What antidepressants interact with tamoxifen (Nolvadex) and metformin (Glucophage)?

Antidepressant Interactions with Tamoxifen and Metformin

When prescribing antidepressants to patients on tamoxifen, avoid potent CYP2D6 inhibitors (paroxetine, fluoxetine, fluvoxamine, bupropion, duloxetine) and instead use mild CYP2D6 inhibitors (sertraline, citalopram, venlafaxine, escitalopram, desvenlafaxine) to maintain tamoxifen efficacy. 1

Tamoxifen Interactions

Mechanism of Interaction

Tamoxifen is a prodrug requiring metabolism by CYP2D6 to its active metabolite endoxifen. Inhibition of CYP2D6 can significantly reduce tamoxifen's efficacy in treating breast cancer.

Antidepressants to AVOID with Tamoxifen

• Strong CYP2D6 inhibitors:
  • Paroxetine 1, 2
  • Fluoxetine 1
  • Fluvoxamine 1
  • Bupropion 1
  • Duloxetine 1

Clinical studies indicate increased risk of breast cancer recurrence in patients treated with tamoxifen and strong CYP2D6-inhibiting SSRIs compared to those receiving tamoxifen alone 1. Paroxetine co-administration can decrease endoxifen levels by approximately 3-fold 3.

Preferred Antidepressants with Tamoxifen

• Mild CYP2D6 inhibitors:
  • Citalopram 1
  • Escitalopram 1
  • Sertraline (at standard doses) 1
  • Venlafaxine 1
  • Desvenlafaxine (preferred - minimal to no CYP2D6 inhibition) 4

Switching patients from paroxetine/fluoxetine to escitalopram has been shown to safely increase endoxifen concentrations approximately 3-fold 3.

Metformin Interactions

Unlike tamoxifen, metformin has fewer documented significant pharmacokinetic interactions with antidepressants. Metformin is not metabolized through the CYP450 system but is eliminated unchanged in urine.

Key Considerations for Metformin

• Metformin is primarily eliminated through renal excretion, not hepatic metabolism
• No significant direct pharmacokinetic interactions between metformin and SSRIs/SNRIs have been documented in the provided evidence

Clinical Algorithm for Antidepressant Selection

1. For patients on tamoxifen:

   • First-line: Desvenlafaxine (minimal CYP2D6 interaction) 4
   • Second-line: Escitalopram, citalopram, venlafaxine 1
   • Third-line: Sertraline (at standard doses) 1
   • Avoid: Paroxetine, fluoxetine, fluvoxamine, bupropion, duloxetine 1

2. For patients on metformin only:

   • Standard antidepressant selection criteria apply
   • No specific restrictions based on the provided evidence

3. For patients on both tamoxifen and metformin:

   • Follow the tamoxifen interaction guidelines above
   • Desvenlafaxine would be the preferred option 4

Important Clinical Considerations

• If a patient is already taking a strong CYP2D6 inhibitor with tamoxifen, consider switching to a mild inhibitor under psychiatric supervision 3
• The NCCN does not recommend routine CYP2D6 testing but advises avoiding strong CYP2D6 inhibitors when possible 1
• For patients with depression and hot flashes (common in tamoxifen users), venlafaxine has demonstrated efficacy for both conditions 4
• Monitor patients closely during antidepressant switches to ensure psychiatric stability 3

Common Pitfalls to Avoid

1. Continuing paroxetine or fluoxetine in tamoxifen-treated patients despite evidence of reduced tamoxifen efficacy 5
2. Failing to review co-medications when initiating tamoxifen therapy 5
3. Overlooking the potential impact of antidepressant selection on breast cancer outcomes 1
4. Assuming all SSRIs/SNRIs have similar effects on tamoxifen metabolism 1