Serotonin Reuptake Inhibitor Increases Pseudarthrosis Rates in Anterior Cervical Discectomy and Fusions

Article information

Asian Spine J. 2023;17(2):304-312
Publication date (electronic) : 2023 January 10
doi :
Department of Orthopaedic Surgery, Rothman Orthopaedic Institute at Thomas Jefferson University Hospital, Philadelphia, PA, USA
Corresponding author: Mark James Lambrechts, Rothman Orthopaedic Institute at Thomas Jefferson University, 925 Chestnut St., 5th Floor, Philadelphia, PA 19107, USA, Tel: +1-215-955-6060, Fax: +1-215-503-5651, E-mail:
Received 2022 February 11; Revised 2022 April 18; Accepted 2022 April 19.


Study Design

Retrospective cohort.


To determine (1) the effects of serotonin reuptake inhibitors in pseudarthrosis rates after anterior cervical decompression and fusion (ACDF) and (2) to identify patient-reported outcome measures in patients taking serotonin reuptake inhibitors.

Overview of Literature

Recent literature suggests that selective serotonin reuptake inhibitors (SSRIs) may inhibit fracture healing via downregulation of osteoblast differentiation. Spinal fusion supplementation with osteoblast-rich substances enhances spinal fusion, thus SSRIs may be detrimental.


Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p-values of <0.05.


Of the 523 patients who meet the inclusion criteria, 137 (26.2%) were prescribed an SSRI, SNRI, or TCA. Patients with these prescriptions were more likely to have pseudarthrosis (p=0.008) but not a revision surgery due to pseudarthrosis (p=0.219). Additionally, these patients had worse 1-year postoperative mental component summary (MCS)-12 (p=0.015) and Neck Disability Index (NDI) (p=0.006). The multivariate logistic regression analysis identified SSRI/SNRI/TCA use (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.11–2.99; p=0.018) and construct length (OR, 1.91; 95% CI, 1.50–2.44; p<0.001) as pseudarthrosis predictors. A SSRI/SNRI/TCA prescription was a revision surgery predictor due to adjacent segment disease on univariate analysis (OR, 2.51; p=0.035) but not on multivariate logistic regression analysis (OR, 2.24; p=0.10).


Patients taking serotonin reuptake-inhibiting antidepressants are at increased risk of worse postoperative outcome scores, including NDI and MCS-12, likely due to their underlying depression. This may contribute to their greater likelihood of having adjacent segment surgery. Additionally, preoperative use of serotonin reuptake inhibitors in patients undergoing an ACDF is a predictor of radiographic pseudarthrosis but not pseudarthrosis revision.


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 [1315]. 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.

Materials and Methods

1. Inclusion criteria

This study was approved by the Institutional Review Board at Thomas Jefferson University (Control #19D.508) with exempt status from requiring informed consent due to its retrospective design and minimal risk to subjects. Upon obtaining approval, all patients >18 years of age with preoperative and postoperative flexion-extension radiographs who underwent primary 1- to 4-level ACDF at Thomas Jefferson University from 2010 to 2019 were retrospectively identified. Patients who underwent index ACDF for a revision procedure, utilized a combined anterior/posterior approach, with a concomitant cervical corpectomy, or indicated in trauma, infection, or neoplasm settings were excluded.

