Talking With Titans: Sheldon Preskorn, MD, on the Evolution of Psychopharmacology

Sheldon Preskorn, MD, shared with host John Miller, MD, about Impaired drug metabolism and the characterization of cytochrome P450 enzymes. Preskorn shared a story of a patient treated with amitriptyline for depression who developed confusion out of proportion to her depressive severity, and her plasma amitriptyline level was found at 4 to 5 times the expected range. Toxicity recurred when a family practitioner increased the dose, which established that she could not clear the drug. The enzyme responsible, later identified as cytochrome P450 2D6 (CYP2D6), also metabolized dextromethorphan and debrisoquine and converted codeine to morphine, which unified previously disparate observations.

Genotype alone underestimated impaired CYP2D6 function, Preskorn said. In a 2013 study, genotyping identified 4% of patients as poor metabolizers, and a venlafaxine test dose with measurement of the O-desmethylvenlafaxine to venlafaxine ratio identified another 26% as phenotypic poor metabolizers because of concomitant medications.¹ Preskorn said phenotype mattered more clinically because “what’s going to affect the person is their functional capability, which is their phenotype, not what genetically they might be able to do.” Drug-induced phenoconversion was conceptually similar to epigenetic phenoconversion, although the mechanisms differed, and fluoxetine substantially inhibited CYP2D6 in earlier work.² In patients with AIDS who were stable on antiretroviral therapy, St John wort induced cytochrome P450 3A, increased antiretroviral clearance, and produced viral escape, with falling CD4 counts and rising viral load.

Psychopharmacology progressed through 3 eras, Miller and Preskorn outlined. The first depended on chance discovery. The second used receptor pharmacology to strip muscarinic, histamine, and alpha-1 affinity from amitriptyline, which yielded the selective serotonin reuptake inhibitors. Preskorn said, “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.”

Dexmedetomidine for agitation illustrated the circuit-based approach. The locus coeruleus contains about 100,000 noradrenergic neurons at the floor of the fourth ventricle that sense hydronium ion concentration in cerebrospinal fluid, and firing when acid-base balance shifted drove panic attacks and agitation. Orexin antagonists followed a similar path: after the orexin gene was identified, mapping of its messenger RNA localized the system to the lateral hypothalamus, which allowed stereospecific drug design. Preskorn added that further education on this area of expertise is being documented in his EdYou Technologies program, which can be found here

Dr Preskorn is a professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine-Wichita. He has been a principal investigator at the site level on all antipsychotic and antidepressant medications approved in the United States over a 25-year period.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Preskorn SH, Kane CP, Lobello K, et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614-621.

2. Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol. 1994;14(2):90-98.