Case Report: Life-Threatening Fluoxetine-Linked Postoperative Bleeding Informed by Pharmacogenetic Evaluation

Selective serotonin reuptake inhibitors (SSRI) are first-line therapies for the treatment of depression and anxiety [1]. These drugs selectively inhibit serotonin reuptake by binding to the serotonin transporter (SERT) to block serotonin transport, with only minimal inhibition of norepinephrine and dopamine reuptake. Additionally, SSRIs block the uptake of serotonin into platelets, leading to impairment of the platelet hemostatic response [2]. In this report, we present a patient who developed severe postoperative bleeding associated with polymorphic variations in pharmacogenes involved in fluoxetine metabolism.

A 52-year-old white male patient with no history of liver or kidney disease presented to the emergency department (ED) complaining of postsurgical bleeding, one day post panniculectomy. His previous medical history included posttraumatic stress disorder (PTSD), mental depression, and anxiety managed with 30 mg fluoxetine daily, and gastric sleeve surgery 2-years prior. Upon presentation to the ED, the patient reported becoming extremely hypotensive with a blood pressure of 60/40 mmHg and sudden loss of vision. Computerized tomography (CT) scanning at the ED revealed a hematoma in the subcutaneous space of the postsurgical field. The panniculectomy space had a clot with mild oozing relative to the upper region of the cavity where no direct bleeding source was noted. The patient required a 4-day hospitalization for hematoma evacuation and correction of significant bleeding with three units of packed red blood cells for a drop in hemoglobin from 16.7 g/dL at baseline to 8.4 g/dL. Other laboratory values are listed in Table 1.

Prior to fluoxetine, the patient had been taking escitalopram 10 mg daily and bupropion 300 mg daily. Approximately 2 months prior to the panniculectomy, the escitalopram and bupropion were discontinued, and the patient switched to fluoxetine 20 mg to optimize management of PTSD, anxiety, and depression. A total of 30 days after the initial dose, the fluoxetine was increased to 30 mg daily. During this time, aripiprazole 2.5mg was also initiated. He was not taking any anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), or other blood-thinning medications prior to the panniculectomy. A list of the patient’s home medications at the time of surgery is presented in Table 2.

The patient was referred to the pharmacogenomics service for polypharmacy assessment prior to surgery, and the results were returned following the inpatient stay detailed in this report. Pharmacogenetic testing revealed a CYP2D6 *4/*10 intermediate metabolizer status, increasing the risk for fluoxetine-induced adverse effects due to increased plasma concentrations (Table 3).

A study by Li and colleagues on the effect of fluoxetine on bleeding time in mice found that inhibition of SERT function by fluoxetine at doses of 20–30 mg/day decreases intraplatelet serotonin in a dose-dependent manner. Reduced serotonin levels induce the platelet adhesion receptor, GPIbα, and promote platelet aggregation and GPIbα shedding in the presence of thrombin [3]. SERT inhibition also inhibits clot formation by blocking platelet integrin αIIbβ3 and its affinity for fibrinogen. These actions lead to prolonged bleeding times in mice that can be corrected within 2 weeks upon withdrawal of fluoxetine [3].

A meta-analysis published in 2014 by Singh et al., details the risk of bleeding associated with SSRIs. Although a need for surgical intervention due to bleeding from serotoninergic antidepressants was not statistically significant, an elevated risk for transfusions with an odds ratio of 1.19 (1.09–1.3) was reported [4]. Auerbach et al. found that patients treated with SSRIs, including citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine, have increased risk of bleeding (1.09 (1.04–1.15)) compared with patients without any antidepressant treatment who underwent major surgery and received perioperative SSRI treatment [5].

