Anterior cervical discectomy and fusion (ACDF) is one of the most common cervical spinal procedures, accounting for approximately 80% of all cervical spinal surgeries [1]. Current estimates expect an increased ACDF prevalence by 13.3% in 2020–2040 [2,3]. The popularity of ACDFs can be attributed to excellent patient satisfaction scores and improvements in both short- and long-term clinical outcomes [3,4].

ACDFs have a favorable complication profile; however, pseudarthrosis is one of the most commonly identified complications with rates ranging from 3%–20% in 1-level procedures to 50% in 4-level procedures [5,6]. Most patients remain asymptomatic, but symptomatic pseudarthrosis or adjacent segment disease (ASD) are two of the leading causes of revision surgery following ACDF, resulting in a combined revision rate of 15% with an average follow-up duration of 31 months [7]. The annual incidence of ASD is low at 2.2%, which leads to clinically symptomatic ASD in 22% of patients at 10-year follow-up [8]. Therefore, identifying the risk factors that contribute to pseudarthrosis or ASD is a critical necessity due to the high surgical volume of ACDF procedures.

Previous literature has suggested a depression diagnosis that leads to worse mental and physical components of patient-reported outcome measures (PROMs) following ACDF [9]. One rationale for the link between depression and inferior postoperative PROMs is a greater complication profile in this population [10,11]. A plausible explanation for this relationship is medication-related. Serotonin reuptake-inhibiting drugs can be prescribed as an alternative method for pain management; however, these drugs are primarily given to patients with depression [12].

Basic science research has identified a potential mechanism where selective serotonin reuptake inhibitors (SSRIs) inhibit osteoblast differentiation leading to reduced mineralization in an animal fracture model [13]. Combined with clinical research that identifies the role of SSRIs in increased bleeding and pseudarthrosis rates in patients with ACDF, this provides a compelling rationale for a link between depression and inferior PROMs [13–15]. Therefore, we hypothesized that patients with serotonin reuptake-inhibiting drug prescriptions (SSRIs, serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs]) would have increased rates of pseudarthrosis leading to inferior PROMs compared to patients without serotonin reuptake-inhibiting drug prescriptions.

ACDF is one of the most successful orthopedic procedures with previous literature suggesting that they outperform total hip and total knee arthroplasty in the physical and mental components of the 36-item Short Form Survey (SF-36) [17]. However, variability in patient-reported outcomes continues to persist between patients with and without depression who undergo ACDF [9]. Identifying the causation of inferior PROMs in this population is imperative, given that an estimated 13.2% of United States adults are prescribed antidepressant medications, making them the third most commonly prescribed drug class [18]. Our study suggests that serotonin reuptake-inhibiting antidepressants are one contributing factor to inferior postoperative patient-reported outcomes in patients undergoing ACDF due to a higher pseudarthrosis rate. However, our data suggest that antidepressant use alone is not the sole cause of inferior PROMs since the RR between our two groups was significantly worse only for NDI at 1-year.

Over the last decade, a growing body of literature has emerged documenting SSRIs’ inhibition of osteoblast differentiation leading to impaired fracture healing [19]. Additionally, SSRI imparts an elevated risk of future fractures [20], which is hypothesized from an increased rate of osteoblast apoptosis leading to approximately 80% reduction in osteoblast viability based on an in vitro model [21]. Osteoblasts are an integral factor in obtaining an osseous spinal fusion, thus serotonin reuptake-inhibiting drugs are one potential causative agent leading to pseudarthrosis [22]. Our study findings support our hypothesis that serotonin reuptake-inhibiting drugs hinder spinal fusion, potentially through osteoblast inhibition; however, this requires confirmation through well-designed translational research, including animal models.

Patient-reported outcomes have become integral in determining patient improvements following surgery. A history of depression is believed to cause worse preoperative and postoperative PROMs in patients undergoing spinal surgery, but most studies have shown similar degrees of improvement following surgery [9,23]. We identified inferior preoperative and postoperative PROMs in patients taking a serotonin reuptake-inhibiting drug compared to those who do not. However, differences in the degree of improvement and RRs revealed significant changes between groups only in the 3-month PCS-12 and 3-month RR for PCS-12, as well as the 1-year NDI and 1-year recovery ratio for NDI, which were worse in the serotonin reuptake-inhibiting group. A previous retrospective study by Jenkins et al. [24] demonstrated a greater magnitude of depression based on the Patient Health Questionnaire-9 correlated with inferior PCS-12 scores at 3 months but not 1 year. We demonstrated similar findings. Serotonin reuptake-inhibiting drugs may result in worse 3-month PCS-12 scores due to delayed construct union; however, this was not confirmed by our data. Additionally, our data does strongly suggest depression alone, and the antidepressant medication is not the major contributing component of worse preoperative and postoperative PROMs based on the minimal differences in the 3-month and 1-year recovery ratios.

