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20. Antipsychotic Drug Interactions
Keywords
Drug-drug interactionsPharmacokineticsPharmacodynamicsTherapeutic drug monitoring (TDM)Pharmacogenomic testingEssential Concepts
Almost 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 and 2D6 metabolize the bulk of antipsychotics, inducers, inhibitors, or genetic variants of those enzymes 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.
Antipsychotic plasma drug levels are useful in clinical situations in which you want to confirm that a patient has either very low (close to zero) or very high (toxic) drug levels, due to genetic factors or due to nonadherence. Drug levels provide actionable information compared to pharmacogenomic testing which is most helpful to explain unexpectedly high or low drug levels in adherent patients.
“I beseech you, in the bowels of Christ, think it possible you may be mistaken.” [1]
–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 genetic variant affecting drug metabolism or a drug interaction (Cromwell puts the patient’s complaint in more dramatic language).
In this chapter, I focus on pharmacokinetic drug interactions related to the all-important hepatic cytochrome P450 (CYP450) enzyme system that does the bulk of metabolism of psychotropics, including antipsychotics, and how it relates to serum drug levels. Renal excretion and plasma binding are generally not a clinical issue with antipsychotics, at least not in routine outpatient care. Important pharmacodynamic drug interactions are mentioned for commonly used medication combinations.
Antipsychotic Drug Metabolism
Antipsychotic metabolic pathways
Antipsychotic | Relevant metabolite | CYP450 metabolism | Alternative metabolism |
|---|---|---|---|
First-generation antipsychotics | |||
Haloperidol | HP+a | 3A4, 2D6 | Glucuronidation |
Fluphenazine | 7-OH-FLUb | 2D6 | |
Perphenazine | 2D6 | ||
Second-generation antipsychotics | |||
Asenapine | 1A2 | Glucuronidation | |
Clozapine | nor-CLZc | 1A2, 3A4, 2D6 | |
Iloperidone | 3A4, 2D6 | ||
Lurasidone | 3A4 | ||
Olanzapine | 1A2 | Glucuronidation | |
Paliperidone | Renal (non-P450) | ||
Quetiapine | 3A4 | ||
Risperidone | 9-OH-RISPd | 2D6, 3A4 | |
Ziprasidone | 3A4 (33%) | Aldehyde oxidase (66%) | |
Third-generation antipsychotics (partial agonists) | |||
Aripiprazole | One metabolite | 2D6, 3A4 | |
Brexpiprazole | 2D6, 3A4 | ||
Cariprazine | Two metabolites | 3A4, 2D6 | |
Key Point
Note in Table 20.1 that most antipsychotics are metabolized by more than one enzyme or enzyme system. For example, haloperidol, olanzapine, and ziprasidone can be directly deactivated through CYP450-independent pathways. This serves as a built-in safety valve, particularly if enzyme systems cannot be inhibited or induced, as in the case of aldehyde oxygenase.
It is useful to know that antipsychotics do not inhibit P450 enzymes (with the exception of 2D6, which is inhibited by some antipsychotics) and that they do not induce P450 enzymes. In that respect, antipsychotics can generally be safely added to other treatment regimens.
It helps to recall a few general facts about the P450 system to anticipate drug interactions. Some (but not all) isoenzymes can be induced or inhibited, the most important ones being 3A4 and 1A2. Antipsychotic drug levels will be lower in the presence of an inducer and higher in the presence of an inhibitor if either of these isoenzymes metabolizes the antipsychotic. The main inducer for 1A2 is not a medication but smoking (polycyclic aromatic hydrocarbons in tobacco smoke, not nicotine [4]); consequently, smokers predictably require higher doses, compared to nonsmokers, of 1A2-dependent antipsychotics (i.e., olanzapine and clozapine). When smokers quit smoking, olanzapine and clozapine levels will rise, and the dose should be adjusted [5, 6]. The downregulation of 1A2 after smoking cessation occurs rapidly, and dose reductions should be considered already within a few days of stopping [7].
Pharmacogenomics
Differences between patients in how drugs are metabolized are to a large part determined by genetic factors. Many metabolizing enzymes show genetic polymorphism, the most important ones being the highly polymorphic 2D6 gene [8]. 2D6 genetic polyphorphism results in four clinical phenotypes: so-called extensive (or normal) metabolizers, poor metabolizers (inactive enzyme), intermediate metabolizers (some enzyme activity), and ultrarapid metabolizers (greatly increased enzyme activity) [9]. There is no way of knowing your patient’s 2D6 genotype without genotyping, although you can take into account a patient’s ethnic background (e.g., some Middle Eastern and African populations have high rates of ultrarapid metabolizers) when considering side effects or nonresponse at usual doses. 2D6 phenotypes matter for risperidone, or older antipsychotics like that have significant 2D6-dependent metabolism [10]: ultrarapid metabolizers might never achieve sufficient plasma levels and be accused of nonadherence; poor metabolizers will appear exquisitely sensitive to standard doses (extrapyramidal symptoms, or EPS) and be labeled “histrionic.” Genetic 1A2 variants may be important to consider in nonresponsive clozapine patients (see Case below).
With the advent of pharmacogenomics and personalized medicine, genetic testing for enzymes involved in drug metabolism and proteins responsible for drug action has become available [11]. Sometimes, families arrive for their initial visit with a printout of their genetic testing that includes metabolizing enzymes so you need to be able to interpret the results and put them in a clinical context for the family. Importantly, genotyping does not provide you with a full picture unless the complete metabolic pathway is known, including the relative importance of involved isoenzymes. Genetic information merely provides an often incomplete snapshot of somebody’s potential for unusual drug metabolism due to genetic factors. Hopefully, we will soon be able to incorporate genetic information to assess the risk for serious side effects (e.g., clozapine-induced agranulocytosis) [12]. At this point, biomarkers other than those involved in drug metabolism are not clinically useful for matching antipsychotics and patients with regard to treatment response [13].
Tip
Undoubtedly, pharmacogenomics and personalized medicine will expand, and possibly one day, we will be in a position to choose the dose and type of antipsychotic based on somebody’s genetic makeup before you start treatment. In the interim, check an antipsychotic drug level if you are unsure about the adequacy of dosing. The information you get from drug levels is immediately actionable as you get distal information about the summative effects of genes and drug interactions (and adherence). Pharmacogenomic testing can then confirm that genetic variants are in fact responsible for unexpectedly high or low drug level (in an adherent patient) and guide your subsequent dosing and even drug selection.
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