Psychiatrist Sheldon Preskorn, M.D., has challenged the clinical reliance on genetic testing, arguing that a patient’s actual metabolic function—their phenotype—is a reliable gauge for treatment. Preskorn detailed how modern psychopharmacology must move beyond genetic potential to focus on how drugs interact with a patient’s active biological circuitry.
The Shift from Genotype to Functional Reality
Preskorn observes that the field has evolved from relying on accidental drug discoveries to a precise, targeted approach. He credits this progress to our growing ability to isolate the specific circuits that govern behavioral health.
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.
Sheldon Preskorn, MD
Why Genetic Testing Often Falls Short
The danger of relying solely on genotyping, Preskorn warns, is that it frequently underestimates metabolic impairment. He points to a 2013 study where genotyping flagged 4 percent of patients as poor metabolizers of cytochrome P450 enzymes, such as CYP2D6. However, when researchers performed a functional test using venlafaxine, they discovered an additional 26 percent of patients were phenotypic poor metabolizers—a discrepancy caused by the influence of other 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.
Sheldon Preskorn, MD
The Risks of Phenoconversion
Clinical consequences of ignoring phenoconversion can be severe. Preskorn cites the case of a patient treated with amitriptyline for depression who suffered from acute confusion because she could not clear the drug. Her plasma levels hit 4 to 5 times the expected range; when a family practitioner increased her dose, the toxicity returned, confirming the metabolic block.
External factors, such as supplements, further complicate these metabolic pathways. In patients with AIDS, the use of St. John’s wort was shown to induce cytochrome P450 3A. This accelerated the clearance of antiretroviral therapy, resulting in viral escape, as evidenced by rising viral loads and falling CD4 counts. Preskorn, who completed his residency at Washington University School of Medicine in St. Louis, now teaches PGY3 resident psychiatrists and has authored over 500 professional publications in the medical literature.