2. Data extraction

Patient demographics and surgical characteristics were collected through a Structured Query Language search and manual chart review of electronic medical records. Dual-energy X-ray absorptiometry scans were utilized to identify patients with osteoporosis, defined by a T-score of ≤−2.5. Preoperative antidepressant prescriptions were recorded for each patient and classified by the following criteria: SSRI: citalopram, escitalopram, fluoxetine, paroxetine, and sertraline; SNRI: desvenlafaxine, duloxetine, venlafaxine; TCA: amitriptyline, doxepin, and nortriptyline; and atypical antidepressant: bupropion, lurasidone, mirtazapine, quetiapine, trazodone, and ziprasidone. PROMs were retrospectively collected through our institution’s prospectively collected database (OBERD, Columbia, MO, USA) and were included at the preoperative, 3-month postoperative, and 1-year postoperative time points. The extracted PROMs included the Visual Analog Scale for neck pain (VAS neck) and arm pain (VAS arm), the Neck Disability Index (NDI), the modified Japanese Orthopedic Association Scale (mJOA), and the mental and physical component summary scores of the Short Form 12 (SF-12) Health Survey (MCS-12 and PCS-12, respectively). The change in each PROM score (Δ) at the 3-month and 1-year postoperative point was calculated by subtracting the preoperative from the postoperative values. A recovery ratio (RR) was calculated for the 3-month and 1-year postoperative point for each PROM from the following formula: [Δ PROM/(optimal PROM–preoperative PROM)]. Optimal scores for each PROM were defined as VAS neck and VAS arm of 0 points, mJOA of 18 points, and SF-12 MCS/PCS of 100 points.

3. Radiographic evaluation

Postoperative dynamic radiographs were reviewed by a single reviewer through our institution’s Picture Archiving and Communication System (Sectra AB, Linköping, Sweden). The distance (in millimeters) between the superior and inferior spinous process at each ACDF level was measured on postoperative flexion and extension radiographs. Radiographic fusion was defined as <1 mm of interspinous motion between each instrumented level and ≥4 mm of motion at any adjacent unfused level following the guidelines published by the Cervical Spine Research Society Special Project Committee [16]. ASD was defined as any patient with symptomatic postoperative pain and supra-adjacent or infra-adjacent progressive listhesis or degenerative disk disease, which resulted in a revision procedure.

4. Surgical procedure

All surgeons at our institution use a standard Smith-Robinson approach. A combination of sharp and blunt dissection is performed until reaching the longus colli muscle, which is subperiosteally elevated with electrocautery so retractors can be placed posterior to the muscle for appropriate disk space and endplate visualizations. The posterior longitudinal ligament is taken and the pedicles are skeletonized. The cartilaginous endplate is then removed to optimize fusion rates. Machined allograft was used as the interbody spacer in 86% of the cases, but some surgeons alternatively use poly-ether-ether-ketone (PEEK) (5%) or titanium cages (9%) with local autograft, when available, and allograft chips. Following anterior cervical plate and locking screw placement, the wound is irrigated and intraoperative lateral cervical radiographs are taken to confirm instrumentation positioning.

5. Statistical analysis

Descriptive statistics, including mean and standard deviation, were used to record patient demographics, surgical characteristics, and surgical outcomes. Continuous and categorical variables were analyzed using independent t-tests and Pearson’s chi-square tests, or the corresponding non-parametric test, respectively. Multiple logistic regression models were developed to measure the effect of patient demographics, preoperative antidepressant medication usage, and surgical characteristics on the likelihood of radiographic fusion and revision surgery for ASD after the index ACDF. R software ver. 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) was used for all data analysis. Statistical significance was set at p-values of <0.05.


1. Patient demographics

Of the 523 patients who met the inclusion criteria, 137 patients (26.2%) were taking serotonin reuptake-inhibiting antidepressants. Of the 137 patients, 81 (59.1%) were prescribed SSRI, 42 (30.7%) SNRI, and 14 (10.2%) TCA. Patients taking serotonin reuptake-inhibiting antidepressants were significantly more likely females than males (N=94 [68.6%] versus N=43 (31.4%), p<0.001), with a greater Elixhauser Comorbidity Index (2.31±1.76 versus 1.42±1.50, p<0.001), osteoporosis (18.2% versus 7.5%, p=0.001), and anxiety (p<0.001) or depression (p<0.001) diagnosis. The remaining patient demographics were not significantly different (Table 1).

