepatic cytochrome P450 (CYP450) isoenzymes 3A4, 2D6, and 1A2. Some have additional non-P450 metabolism, which lowers the risk for drug interactions by providing alternative pathways if major pathways are inhibited.
Because 3A4 metabolizes the bulk of antipsychotics, inducers and inhibitors of 3A4 are important clinically.
Smoking increases the metabolism of 1A2-dependent antipsychotics, requiring dose adjustment for olanzapine and clozapine.
Although antipsychotics are generally safe even with excessive drug serum levels, pimozide, mesoridazine/thioridazine (cardiac toxicity), and clozapine (seizures and hypotension) are exceptions.
Some drug interactions problems are “hidden” in that they merely increase the statistical risk factors for later morbidity (e.g., for tardive dyskinesia or diabetes).
Antipsychotic serum drug levels are not useful routinely, but rather in clinical situations in which you want to confirm that a patient is at the extremes of drug levels.

“I beseech you, in the bowels of Christ, think it possible you may be mistaken.”

—Oliver Cromwell, Lord protector of England, 1599-1658

“I don’t think this is related to my medicine,” you hear yourself telling your patient. Never dismiss a patient’s complaint about a side effect, but consider the possibility that you are wrong and the patient is right, possibly because of a hitherto unrecognized drug interaction (Cromwell puts the patient’s complaint in more dramatic language).

In this chapter, I focus mostly on drug metabolism, particularly the all-important CYP450 enzyme system that does the
bulk of metabolism for psychotropics, including antipsychotics, and how it relates to serum drug levels. Renal excretion and plasma binding are generally not a clinical issue with antipsychotics.

ANTIPSYCHOTIC DRUG METABOLISM

Antipsychotics are mainly metabolized by the hepatic CYP450 enzyme system, but other systems, like the phase II glucuronidation enzyme system (uridine glucuronosyl transferase, or UGT), contribute to the deactivation of antipsychotics. For antipsychotic metabolism, the most important cytochrome isoenzymes are 3A4, 2D6, and 1A2. Consult Table 16.1 for the main metabolic pathways for commonly used antipsychotics.

TABLE 16.1. Antipsychotic Metabolic Pathways

Relevant Metabolite	CYP450 Metabolism	Alternative Metabolism
First-generation antipsychotics
Haloperidol	HP⁺^a	3A4, 2D6	Glucuronidation
Fluphenazine	7-OH-FLU^b	2D6
Perphenazine	None known	2D6
Second-generation antipsychotics
Aripiprazole	None active	3A4, 2D6
Clozapine	nor-CLZ^c	1A2, 3A4, 2C19, (2D6)
Olanzapine	None active	1A2, (2D6, 2C19?)	Glucuronidation
Quetiapine	None relevant	3A4, (2D6)
Risperidone	9-OH-RSP^d	2D6, 3A4
Ziprasidone	None relevant	3A4 (33%)	Aldehyde oxidase (66%)
Main metabolizing enzymes in bold.
^aHP+ is likely a neurotoxic metabolite. ^b7-Hydroxyfluphenazine. ^cNorclozapine or N-desmethylclozapine; possibly responsible for hematologic toxicity. ^d9-Hydroxyrisperidone (paliperidone); active moiety is risperidone plus 9-hydroxyrisperidone; 9-hydroxyrisperidone is equipotent with risperidone.
Based on Freudenreich O, Goff DC. Antipsychotics. In: Ciraulo DA, Shader RI, Greenblatt DJ, et al. eds. Drug interactions in psychiatry. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2006:177-241.