CYP2D6 Metabolism in Psychiatric Medications

Introduction to CYP2D6-Metabolized Psychiatric Medications

The American Academy of Clinical Psychiatrists notes that the most clinically significant psychiatric medications metabolized by CYP2D6 include SSRIs, tricyclic antidepressants, venlafaxine, and most antipsychotics 1, 2

The National Institute of Mental Health guidelines indicate that fluoxetine is a potent CYP2D6 inhibitor and substrate, with single-dose AUC being 3.9-fold higher in poor metabolizers vs extensive metabolizers, and at 60mg doses, S-fluoxetine AUC increases 11.5-fold in poor metabolizers 1, 2
The Mayo Clinic recommends that paroxetine, a potent CYP2D6 inhibitor and substrate, has a median AUC of 30mg dose that is 7-fold higher in poor metabolizers vs extensive metabolizers 1, 2
The Dialogues in Clinical Neuroscience journal states that desipramine is a major CYP2D6 substrate, with plasma concentrations increasing 3-4 fold when co-administered with fluoxetine or paroxetine 3
The American Psychiatric Association notes that nortriptyline is a CYP2D6 substrate with a narrow therapeutic index 3
The Mayo Clinic Proceedings journal reports that venlafaxine is a CYP2D6 substrate, with fatal cardiac arrest documented in a CYP2D6 poor metabolizer with elevated venlafaxine blood concentration 4

The National Institute of Mental Health guidelines indicate that most antipsychotics are CYP2D6 substrates, including phenothiazines, thioridazine, haloperidol, clozapine, risperidone, and pimozide 1

The Dialogues in Clinical Neuroscience journal states that doxepin is a CYP2D6 substrate with an active metabolite demethyldoxepin 3
The American Academy of Clinical Psychiatrists notes that trimipramine is a CYP2D6 substrate with an active metabolite desmethyltrimipramine 3

The Mayo Clinic Proceedings journal reports that CYP2D6 poor metabolizers face substantially elevated drug exposure and toxicity risk, while ultrarapid metabolizers may have subtherapeutic levels 1, 2
The American College of Clinical Pharmacology recommends that PM phenotype results in 3.9-11.5 fold higher AUCs for fluoxetine depending on dose 2, 4

The Mayo Clinic Proceedings journal states that fluoxetine at 20mg/day converts approximately 43% of extensive metabolizers to poor metabolizer phenotype through auto-inhibition, creating a "phenocopy" effect 2, 4

The FDA has issued specific safety warnings for fluoxetine regarding CYP2D6 poor metabolizers, including use with caution in patients with congenital long QT syndrome, previous QT prolongation history, or family history of long QT syndrome/sudden cardiac death 2, 4

The Dialogues in Clinical Neuroscience journal recommends therapeutic drug monitoring when combining potent CYP2D6 inhibitors with substrates having narrow therapeutic indices, particularly tricyclic antidepressants 3