Patient demographics and medication use between patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

2. Surgical characteristics

A significantly higher proportion of patients were prescribed SSRI, SNRI, or TCA versus those who did not undergo a multilevel ACDF (78.8% versus 67.1%, p=0.045). No significant differences were found in implant composition (p=0.926), length of clinical follow-up (21.4±11.6 versus 21.4±11.5 months, p=0.910), 90-day all cause readmission (2.19% vesus 0.26%, p=0.057), subsidence rates (0.8±1.13 versus 0.8±1.13, p=0.718), or rate of revision surgery due to pseudarthrosis (7.30% versus 4.15%, p=0.219) between the patients with and without SSRI/SNRI/TCA prescriptions. However, a significantly greater pseudarthrosis rate (46.7% versus 33.4%, p=0.008) and rate of revision surgery due to ASD (8.76% versus 3.63%, p=0.032) were found in patients with and without SSRI, SNRI, or TCA prescriptions (Table 2).

Surgical characteristics comparing patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

3. Patient-reported outcome measures

A preoperative prescription for a SSRI, SNRI, or TCA was associated with an inferior preoperative (42.9 versus 48.8, p<0.001), 3-month postoperative (45.8 versus 51.9, p=0.004), and 1-year postoperative MCS-12 (45.3 versus 50.8, p=0.015), but did not significantly affect ∆MCS-12 at 3-months (2.05 versus 2.92, p=0.657) or 1-year (1.24 versus 1.42, p=0.877). The preoperative (34.5 versus 34.0, p=0.702) and 3-month postoperative PCS-12 (34.9 versus 37.5, p=0.083) were not significantly different, the ∆PCS-12 at 3-months (0.85 versus 4.76, p=0.016) and the PCS-12 RR at 3-months (0.00 versus 0.06, p=0.004) did demonstrate a significant decrease in patient improvement with a preoperative SSRI, SNRI, or TCA prescription. These differences did not persist at 1-year for the ΔPCS-12 (6.30 versus 7.72, p=0.451) or PCS-12 RR (0.09 versus 0.11, p=0.384). The preoperative NDI (45.4 versus 39.3, p=0.003), 1-year postoperative NDI (31.1 versus 22.0, p=0.006), and NDI RR at 1-year (0.24 versus 0.32, p=0.047) demonstrated worse outcomes for the SSRI, SNRI, or TCA group. VAS arm and VAS neck analyses revealed a significantly worse outcome only in the 3-month postoperative VAS neck (3.77 versus 2.91, p=0.031) for the SSRI, SNRI, and TCA group (Table 3).

Patient-reported outcomes based on patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA-yes) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

4. Multiple logistic regression analysis

The analyses of radiographic fusion as the dependent variable revealed SSRI/SNRI/TCA use (odd ratio [OR], 1.82; 95% confidence interval [CI], 1.11–2.99; p=0.018) and construct length (OR, 1.91; 95% CI, 1.50–2.44; p<0.001) as radiographic pseudarthrosis predictors. Age (OR, 1.02; 95% CI, 1.00–1.04), male sex (OR, 1.33; 95% CI, 0.90–1.99), body mass index (OR, 0.97; 95% CI, 0.93–1.00), current smoking status (OR, 4.03; 95% CI, 0.70–32.26), osteoporosis (OR, 0.79; 95% CI, 0.41–1.49), and atypical antidepressant prescriptions (OR, 1.44; 95% CI, 0.62–3.26) were not identified as independent pseudarthrosis predictors (Table 4).

Multiple logistic regression analysis of radiographic pseudarthrosis

The analyses of revision surgery for ASD as the dependent variable revealed that SSRI/SNRI/TCA use (OR, 2.24; 95% CI, 0.84–5.84; p=0.10) is not an independent predictor for increased revision surgery rates for ASD but for increased age (OR, 0.96; 95% CI, 0.92–0.99; p=0.030) did. No other independent variables were revision for ASD predictors (Table 5).

