Chapter 8: Psychiatry and Neurology Pharmacogenomics

INTRODUCTION

ANTIDEPRESSANTS AND ANTIPSYCHOTICS

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy options for depression.¹ The six traditional SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) function by blocking the serotonin transporter, preventing reuptake of serotonin into the presynaptic neuron. This is thought to lead to elevated serotonin levels in the synapse and therefore increase the amount of serotonin available to bind to postsynaptic receptors.

SSRIs and CYP2D6 and CYP2C19

Many CYP450 genes are involved in the metabolism of SSRIs, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued guidelines on prescribing SSRIs in the presence of genetic variation in two important pathways: CYP2D6 and CYP2C19. The clinical impact of genetic variation in these pathways on SSRI metabolism is addressed next.

Mechanism of Drug–Gene Interaction

In addition to the potential biological activity of the resulting metabolite, the impact of genetic variation on a drug’s metabolism depends on the overall contribution of the enzymatic pathway. Because CYP2D6 and CYP2C19 genes are involved in the metabolism of SSRIs, variation in these pathways can have significant effects on drug efficacy and safety.

Consequence of Drug–Gene Interaction

Paroxetine and fluoxetine rely heavily on CYP2D6 for biotransformation. Fluvoxamine is metabolized by both CYP2D6 and CYP1A2. For this reason, CYP2D6 variation may greatly affect the activity of these SSRIs. CYP2D6 ultrarapid metabolizers (UMs) have been shown to have low or undetectable paroxetine plasma concentrations compared to extensive metabolizers (EMs), putting individuals with this phenotype at risk of therapeutic failure.^2–5 However, while one might reasonably expect to see a decrease in plasma concentrations of fluvoxamine in CYP2D6 UMs, data are currently lacking. For both paroxetine and fluvoxamine, CYP2D6 poor metabolizers (PMs) have significantly greater drug exposure.^2,6–8

On the other hand, CYP2C19 is a major pathway for the biotransformation of citalopram, escitalopram, and sertraline, and thus variations in this gene may alter drug exposure. For citalopram and escitalopram, studies have shown that CYP2C19 UMs have significantly lower drug exposure and therefore increased risk of therapeutic failure.^9–11 It would be reasonable to expect a similar trend for CYP2C19 UMs taking sertraline; however, limited published data for these individuals show only slightly increased metabolism.¹² The CYP2C19 PM phenotype results in elevated concentrations of all three drugs, putting individuals with this phenotype at risk for adverse events.^11,13–15

Treatment Recommendation

CPIC has made recommendations for paroxetine and fluvoxamine based on CYP2D6 phenotype.¹⁶ For paroxetine, they advise considering a 50% reduction of ...