What are the US Food and Drug Administration (FDA) guidelines for genetic testing prior to beginning a course of selective serotonin reuptake inhibitors (SSRIs)?

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

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