Selective Serotonin Reuptake Inhibitors (SSRIs) and CYP2D6

Updated: Feb 03, 2021
Author: Ali Torkamani, PhD; Chief Editor: Keith K Vaux, MD 

Practice Essentials

Selective serotonin reuptake inhibitors (SSRIs) are typically used as antidepressants to treat clinical depression, and they may be used to treat anxiety and panic disorders, personality disorders, obsessive-compulsive disorders, eating disorders, and, less often, stress-related disorders. SSRIs are often the first choice in the pharmacologic 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.[3, 4, 5, 6]

Pharmacogenetic testing is being evaluated for routine implementation, and it has been reported that over 90% of the population has at least one actionable genetic variant. These genetic variants can affect the safety and efficacy of certain drugs. Genetic polymorphisms of CYP2D6 have been shown to affect response to tamoxifen, opioid analgesics, antidepressants, and antipsychotics, for example.[3, 4, 5, 6]

Patients are classified into the following 4 categories of CYP2D6 activity, from highest to lowest functioning: ultrarapid metabolizer (UM); extensive, or normal, metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM). Tables for the conversion of star allele diplotypes to these metabolizer categories were updated in October 2019 and are available at the CPIC website.[7]

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.[8] When CYP2D6 activates the prodrug, as with the conversion of codeine to morphine, UMs may experience an exaggerated pharmacologic 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 pharmacologic response or toxicity in PMs.[9]

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, fluoxetine, and citalopram, 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.[10] However, 4 of the most prevalent alleles, CYP2D6*3, *4, *5, and *6, accounts for 93 to 97% of PMs.[8]  CYP2D6*4, the most common variant (about 25% frequency in individuals of European ancestry), 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.


Clinical Implications

The FDA recommends, but does not require, genetic testing prior to initiating treatment with many SSRIs.[11]  The International Society of Psychiatric Genetics finds genetic testing to be most beneficial after an inadequate response or adverse reaction to treatment with an antidepressant or antiphychotic.[12]

Most SSRIs are deactivated by CYP2D6; thus, CYP2D6 PMs are at elevated risk for SSRI overdose, which can result in drowsiness, tremor, nausea, vomiting, seizures, and coma. Therefore, administration of SSRIs in PMs and IMs should be approached with caution.

At a minimum, particular care should be exercised with the SSRIs fluoxetine and paroxetine, which are metabolized by and inhibit CYP2D6. Indeed, as noted on the product labels, administration of fluoxetine or paroxetine with other drugs metabolized by CYP2D6 (eg, tricyclic antidepressants, antipsychotics, propafenone, flecainide) should also be executed with caution.[13, 14] Similarly, other drugs that inhibit CYP2D6 activity should be used with caution in combination with SSRIs.[15] Some examples of drugs that inhibit CYP2D6 include celecoxib, cimetidine, clomipramine, methadone, metoprolol, quinidine, ranitidine, ritonavir, thioridazine, and ziprasidone. Again, special care should be exercised with PMs and IMs. Of particular importance, given the long half-life of the inhibitory metabolite, sufficient time must have elapsed before initiating treatment with drugs metabolized by CYP2D6 after withdrawing SSRI treatment.[16]

Genotype testing can be considered for the most common nonfunctional alleles, CYP2D6*3, *4, *5, and *6, which account for the majority of PMs and IMs. However, because of the complex interactions among CYP2D6, SSRIs, and other drugs, as well as the large number of other, less common CYP2D6 variants that might affect drug metabolism, CYP2D6 testing cannot substitute for careful monitoring by a physician.[17]

In a study of 224 psychiatric patients, genotype testing found 4.5% had CYP2D6 genotypes predicting UM; 9.8% had genotypes predicting IM; and 6.3% had genotypes predicting PM.[18]

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has provided guidelines that include the following[10] :

  • CYP2D6 ultrarapid metabolizers may have low or undetectable paroxetine plasma concentrations, when compared to CYP2D6 extensive metabolizers, which may result in therapeutic failure.
  • Adjustments to paroxetine or fluvoxamine therapy are not warranted based on CYP2D6 status for those who are CYP2D6 extensive or intermediate metabolizers.
  • Based on prescribing information, fluoxetine should be used with caution in patients with congenital long QT syndrome.

Dosing tables that were updated in October 2019 because of changes to the *10 allele functional status are available at the CPIC website.[7]


Questions & Answers