Despite longstanding concerns about serotonergic medications and bleeding risk there appears to be no increased short-term mortality or worse acute clinical outcomes associated with antidepressant use prior to a traumatic brain injury (TBI).
Investigators found patients with TBI who were on antidepressants prior to TBI had similar 30-day mortality compared with those who did not take these medications. Antidepressant use also was not associated with longer hospitalizations and was tied to a lower likelihood of acute neurosurgical operations.
The findings were consistent across antidepressant classes and across drugs with weak, intermediate, or strong serotonergic profiles. Notably, antidepressant use did not appear to increase the known risks associated with vitamin K antagonists (VKAs) in patients with TBI.
“Clinically, this supports a reassuring interpretation — baseline SSRI/SNRI [selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor] use alone should not be considered an indicator of worse early prognosis, and acute management should remain guided by established injury and bleeding risk factors rather than antidepressant exposure itself,” lead investigator Jussi P. Posti, MD, PhD, professor of neurosurgery, University of Turku, Turku, Finland, told Medscape Medical News.
The study was published online on January 28 in Neurology.
Why the Concern?
Concerns about antidepressant use in patients with head injury stem from the effects of serotonin-mediated platelet function. SSRI and SNRI reduce platelet serotonin levels, which may impair primary hemostasis, leading to concerns about bleeding risk.
Prior observational studies have linked serotonergic antidepressants to an increased risk for spontaneous intracranial hemorrhage (ICH), although findings have been inconsistent. Some studies suggested higher bleeding risk with strong SSRI, while others have questioned the clinical relevance of this association, the investigators noted.
Smaller single-center studies from Finland have suggested that serotonergic antidepressants do not increase the risk for traumatic ICH or adverse outcomes after mild TBI, but larger population-based analyses are lacking.
Antidepressant use is prevalent among older adults, a population that is already at increased risk for falls and head injury. Posti and his colleagues noted that this makes it clinically important to determine whether these medications influence short-term outcomes following TBI.
No Signal for Harm
For the study, investigators looked at data from national healthcare and prescription registries from patients aged 16 years or older who were admitted to hospital with TBI between 2005 and 2018.
The study included 54,876 patients with TBI. Of these individuals 7845 (14.3%) took antidepressants at the time of injury. Antidepressant users tended to be older (mean age, 64.7 vs 60.1 years in nonusers) and women (56% vs 41%), and had a higher burden of medical comorbidities, including dementia, cardiovascular disease, diabetes, and psychiatric illness (P < .0001 for all)
Antidepressant use was determined from prescription records and categorized by serotonergic profile as weak, intermediate, or strong.
The primary outcome was all-cause mortality within 30 days of admission. Secondary outcomes included the need for acute neurosurgical operations and length of hospital stay. Multivariable models adjusted for age, sex, comorbidities, injury characteristics, admission location, calendar year, and use of VKAs or direct oral anticoagulants (DOACs).
Among antidepressant users, most took agents with strong serotonergic activity (65.1%), followed by weak (20.7%) and intermediate (14.2%) serotonergic drugs. SSRI were the most commonly prescribed drugs (59.8%), followed by atypical antidepressants (19.9%), SNRI (15.3%), and tricyclic antidepressants (5.0%). VKAs usage was more common among antidepressant users than nonusers (8.0% vs 6.7%; P < .0001), particularly among those who took weak serotonergic agents.
Overall, 30-day mortality was similar in patients who took antidepressants and those who did not (7.6% vs 7.5%). After adjustment for confounders, antidepressant use was not associated with increased mortality risk (adjusted hazard ratio [HR], 0.98; 95% CI, 0.91-1.05; P = .696).
Mortality also did not differ by serotonergic profile. Adjusted HRs for 30-day death were 0.94 (95% CI, 0.86-1.03) for strong serotonergic agents, 0.95 (95% CI, 0.84-1.07) for intermediate agents, and 1.12 (95% CI, 0.89-1.41) for weak agents for patients who took antidepressants compared with those who didn’t. None reached statistical significance.
Compared with patients who did not take antidepressants, those who did were less likely to undergo acute neurosurgical operations (adjusted relative risk, 0.89; 95% CI, 0.82-0.96; P = .007).
This association was most significant among patients who used strong serotonergic antidepressants, although investigators cautioned that residual confounding related to injury mechanism and frailty may partly explain this finding.
Posti noted that antidepressant use was associated with a lower adjusted likelihood of acute neurosurgical intervention, including among patients receiving strongly serotonergic agents. However, this association may reflect residual confounding — such as differences in injury mechanism, frailty, or triage and admission pathways not fully captured in the dataset — rather than a true protective pharmacologic effect.
