Selective serotonin reuptake inhibitors (SSRIs) are typically used as antidepressants to treat clinical depression, and may be used to treat anxiety and panic, personality, obsessive compulsive, and eating disorders, and, less often, to treat stress-related disorders. SSRIs are often the first choice in the pharmacological treatment of depression, which, according to the Centers for Disease Control and Prevention (CDC), affects approximately 5% of the U.S. population. [1] Nearly all SSRIs undergo hepatic oxidative metabolism before their elimination from the body; therefore, genetic differences in oxidative metabolism can significantly impact the levels of active drug circulating in a patient.

CYP2D6 is a member of the cytochrome P450 family of enzymes involved in the oxidative metabolism of drugs. CYP2D6 is among the most promiscuous of these enzymes, involved in the metabolism of approximately 20% of drugs in clinical use, and displays large individual-to-individual variability in activity due to genetic polymorphisms. [2] The oxidative metabolism of most approved SSRIs is executed, in part, by CYP2D6.

Patients are classified into the following four categories of CYP2D6 activity, from highest to lowest functioning: ultrarapid metabolizer (UM); extensive, or normal, metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM). [3] Between 5% and 10% of whites are classified as PM, ~5% are classified as UM, 20% to 30% are classified as IM, and the rest are EM. [4]

The impact of CYP2D6 activity differs on a drug-by-drug basis, depending on whether CYP2D6 is involved in the activation or inactivation of the drug. [5] When CYP2D6 activates the prodrug, as with the conversion of codeine to morphine, UMs may experience exaggerated pharmacological response, whereas IMs and PMs may experience attenuated effects. The opposite clinical effects would be expected for drugs deactivated by CYP2D6 — that is, drugs deactivated by CYP2D6 may show attenuated effects in UMs and exaggerated pharmacological response or toxicity in PMs. [6]

The impact of CYP2D6 activity in drug metabolism is further complicated by the activity of the drug itself on CYP2D6. Some SSRIs, such as paroxetine (Paxil), fluoxetine (Prozac), and citalopram (Celexa), as well as statins, are known to inhibit CYP2D6 activity and may make EMs resemble IMs or PMs. Finally, since most SSRIs are also substrates of CYP2D6; SSRIs that both inhibit and are metabolized by CYP2D6 can inhibit their own metabolism and produce higher than expected plasma concentrations.

More than 100 CYP2D6 variant alleles have been identified. [7] However, 4 of the most prevalent alleles, CYP2D6*3, *4, *5, and *6, accounts for 93% to 97% of PMs.[6] CYP2D6*4, the most common variant (~25% frequency in whites), causes a splicing defect. CYP2D6*3 (2.7% frequency) causes a frameshift mutation, and CYP3D6*5 (2.6%) is an entire deletion of the CYP2D6 gene. Individuals homozygous for these alleles have no CYP2D6 activity. IMs tend to have only one functional copy of CYP2D6, whereas UMs have extra CYP2D6 gene copies.