Multiple logistic regression analysis of adjacent segment revision surgery


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.


Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: MJL, GRT, JKL; data curation: NDA, GRT, JDP, DMF; formal analysis: NDA, GRT; funding acquisition: none; methodology: MJL; project administration: IDK, BIW, JAR, MFK, JKL, ASH, CKK, ARV, GDS; visualization: MJL; writing–original draft: MJL, NDA; writing–reivew & editing: GRT, BAK, BIW, JAR, MFK, ASH, CKK, ARV, GDS; and final approval of the manuscript: all authors.


1. Oglesby M, Fineberg SJ, Patel AA, Pelton MA, Singh K. Epidemiological trends in cervical spine surgery for degenerative diseases between 2002 and 2009. Spine (Phila Pa 1976) 2013;38:1226–32.
2. Neifert SN, Martini ML, Yuk F, et al. Predicting trends in cervical spinal surgery in the United States from 2020 to 2040. World Neurosurg 2020;141:e175–81.
3. Buttermann GR. Anterior cervical discectomy and fusion outcomes over 10 years: a prospective study. Spine (Phila Pa 1976) 2018;43:207–14.
4. Garvey TA, Transfeldt EE, Malcolm JR, Kos P. Outcome of anterior cervical discectomy and fusion as perceived by patients treated for dominant axial-mechanical cervical spine pain. Spine (Phila Pa 1976) 2002;27:1887–95.
5. Emery SE, Fisher JR, Bohlman HH. Three-level anterior cervical discectomy and fusion: radiographic and clinical results. Spine (Phila Pa 1976) 1997;22:2622–4.
6. Kreitz TM, Hollern DA, Padegimas EM, et al. Clinical outcomes after four-level anterior cervical discectomy and fusion. Global Spine J 2018;8:776–83.
7. van Eck CF, Regan C, Donaldson WF, Kang JD, Lee JY. The revision rate and occurrence of adjacent segment disease after anterior cervical discectomy and fusion: a study of 672 consecutive patients. Spine (Phila Pa 1976) 2014;39:2143–7.
8. Lee JC, Lee SH, Peters C, Riew KD. Adjacent segment pathology requiring reoperation after anterior cervical arthrodesis: the influence of smoking, sex, and number of operated levels. Spine (Phila Pa 1976) 2015;40:E571–7.
9. Divi SN, Goyal D, Mangan JJ, et al. Are outcomes of anterior cervical discectomy and fusion influenced by presurgical depression symptoms on the mental component score of the short form-12 survey? Spine (Phila Pa 1976) 2020;45:201–7.
10. Wu JC, Chang HK, Huang WC, Chen YC. Risk factors of second surgery for adjacent segment disease following anterior cervical discectomy and fusion: a 16-year cohort study. Int J Surg 2019;68:48–55.
11. Chen J, Li JY, Tian GH, et al. A national snapshot of the impact of clinical depression on post-surgical pain and adverse outcomes after anterior cervical discectomy and fusion for cervical myelopathy and radiculopathy: 10-year results from the US Nationwide Inpatient Sample. PLoS One 2021;16:e0258517.
12. Patetsos E, Horjales-Araujo E. Treating chronic pain with SSRIs: what do we know? Pain Res Manag 2016;2016:2020915.
13. Bradaschia-Correa V, Josephson AM, Mehta D, et al. The selective serotonin reuptake inhibitor fluoxetine directly inhibits osteoblast differentiation and mineralization during fracture healing in mice. J Bone Miner Res 2017;32:821–33.
14. Sayadipour A, Mago R, Kepler CK, et al. Antidepressants and the risk of abnormal bleeding during spinal surgery: a case–control study. Eur Spine J 2012;21:2070–8.
15. Pirkle S, Bhattacharjee S, El Dafrawy M, Leucht P, Shi LL, Lee MJ. The influence of selective serotonin reuptake inhibitors on lumbar arthrodesis. Clin Spine Surg 2021;34:E200–4.
16. Rhee JM, Chapman JR, Norvell DC, Smith J, Sherry NA, Riew KD. Radiological determination of postoperative cervical fusion: a systematic review. Spine (Phila Pa 1976) 2015;40:974–91.
17. Anderson PA, Puschak TJ, Sasso RC. Comparison of short-term SF-36 results between total joint arthroplasty and cervical spine decompression and fusion or arthroplasty. Spine (Phila Pa 1976) 2009;34:176–83.
18. Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015–2018 NCHS. Data Brief 2020. 377p. 1–8.
19. Howie RN, Herberg S, Durham E, et al. Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model. Int J Oral Sci 2018;10:25.
20. Sheu YH, Lanteigne A, Sturmer T, Pate V, Azrael D, Miller M. SSRI use and risk of fractures among perimenopausal women without mental disorders. Inj Prev 2015;21:397–403.
21. Hodge JM, Wang Y, Berk M, et al. Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function. Biol Psychiatry 2013;74:32–9.
22. Makino T, Tsukazaki H, Ukon Y, Tateiwa D, Yoshikawa H, Kaito T. The biological enhancement of spinal fusion for spinal degenerative disease. Int J Mol Sci 2018;19:2430.
23. Phan K, Moran D, Kostowski T, et al. Relationship between depression and clinical outcome following anterior cervical discectomy and fusion. J Spine Surg 2017;3:133–40.
24. Jenkins NW, Parrish JM, Yoo JS, et al. Are preoperative PHQ-9 scores predictive of postoperative outcomes following anterior cervical discectomy and fusion? Clin Spine Surg 2020;33:E486–92.
25. Harris AB, Marrache M, Puvanesarajah V, et al. Are preoperative depression and anxiety associated with patient-reported outcomes, health care payments, and opioid use after anterior discectomy and fusion? Spine J 2020;20:1167–75.
26. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 2015;23:1–21.
27. Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry 2004;6:159–66.
28. Roose SP, Rutherford BR. Selective serotonin reuptake inhibitors and operative bleeding risk: a review of the literature. J Clin Psychopharmacol 2016;36:704–9.
29. Epstein NE. When to stop anticoagulation, anti-platelet aggregates, and non-steroidal anti-inflammatories (NSAIDs) prior to spine surgery. Surg Neurol Int 2019;10:45.
30. Zigler JE, Rogers RW, Ohnmeiss DD. Comparison of 1-level versus 2-level anterior cervical discectomy and fusion: clinical and radiographic follow-up at 60 months. Spine (Phila Pa 1976) 2016;41:463–9.