After multivariable adjustment, length of hospitalization did not differ significantly between antidepressant users and nonusers. Admission duration was also not associated with antidepressant type or serotonergic class.
The use of VKAs remained independently associated with higher mortality and greater need for neurosurgical intervention, but no interaction was observed between anticoagulant use and antidepressant exposure.
Posti said that in this cohort, serotonergic antidepressants were not associated with an increased risk for adverse short-term outcomes among patients receiving VKAs or DOACs. However, he noted that the analysis was limited by the absence of data on medication adherence, postinjury antidepressant changes, dose-response relationships, and the short-term, registry-based nature of the outcomes.
Early Clinical Outcomes
Patients taking antidepressants were generally older, more often women, and had a higher burden of comorbidities than those not on these medications. They were also more frequently admitted initially to nontertiary care centers, which suggests differences in injury patterns and overall clinical severity.
Investigators observed that antidepressant users had fewer skull or facial fractures (6.5% vs 9.0%; P < .0001), which is a pattern that is consistent with lower-energy trauma, such as falls.
The lack of a clear dose-response relationship across serotonergic profiles suggests that serotonin-mediated platelet dysfunction is unlikely to play a major role in early TBI outcomes. Rather, traumatic bleeding appears to be driven more by injury mechanism and severity than subtle differences in platelet function.
“The study is strongest for its population coverage of the whole country and robust 30-day endpoints, but it is limited by the absence of classic injury-severity variables (eg., Glasgow Coma Scale, duration of unconsciousness/posttraumatic amnesia, radiologic scoring) and by lack of long-term outcomes,” Posti said.
He cautioned that these conclusions focus on early clinical outcomes, using 30-day mortality and the need for acute neurosurgical procedures as reliable indicators of severe TBI complications.
He noted that the findings only apply to short-term outcomes and cannot be used to draw conclusions about more detailed measures of injury severity or patient recovery beyond 30 days.
Reassuring Data
Commenting on the findings for Medscape Medical News, Brian Hainline, MD, clinical professor of neurology at NYU Grossman School of Medicine, New York City, said the findings help ease long-standing concerns about serotonergic antidepressants and their negative impact on platelet function.
“The core results tell us that antidepressants do not behave like anticoagulants in individuals who have suffered head trauma. The primary early risk concerns remain injury mechanism, frailty, and true coagulopathy,” said Hainline who was not involved in the study.
The findings of no increased 30-day mortality or need for acute neurosurgical intervention is meaningful, he said.
“SSRI/SNRI drugs do not change acute TBI risk stratification in the manner as VKA use and coagulopathy. This is consistent with most neurology and neurosurgical settings, where we worry about warfarin, DOACs, liver disease, frailty, and injury mechanism much more than SSRI/SNRI drugs when predicting expanding intracranial bleeds, emergency surgery, and early mortality,” Hainline added.
Regarding the lower rates of neurosurgical intervention among antidepressant users, Hainline cautioned against assuming this was a drug-related benefit. He highlighted that patients who took antidepressants were more likely to be older, female, and burdened with multiple comorbidities, and they more often sustained lower-energy injuries, such as falls.
“The lower neurosurgical rate likely reflects injury phenotype and triage patterns rather than pharmacologic protection,” he said.
He also noted the study’s reassurance regarding anticoagulant interactions, noting that antidepressants do not appear to increase bleeding or surgical risk in patients treated with VKAs or DOACs, and that management should therefore focus on anticoagulation status.
“The study reassures clinicians regarding antidepressant use in patients who have suffered TBI, as these drugs do not appear to worsen early clinical outcomes. Antidepressants should therefore not be reflexively discontinued in this setting.
“Given the importance of post-TBI mood, cognition, and behavioral regulation for recovery, unnecessary discontinuation could theoretically contribute to adverse longer-term outcomes,” Hainline said.
This study was funded by State Research Funding (VTR, Finland) and received grants from the Paulo Foundation, the Paavo Nurmi Foundation, and the Finnish Foundation for Cardiovascular Research. Posti reported receiving speaker’s fees from Sanofi S.A., the Finnish Medical Association, Wellbeing Services County of North Karelia, and Finnish Association of Otorhinolaryngology — Head and Neck Surgery, as well as travel and expert fees from the National Institute of Neurological Disorders and Stroke and reported being supported by the Research Council of Finland and the Sigrid Juselius Foundation. Hainline reported having no relevant financial disclosures.
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