Fluoxetine is well absorbed when taken orally, with peak plasma concentrations reached within 6–8 h after ingestion. Absorption is not affected significantly by food intake, so it can be taken with or without food. Once absorbed, fluoxetine is extensively distributed throughout the body due to its high lipophilicity [6]. Fluoxetine undergoes extensive metabolism in the liver, primarily through the cytochrome P450 (CYP) enzyme system. Fluoxetine is metabolized to its active metabolite norfluoxetine by CYP2D6, CYP2C9, and CYP2C19, with CYP2D6 playing the greatest role in metabolism of the parent compound. Both fluoxetine and norfluoxetine are potent inhibitors of CYP2D6, an important enzyme involved in the metabolism of other drugs. This inhibition can lead to drug–drug interactions and affect the metabolism of co-administered medications. As fluoxetine is extensively metabolized by cytochrome P450 (CYP450) enzymes, the metabolizer status of the patient can influence the bleeding risk [7]. Individual variations in the metabolism of fluoxetine can occur due to genetic factors and interactions with other drugs. Certain individuals may be slow metabolizers of fluoxetine, leading to higher drug concentrations and increased risk of side effects. Conversely, fast metabolizers may have lower drug concentrations, potentially reducing the effectiveness of the medication.

The genetic polymorphisms identified in the patient’s pharmacogenetic panel are outlined in Table 3. The patient was identified as a CYP2D6 *4/*10 intermediate metabolizer, increasing the risk of complications due to increased plasma concentrations of fluoxetine. CYP2D6*4 is a non-functional haplotype that accounts for the majority of the poor metabolizers (PM) among white populations [8]. CYP2D6*10 is a reduced function haplotype of CYP2D6 that is extremely common in populations of Asian ancestry [9]. A 2020 systematic review and meta-analysis conducted by Milosavljević et al. concluded that the association of CYP2C19/CYP2D6 variants to plasma drug concentration of SSRIs can be clinically significant and should be taken into consideration [10]. Furthermore, Zastrozhin et. al. concluded that polymorphisms of gene CYP2D6 can affect the safety profile of fluoxetine [11]. In our case, the patient was also identified as CYP2C19 1/*17 genotype and a predicted rapid metabolizer phenotype that may negatively impact the formation of norfluoxetine from fluoxetine.

Another case–control study conducted by Kim and colleagues examined reports of antidepressant drug use between December 1988 and December 2017 in the Korea Adverse Events Reporting System (KAERS) database. A total of 16,517 adverse events related to antidepressants were reported. The reporting odds ratios for fluoxetine were 2.34 [95% confidence interval (CI), 1.03–5.34] for total bleeding, 4.41 (95% CI, 1.60–12.15) for major bleeding, 2.06 (95% CI, 0.28–15.03) for gastrointestinal bleeding, and 6.12 (95% CI, 2.14–22.60) for brain hemorrhage compared with all other antidepressants [12].

Auerbach et. al. concluded that patients receiving SSRIs showed higher odds of bleeding and risk of readmission at 30 days (1.22 [1.18–1.26]) [5]. The case establishes the potential link between fluoxetine and increased risk of severe, life-threatening bleeding during the perioperative period. Up to this point, SSRI-induced perioperative bleeding necessitating hospitalization and blood transfusion has not been described in the literature. It is hypothesized that this risk may be driven by interindividual differences in pharmacogenetics profiles.

We conclude that a relationship between fluoxetine and postoperative bleeding in our patient is probable, with a pharmacogenetic profile consistent with elevated drug levels due to deficient metabolism. Prescribers and users of fluoxetine should be alerted to the possibility of such adverse reactions, and genetic information, if and when available, should be considered. This specific case has been reported to the US Food and Drug Administration Adverse Event Reporting Program.

Clinicians must consider the potential benefits against potential risks of discontinuing or decreasing an SSRI before an elective operative procedure. Discontinuing or decreasing SSRI medications may result in withdrawal symptoms and/or worsening of symptoms, while continuing an SSRI during surgery exposes patients to significant bleeding risks. Antidepressant prescribers should be aware of and take responsibility for discussing this potential problem with their patients so that they in turn can discuss this with other providers involved in their care and participate in exploring alternative options. The surgeon should also be aware of the bleeding risks tied to SSRIs and consider them when planning surgical intervention. Often, it may be the prescribing physician or pharmacist who alerts the surgeon to the potential bleeding risk associated with SSRIs [13].

It is essential to approach risk assessment comprehensively as detailed in Table 4, considering multiple factors and not relying on a single test or a piece of medical history. If there are concerns, collaboration between psychiatrists, primary care physicians, surgeons, pharmacists, and other specialists can help provide the best patient care.