Article information Continued

Table 1

Patient demographics and medication use between patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

Characteristic No (N=386) Yes (N=137) p-value
Age (yr) 53.8±11.1 52.5±10.6 0.222
Sex: <0.001*
 Female 193 (50.0) 94 (68.6)
 Male 193 (50.0) 43 (31.4)
Body mass index (kg/m2) 29.0±5.69 29.5±6.11 0.376
Smoking 0.162
 Never 243 (63.0) 77 (56.2)
 Current 3 (0.78) 3 (2.19)
 Former 140 (36.3) 57 (41.6)
Elixhauser Comorbidity Index 1.42±1.50 2.31±1.76 <0.001*
History of osteoporosis 0.001*
 No 357 (92.5) 112 (81.8)
 Yes 29 (7.51) 25 (18.2)
History of diabetes mellitus 0.211
 No 354 (91.7) 120 (87.6)
 Yes 32 (8.29) 17 (12.4)
History of rheumatoid arthritis 0.584
 No 357 (92.5) 124 (90.5)
 Yes 29 (7.51) 13 (9.49)
History of anxiety <0.001*
 No 363 (94.0) 99 (72.3)
 Yes 23 (5.96) 38 (27.7)
History of depression <0.001*
 No 334 (86.5) 63 (46.0)
 Yes 52 (13.5) 74 (54.0)
SSRI <0.001*
 No 386 (100.0) 56 (40.9)
 Yes 0 81 (59.1)
SNRI <0.001*
 No 386 (100.0) 95 (69.3)
 Yes 0 42 (30.7)
TCA <0.001*
 No 386 (100.0) 123 (89.8)
 Yes 0 14 (10.2)
Atypical 0.001*
 No 351 (90.9) 137 (100.0)
 Yes 35 (9.07) 0

Values are presented as mean±standard deviation or number (%).

