In a discussion hosted by John Miller, MD, Sheldon Preskorn, MD, shared insights on the evolution of psychopharmacology and the critical role of impaired drug metabolism, particularly concerning the cytochrome P450 enzyme system. Dr. Preskorn illustrated this with a case study of a patient treated with amitriptyline for depression who developed significant confusion. The patient’s plasma amitriptyline level was found to be 4 to 5 times the expected range. This toxicity recurred when a family practitioner increased the dose, establishing that the patient could not clear the drug effectively.
Psychopharmacology Evolves With Focus on Drug Metabolism
The enzyme responsible, later identified as cytochrome P450 2D6 (CYP2D6), was also found to metabolize other substances like dextromethorphan and debrisoquine, and to convert codeine to morphine. This discovery unified previously disparate observations. Dr. Preskorn emphasized that while genotyping can identify some patients as poor metabolizers, it can underestimate impaired CYP2D6 function. A 2013 study showed that genotyping identified 4% of patients as poor metabolizers, but a venlafaxine test dose with measurement of the O-desmethylvenlafaxine to venlafaxine ratio identified an additional 26% as phenotypic poor metabolizers due to concomitant medications.
What’s going to affect the person is their functional capability, which is their phenotype, not what genetically they might be able to do,
Dr. Preskorn stated. This phenomenon, known as drug-induced phenoconversion, was noted to be conceptually similar to epigenetic phenoconversion, although the mechanisms differ. He cited earlier work demonstrating that fluoxetine substantially inhibits CYP2D6. In another example, St. John’s wort was shown to induce cytochrome P450 3A in patients with AIDS who were stable on antiretroviral therapy, which increased antiretroviral clearance and led to viral escape, with falling CD4 counts and rising viral load.
Miller and Preskorn outlined three distinct eras in the history of psychopharmacology. The first era was characterized by chance discoveries. The second era utilized receptor pharmacology to refine drugs by stripping away unnecessary targets, such as muscarinic, histamine, and alpha-1 affinity from amitriptyline, which led to the development of selective serotonin reuptake inhibitors (SSRIs).
We’d moved from being dependent on chance discoveries to an era of refining the drugs by stripping away unnecessary targets to circuitry in which we understand actually what’s mediating specific behavioral problems, Dr. Preskorn explained
The CYP2D6 enzyme is a member of the cytochrome P450 family of proteins predominantly located in the liver, which serves as the body’s primary mechanism for processing and clearing foreign substances, including medications. This single enzyme is responsible for the metabolism of approximately 20 to 25% of all commonly prescribed medicines. Its role can involve converting an active drug into an inactive metabolite for clearance or bioactivating an inactive prodrug into its therapeutically active form. Many psychiatric medications, including numerous SSRIs and tricyclic antidepressants like amitriptyline and paroxetine, are substrates for CYP2D6.
The variability in individual responses to CYP2D6-metabolized drugs stems from genetic polymorphism in the CYP2D6 gene. This high variability results in different enzyme activity levels among individuals, categorized as Extensive Metabolizers, who have normal enzyme activity, and Ultrarapid Metabolizers, who have an increased rate of enzyme activity. Understanding a patient’s metabolic status allows a physician to adjust dosage, select an alternative drug, or choose a drug with a different metabolic pathway, leading to safer and more effective treatment from the outset.
Dr. Preskorn is a medical doctor specializing in psychiatry and currently teaches PGY3 resident psychiatrists in the assessment and management of outpatients with psychiatric illness. He has authored over 500 professional publications and has been cited over 15,000 times in the medical literature.
