How should I start a selective serotonin reuptake inhibitor (SSRI) in a patient on anticoagulants (warfarin or a direct oral anticoagulant)?

Starting an SSRI in Patients on Anticoagulants

When initiating an SSRI in a patient on anticoagulants, preferentially select sertraline, citalopram, or escitalopram over fluoxetine or fluvoxamine, and implement close monitoring for bleeding complications and INR changes (if on warfarin) during the first 2-4 weeks after SSRI initiation. 1

SSRI Selection Based on Drug Interaction Profile

Preferred SSRIs (Lower Risk)

• Choose sertraline, citalopram, or escitalopram as first-line options because they have minimal CYP2C9 and CYP3A4 inhibition, reducing pharmacokinetic interactions with warfarin 1
• These agents still carry bleeding risk through pharmacodynamic effects on platelet function but avoid compounding the risk with metabolic interactions 2

SSRIs to Avoid (Higher Risk)

• Avoid fluoxetine and fluvoxamine as they potently inhibit CYP2C9 and CYP3A4, which metabolize warfarin, leading to elevated INR and increased bleeding risk 1
• Fluvoxamine deserves particular caution given its strong CYP enzyme inhibition profile 1

Monitoring Protocol After SSRI Initiation

For Patients on Warfarin

• Check INR within 3-7 days of starting the SSRI, then weekly for the first 2-4 weeks, as SSRIs can cause INR elevation through CYP2C9 inhibition 1, 2
• The risk of high INR (≥5) is increased 2.41-fold with any SSRI and 3.14-fold with CYP2C9-inhibiting SSRIs compared to non-users 2
• Be prepared to reduce warfarin dose by approximately 10-20% if INR rises above therapeutic range 2

For Patients on Direct Oral Anticoagulants (DOACs)

• Monitor clinically for bleeding signs and symptoms during the first month after SSRI initiation, as standard coagulation tests do not reliably assess DOAC levels 3
• The ROCKET AF trial found no statistically significant increase in major/non-major clinically relevant bleeding when SSRIs were combined with rivaroxaban (adjusted HR 1.11,95% CI 0.82-1.51) 3
• However, there was a numerical trend toward increased major bleeding with SSRIs plus warfarin (adjusted HR 1.58,95% CI 0.96-2.60) that did not reach statistical significance 3

Bleeding Risk Assessment and Mitigation

Quantifying the Risk

• Concomitant SSRI and warfarin use more than doubles the risk of bleeding compared to warfarin alone in retrospective studies 1
• The mechanism involves both pharmacokinetic interactions (CYP450 inhibition) and pharmacodynamic effects (impaired platelet serotonin reuptake leading to decreased platelet aggregation) 2
• SSRIs specifically increase the risk of gastrointestinal bleeding through depletion of platelet serotonin stores 1

High-Risk Scenarios Requiring Extra Caution

• Patients with prior gastrointestinal bleeding or peptic ulcer disease are at particularly elevated risk 4
• Concomitant use of NSAIDs, aspirin, or other antiplatelet agents substantially amplifies bleeding risk and should be avoided when possible 1, 4
• Elderly patients face both higher bleeding risk and potentially greater cardiovascular benefit, requiring careful risk-benefit assessment 4

Protective Strategies

• Add a proton pump inhibitor (PPI) or H2-blocker for gastric protection in patients with gastrointestinal bleeding risk factors, prior ulcer disease, or those taking NSAIDs/antiplatelet agents 4
• Discontinue NSAIDs if possible when initiating an SSRI in anticoagulated patients, as the combination creates compounding bleeding risk 4
• Educate patients to report any signs of bleeding immediately, including unusual bruising, blood in stool/urine, prolonged bleeding from cuts, or severe headaches 4

Common Pitfalls to Avoid

• Do not assume all SSRIs have equivalent risk profiles—the CYP2C9-inhibiting SSRIs (fluoxetine, fluvoxamine) carry substantially higher risk with warfarin 1
• Do not rely on baseline INR alone—the interaction develops after SSRI initiation, requiring serial monitoring 2
• Do not overlook the pharmacodynamic platelet effect—even SSRIs without significant CYP interactions still impair platelet function and increase bleeding risk 5, 2
• Do not forget that the bleeding risk is highest in the first 2-4 weeks after SSRI initiation, when monitoring should be most intensive 2