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.


p<0.05 (statistical significance).

Table 2

Surgical characteristics comparing patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

Variable No (N=386) Yes (N=137) p-value
Total no. of levels in construct 0.045*
 1 127 (32.9) 29 (21.2)
 2 160 (41.5) 63 (46.0)
 3 88 (22.8) 38 (27.7)
 4 11 (2.85) 7 (5.11)
Implant composition 0.926
 Allograft 332 (86.0) 118 (86.1)
 PEEK 20 (5.18) 8 (5.84)
 Titanium 34 (8.81) 11 (8.03)
Follow-up (mo) 21.4±11.5 21.4±11.6 0.910
Interbody subsidence (mm) 0.80±1.09 0.80±1.13 0.718
Radiographic fusion at follow-up 0.008*
 No 129 (33.4) 64 (46.7)
 Yes 257 (66.6) 73 (53.3)
All-cause 90-day readmission 0.057
 No 385 (99.7) 134 (97.8)
 Yes 1 (0.26) 3 (2.19)
Pseudarthrosis revision surgery 0.219
 No 370 (95.9) 127 (92.7)
 Yes 16 (4.15) 10 (7.30)
Adjacent segment revision surgery 0.032*
 No 372 (96.4) 125 (91.2)
 Yes 14 (3.63) 12 (8.76)

Values are presented as number (%) or mean±standard deviation.

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; PEEK, poly-ether-ether-ketone.


p<0.05 (statistical significance).

Table 3

Patient-reported outcomes based on patients with a prescription for a serotonin reuptake inhibiting drug (SSRI/SNRI/TCA-yes) compared to no serotonin reuptake inhibiting drug (atypical antidepressant/no antidepressant)

