Sertraline would require the most significant adjustment

Because it is primarily metabolized by CYP2D6, and poor metabolizers will accumulate dangerously high plasma levels at standard doses. The FDA recommends reducing the starting dose by 75% in CYP2D6 poor metabolizers and monitoring serum levels closely. Sertraline is one of the most CYP2D6-dependent SSRIs and should generally be avoided entirely in this population due to the risk of serotonin toxicity. Sertraline is primarily metabolized by CYP2C19 and CYP2B6, with CYP2D6 playing a relatively minor role. Therefore, CYP2D6 poor metabolizer status has minimal clinical impact on sertraline dosing. Sertraline would actually be a reasonable choice for this patient because its metabolism is less dependent on CYP2D6 compared to other antidepressants.

Nortriptyline would require the most significant dose adjustment as it is heavily dependent on CYP2D6 for metabolism

CYP2D6 poor metabolizers can develop plasma levels 3-5 times higher than expected at standard doses, significantly increasing the risk of anticholinergic toxicity, cardiac arrhythmias, and seizures. CPIC guidelines recommend a 50% reduction in starting dose or selecting an alternative agent not dependent on CYP2D6 for metabolism. Tricyclic antidepressants, particularly nortriptyline, are heavily dependent on CYP2D6 for hydroxylation. In poor metabolizers, plasma levels can become dangerously elevated, increasing risk of cardiac toxicity (QTc prolongation, arrhythmias), anticholinergic crisis, and seizures. CPIC guidelines provide specific dose reduction recommendations for TCAs in CYP2D6 poor metabolizers, making this the most clinically significant interaction.

Escitalopram would require the most significant dose reduction

Because it undergoes extensive CYP2D6 metabolism to its active metabolite. In poor metabolizers, the parent compound accumulates while the active metabolite is not formed, creating both toxicity risk and reduced efficacy. The CPIC guidelines recommend a 50% dose reduction for CYP2D6 poor metabolizers starting escitalopram, with therapeutic drug monitoring at 4 weeks. Escitalopram is primarily metabolized by CYP2C19 and CYP3A4, not CYP2D6. CYP2D6 metabolizer status has minimal impact on escitalopram pharmacokinetics. If pharmacogenomic results showed CYP2C19 poor metabolizer status, that would be more clinically relevant for escitalopram dosing. Escitalopram could be a reasonable option for this CYP2D6 poor metabolizer.

Bupropion would require the most significant dose adjustment

Because CYP2D6 converts bupropion to its primary active metabolite hydroxybupropion, and poor metabolizers cannot form adequate levels of this metabolite. This results in both reduced efficacy (insufficient active metabolite) and toxicity from parent compound accumulation. The PMHNP should avoid bupropion entirely in CYP2D6 poor metabolizers and select an SSRI instead. While CYP2D6 does play a role in bupropion metabolism, the primary enzyme converting bupropion to hydroxybupropion is CYP2B6, not CYP2D6. Additionally, bupropion is actually an inhibitor of CYP2D6. The clinical impact of CYP2D6 poor metabolizer status on bupropion is much less significant than its impact on TCAs like nortriptyline, which are heavily CYP2D6-dependent for clearance.