In addition to worse preoperative and postoperative PROMs, patients with depression are well established to have an increased complication profile after ACDF procedures due to an elevated incidence of ASD, 90-day readmissions, and revision surgery within 2 years [25]. This results in an estimated increase in healthcare costs by $4,471 over 2 years following ACDFs [25]. As healthcare continues to transition to bundled payments, further research targeted at identifying a concrete link between serotonin reuptake-inhibiting drugs and its contribution to elevated complication rates and escalating healthcare expenditures is critical.

The US Food and Drug Administration approved the first SSRI, fluoxetine, in 1987, and the first atypical antidepressant was approved 2 years later when bupropion was approved in 1989 [26]. Instead of targeting serotonin reuptake, bupropion dually targets norepinephrine and dopamine reuptake, giving it unique antidepressant properties [27]. SRIs were associated with greater rates of revision surgery due to ASD on univariate analysis; however, patients taking atypical antidepressants had similar ASD and pseudarthrosis rates as those who were not prescribed these medications. Therefore, atypical antidepressants are a potentially interesting avenue for future research, as switching antidepressant therapy to an atypical antidepressant before ACDFs may decrease revision surgery rates and improve patient-reported outcomes. Although outside the scope of our study, an elevated risk of bleeding should be noted in patients taking either SSRIs or bupropion due to drug-induced platelet inhibition [28]. Additionally, no formal guidelines exist for SSRI or bupropion cessation before ACDF procedures, due to concerns including depression relapse and discontinuation syndrome [29].

The higher ASD rate observed on univariate analysis deserves further comment. Patients taking SSRI/SNRI/TCA medications were noted to have a higher pseudarthrosis rate, possibly due to the inhibitory effects of these medications on osteoblast function. However, this biological effect is highly unlikely related to an increased ASD incidence. Contrarily, if a new disease at adjacent levels is promoted by “fusion,” then the SSRI/SNRI/TCA group, which has a higher nonunion rate, would be expected to have a lower ASD incidence. Our multivariate linear regression analysis suggests that ASD was not caused by mechanical factors, but rather the result of the way these patients, medicated for depression, may have presented to their surgeons with residual symptoms following their index procedure in short-term follow-up.

Unsurprisingly, our study found that longer construct length was a risk factor for pseudarthrosis, which is consistent with previous literature [30]. A previous retrospective study that compared 1-level versus 2-level ACDFs suggested that the radiographic union of an ACDF construct is half as likely for 2-level ACDFs at 2-year follow-up [30]. Similarly, we report an OR of 0.53 (CI, 0.42–0.68) for the radiographic union of multilevel constructs compared to 1-level ACDFs at approximately 22 months of follow-up.

Our study limitations include the inherent nature of retrospective studies and the reliance on accurate information when performing a chart review. We were able to review the patient’s chart for prescriptions; however, the consumption of patients of the prescribed medication and the medication prescription duration were not determined. Our data was limited to the collection of SSRI/SNRI/TCA use (yes/no), and we believe the benefit of understanding dose-response relationships between serotonin reuptake-inhibiting medications and pseudarthrosis rates. Well-designed prospective trials and animal models may be beneficial in establishing this relationship. Further, we did not evaluate an exhaustive list of antidepressant medications, and certain serotonin reuptake-inhibiting drugs may be more potent at inhibiting spinal fusion or have a greater impact on ASD; thus, higher-powered studies would be required to evaluate the interaction of each antidepressant on spinal fusion. Surgical technique was different between each surgeon, including some surgeons’ preference to incorporate allograft, titanium, or PEEK as the interbody device. Further, 1–4-level fusions were included in our analysis. However, we attempted to account for this heterogeneity through multivariate analysis. The short length of clinical follow-up limited our ability to identify all patients who will develop symptomatic ASD. Each year provides a 2.2% increase in ASD, thus a longer follow-up would provide additional insight into the role of serotonin reuptake-inhibiting agents in ASD [8]. However, the number of patients with 1-year dynamic radiographs limited our cohort size, and to our knowledge, this is the largest number of patients with dynamic cervical spine radiographs stratified into groups based on serotonin reuptake-inhibiting medication prescriptions.

Serotonin reuptake-inhibiting drugs lead to an elevated risk of pseudarthrosis and revision surgery due to ASD in patients undergoing ACDF. Additionally, patients taking these medications have worse preoperative and postoperative PROMs, but this is likely due to their underlying depression, as demonstrated in the similar recovery ratios and degree of improvement after surgery compared to patients without serotonin reuptake-inhibiting antidepressant prescriptions.