What are the key drug-drug interactions (DDI) with antipsychotics?

From the Guidelines

Antipsychotics can have significant drug-drug interactions (DDIs) that affect morbidity, mortality, and quality of life, particularly with medications that prolong the QT interval, inhibit or induce cytochrome P450 enzymes, or enhance central nervous system depression. When considering DDIs with antipsychotics, it is crucial to prioritize the most recent and highest quality evidence. According to the study by 1, antipsychotics such as thioridazine, haloperidol, and chlorpromazine can prolong the QT interval, creating potentially dangerous additive effects when combined with other QT-prolonging drugs like certain antibiotics (e.g., erythromycin, moxifloxacin) or antiarrhythmics (e.g., amiodarone). Some key points to consider when evaluating DDIs with antipsychotics include:

• QT interval prolongation: Antipsychotics like ziprasidone, thioridazine, and haloperidol can prolong the QT interval, increasing the risk of cardiac arrhythmias when combined with other QT-prolonging medications.
• Cytochrome P450 enzyme interactions: Antipsychotics metabolized by CYP enzymes (especially CYP1A2, CYP2D6, and CYP3A4) can have altered blood levels when combined with inhibitors or inducers of these enzymes, as noted in the study by 1.
• Central nervous system depression: CNS depressants such as benzodiazepines, opioids, and alcohol can enhance sedation and respiratory depression when combined with antipsychotics, as highlighted in the study by 1.
• Anticholinergic effects: Antipsychotics with high anticholinergic properties (like olanzapine or clozapine) can potentiate anticholinergic effects when combined with other anticholinergic medications.
• Lithium and antihypertensive interactions: Lithium combined with antipsychotics may increase the risk of neurotoxicity, while combining antipsychotics with antihypertensives can enhance hypotensive effects. Given the potential for serious adverse effects, careful medication review and monitoring are essential when prescribing antipsychotics, particularly in patients with pre-existing medical conditions or those taking multiple medications.

From the FDA Drug Label

Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Concomitant use of Prozac and pimozide is contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS Concomitant use of Strong CYP1A2 Inhibitors: Reduce clozapine dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin).

The key DDI interactions with antipsychotics include:

• Inhibition of CYP2D6: Fluoxetine inhibits CYP2D6, which may increase the levels of antipsychotics metabolized by this enzyme, such as phenothiazines and most atypicals.
• Elevation of blood levels: Concomitant use of fluoxetine with antipsychotics like haloperidol and clozapine may elevate their blood levels.
• Contraindication: Concomitant use of fluoxetine and pimozide is contraindicated, and thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued.
• Dose reduction: Reduce clozapine dose to one-third when coadministered with strong CYP1A2 inhibitors 2.

From the Research

Key DDI Interactions with Antipsychotics

• Antipsychotics can interact with other drugs through pharmacokinetic and/or pharmacodynamic mechanisms, leading to adverse effects such as extrapyramidal symptoms, drowsiness, metabolic disturbances, and cardiac problems 3
• The risk of drug-drug interactions (DDIs) is higher when antipsychotics are combined with other drugs that affect the cytochrome P450 enzymes or P-glycoproteins, such as selective serotonin reuptake inhibitors (SSRIs) 4, 5
• Some antipsychotics, such as clozapine, can cause agranulocytosis, and the risk of this adverse effect may be increased when combined with other drugs that affect the bone marrow 6
• The combination of antipsychotics with other drugs that affect the central nervous system, such as benzodiazepines, can increase the risk of sedation, cognitive impairment, and delirium 3, 6
• Therapeutic drug monitoring (TDM) can be useful in managing DDIs with antipsychotics, especially when combined with other drugs that affect their plasma concentrations 3

Mechanisms of DDI Interactions

• Pharmacokinetic interactions: antipsychotics can affect the absorption, distribution, metabolism, or excretion of other drugs, leading to changes in their plasma concentrations 4, 3
• Pharmacodynamic interactions: antipsychotics can interact with other drugs at the receptor level, leading to additive or synergistic effects, such as increased risk of extrapyramidal symptoms or sedation 3, 6

Management of DDI Interactions

• Drug interaction software can be used to identify potential DDIs and optimize drug safety 4
• Collaboration with pharmacists and other healthcare professionals can help to prevent clinically significant DDIs and manage their consequences 4, 3
• Therapeutic drug monitoring (TDM) can be used to adjust antipsychotic medication and minimize the risk of adverse effects 3