Patient-reported outcome measure No (N=386) Yes (N=137) p-value
 Preoperative 48.8±11.9 42.9±12.6 <0.001*
 3 Month postoperative 51.9±10.3 45.8±13.0 0.004*
 Δ 3 Month postoperative 2.92±11.5 2.05±10.2 0.657
 3 Month postoperative RR 0.03±0.22 0.03±0.19 0.668
 1 Year postoperative 50.8±10.0 45.3±12.7 0.015*
 Δ 1 Year postoperative 1.42±10.7 1.24±15.2 0.877
 1 Year postoperative RR 0.00±0.20 −0.01±0.29 0.965
 Preoperative 34.0±8.62 34.5±8.12 0.702
 3 Month postoperative 37.5±9.39 34.9±8.76 0.083
 Δ 3 Month postoperative 4.76±8.87 0.85±9.19 0.016*
 3 Month postoperative RR 0.06±0.14 0.00±0.14 0.004*
 1 Year postoperative 41.4±11.4 38.9±10.3 0.169
 Δ 1 Year postoperative 7.72±10.4 6.30±10.5 0.451
 1 Year postoperative RR 0.11±0.15 0.09±0.15 0.384
 Preoperative 39.3±18.1 45.4±16.6 0.003*
 3 Month postoperative 26.6±16.6 30.8±18.4 0.161
 Δ 3 Month postoperative −11.66±16.4 −15.35±18.8 0.288
 3 Month postoperative RR 0.11±1.38 0.29±0.42 0.664
 1 Year postoperative 22.0±18.4 31.1±19.4 0.006*
 Δ 1 Year postoperative −17.83±17.7 −15.30±20.9 0.494
 1 Year postoperative RR 0.32±1.07 0.24±0.66 0.047*
VAS neck
 Preoperative 5.78±2.77 6.30±2.21 0.155
 3 Month postoperative 2.91±2.25 3.77±2.48 0.031*
 Δ 3 Month postoperative −2.94±2.98 −2.79±2.86 0.764
 3 Month postoperative RR 0.43±0.63 0.31±0.68 0.261
 1 Year postoperative 2.53±2.48 3.14±2.64 0.141
 Δ 1 Year postoperative −3.04±3.04 −3.14±3.22 0.845
 1 Year postoperative RR 0.50±0.53 0.36±0.70 0.500
VAS arm
 Preoperative 5.40±3.00 5.54±2.67 0.860
 3 Month postoperative 2.63±2.69 2.81±2.80 0.734
 Δ 3 Month postoperative −2.63±3.46 −2.72±3.31 0.902
 3 Month postoperative RR 0.47±0.66 0.47±0.61 0.941
 1 Year postoperative 2.19±2.58 2.49±2.71 0.497
 Δ 1 Year postoperative −2.92±3.08 −2.82±3.43 0.943
 1 Year postoperative RR 0.59±0.45 0.47±0.88 0.779
 Preoperative 15.0±2.93 15.2±2.70 0.824
 3 Month postoperative 15.9±2.91 16.0±2.04 0.551
 Δ 3 Month postoperative 0.95±3.15 1.16±2.64 0.743
 3 Month postoperative RR 0.11±2.01 0.31±0.79 0.947
 1 Year postoperative 16.2±2.65 16.2±2.04 0.410
 Δ 1 Year postoperative 1.14±3.18 0.62±1.98 0.247
 1 Year postoperative RR 0.30±1.13 0.16±0.92 0.217

Values are presented as mean±standard deviation.

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; MCS, mental component summary; RR, recovery ratio; PCS, physical component summary; NDI, Neck Disability Index; VAS, Visual Analog Scale; mJOA, the modified Japanese Orthopedic Association Scale.


p<0.05 (statistical significance).

Table 4

Multiple logistic regression analysis of radiographic pseudarthrosis

Variable Estimate p-value Odds ratio (95% confidence interval)
Age 0.02 0.077 1.02 (1.00–1.04)
Male sex 0.29 0.158 1.33 (0.90–1.99)
Body mass index −0.03 0.087 0.97 (0.93–1.00)
Elixhauser Comorbidity Index 0.03 0.695 1.03 (0.89–1.18)
Depression −0.13 0.664 0.88 (0.49–1.56)
Osteoporosis −0.24 0.468 0.79 (0.41–1.49)
Smoking status
 Non-smoker Reference
 Current smoker 1.39 0.135 4.03 (0.70–32.26)
 Former smoker −0.19 0.341 0.83 (0.55–1.22)
SSRI/SNRI/TCA 0.60 0.018* 1.82 (1.11–2.99)
Atypical antidepressant 0.34 0.381 1.44 (0.62–3.26)
Total no. of levels in construct 0.64 <0.001* 1.91 (1.50–2.44)

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.


p<0.05 (statistical significance).

Table 5

Multiple logistic regression analysis of adjacent segment revision surgery

Variable Estimate p-value Odds ratio (95% confidence interval)
Age −0.044 0.030* 0.96 (0.92–0.99)
Male sex 0.061 0.886 1.06 (0.45–2.44)
Body mass index 0.042 0.177 1.04 (0.98–1.11)
Depression 0.258 0.603 1.29 (0.48–3.41)
SSRI/SNRI/TCA 0.806 0.100 2.24 (0.84–5.84)
Atypical antidepressant 0.298 0.725 1.35 (0.19–6.01)
Total no. of levels in construct 0.134 0.614 1.14 (0.67–1.92)

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.


p<0.05 (statistical significance).