Drug-drug interactions are one of the most common sources of preventable adverse events in psychiatric prescribing. A clinically useful framework distinguishes pharmacokinetic interactions (one drug changes the levels of another) from pharmacodynamic interactions (two drugs combine their effects at the receptor or system level). Both matter.
- Class
- Drug interaction framework
- Mechanism
- Major interaction categories: (1) CYP inhibition (raises substrate levels — fluoxetine, paroxetine, fluvoxamine, bupropion are inhibitors); (2) CYP induction (lowers substrate levels — carbamazepine, smoking induces 1A2); (3) Pharmacodynamic (additive serotonergic → serotonin syndrome; additive QTc; additive CNS depression); (4) Transporter (P-glycoprotein)
- FDA indications
- All prescribing scenarios — pre-prescription screening, post-prescription monitoring
Key interactions: SSRI/SNRI + MAOI (serotonin syndrome — never combine, requires washout); SSRI + tramadol (serotonin syndrome); fluoxetine/paroxetine 2D6 inhibition raising other psychotropic levels; carbamazepine induction lowering many drugs including oral contraceptives, warfarin; QTc-prolonging combinations (multiple antipsychotics + methadone + ondansetron). Always screen at prescription.
CYP enzyme interactions are the most common pharmacokinetic concern. Inhibitors slow metabolism and raise substrate levels: fluoxetine and paroxetine are potent CYP2D6 inhibitors (raising levels of 2D6 substrates like other psychotropics, tamoxifen, codeine). Fluvoxamine is a potent 1A2 inhibitor. Bupropion is a 2D6 inhibitor (the basis of Auvelity's design). Inducers speed metabolism and lower substrate levels: carbamazepine induces 3A4 (reducing oral contraceptive efficacy, anticoagulant levels, many psychotropics). Smoking induces 1A2 (smokers need higher clozapine doses than non-smokers).
The drug-drug interaction framework in psychiatry rests on two mechanisms — pharmacokinetic (one drug changing another's levels) and pharmacodynamic (additive effects at a shared target).
Mechanism note: Interactions are either pharmacokinetic (CYP inhibition/induction changing levels) or pharmacodynamic (additive effect at a shared target) — the framework lets you anticipate, rather than discover, the clinically dangerous combinations.
Serotonin syndrome is the most dangerous pharmacodynamic interaction in psychiatry. Combining serotonergic drugs can produce excessive serotonergic signaling — hyperreflexia, clonus (especially lower extremity), tremor, hyperthermia, GI symptoms, autonomic instability, altered mental status. The combinations to avoid: SSRI plus MAOI (never; mandatory washout). SSRI plus tramadol, dextromethorphan, linezolid, St. John's Wort, triptans. MAOI plus meperidine. Each strongly serotonergic combination raises the risk.
Additive QTc prolongation is the cardiac interaction. The patient on methadone plus citalopram plus ondansetron plus ziprasidone may accumulate enough QTc effect to risk torsades. ECG screening when multiple QTc-prolonging agents combined. Identify and address electrolyte risk factors (K, Mg).
Additive CNS depression with combined sedatives, benzodiazepines plus opioids being the most consequential (the black-box on both classes). Respiratory depression from combined CNS depressants is responsible for many preventable overdose deaths.
Screen at every prescription. Use interaction checkers. Pay particular attention when adding new drugs, when symptoms emerge that could be interaction-related, and when the patient's medication list grows complex.