Antidepressants, Depression Tied to Increased Thromboembolism Risk

Nancy A. Melville

July 27, 2018

The use of antidepressants, as well as depression itself, are linked to an increased risk for venous thromboembolism (VTE), with no significant differences in risk across the three classes of antidepressants, a new meta-analysis shows.

"Our findings show that depression and use of antidepressants are each associated with an increased risk of venous thromboembolism," first author Setor Kunutsor, PhD, research fellow from the Musculoskeletal Research Unit at the Bristol Medical School: Translational Health Sciences, United Kingdom, told Medscape Medical News.

"We have also shown that each of the various classes of antidepressant medications are associated with an increased risk of venous thromboembolism," said Kunutsor.

The study was published online July 12 in the Annals of Medicine.

Interpret With Caution

Previous research shows that psychosocial factors including stress, depression, anxiety, and low socioeconomic status may be associated with VTE and that these factors may promote hypercoagulable states through autonomic and neuroendocrine pathways, the investigators note. In addition, they point out there is growing evidence that depression and antidepressant use may be associated with VTE.

To investigate, the researchers conducted a meta-analysis, identifying eight observational studies, including five that focused on antidepressant use as an exposure, two that evaluated depression and VTE, and one that evaluated both antidepressant use and depression.

The studies included a total of 960,113 participants and 9027 VTE cases. Although the studies differed in the covariates used in adjustment, most were adjusted for the known VTE risk factors of age, body mass index, smoking status, and comorbidities.

With average follow-up on the development of VTE ranging from 0.9 to 13.5 years, the six studies that investigated antidepressants, involving a total of 828,327 participants and 8273 VTE cases, showed a pooled relative risk (RR) of 1.27 (95% confidence interval [CI], 1.06 - 1.51) of developing VTE with antidepressant use compared to not using antidepressants.

The risk was not statistically different (P = .328) between tricyclic antidepressants (RR, 1.16; 95% CI, 1.06 - 1.27), selective serotonin reuptake inhibitors (SSRIs) (RR, 1.12; 95% CI, 1.02 - 1.23), and drugs in the category of "other antidepressants," which included monoamine oxidase inhibitors, triazolopyridine, serotonin norepinephrine reuptake inhibitors, and norepinephrine dopamine reuptake inhibitors (RR, 1.59; 95% CI, 1.21 - 2.09).

"We checked for statistical differences in venous thromboembolism rates across the three antidepressant classes, and there seemed to be no difference," said Kunutsor. However, he noted that more studies are needed.

"Given the limited number of studies available for this analysis, these results need to be interpreted with caution," he said.

Potential Mechanisms

One study that specifically investigated antidepressant use vs nonuse in the risk for deep vein thrombosis (DVT) showed an RR of just 1.02 (95% CI, 0.91 - 1.13). However, another study that investigated only at the risk for pulmonary embolism (PE) with the use of antidepressants reported a significantly higher RR of 4.90 (95% CI, 1.10 - 22.50) vs nonuse.

A pooled analysis of two studies that compared only women who used antidepressants with women who did not use antidepressants (740,945 participants; 4904 VTE cases) showed an RR for VTE of 1.44 (95% CI, 1.29 - 1.61). One study that reported on the corresponding figure in men showed an RR of 1.38 (95% CI, 0.96 - 1.97).

In examining the association between VTE risk and depression, the analysis showed a combined RR of 1.31 (95% CI, 1.13 - 1.53) of patients with depression vs those without depression.

Two studies that focused on women only showed an RR for VTE of 1.21 in those with depression vs those without depression (95% CI, 1.02 - 1.45). The one study that reported on men only showed an RR of 1.65 (95% CI, 1.12 - 2.44).

One of the studies that involved women was the largest study to date on the issue of VTE and antidepressants. The Million Women Study, a prospective study published in the Journal of the American Heart Association in 2017, followed more than 700,000 women in the United Kingdom for an average of 7.3 years.

Results showed an increased risk for VTE with antidepressant use (hazard ratio [HR], 1.39; 95% CI, 1.23 - 1.56). Women who reported treatment for depression but not with antidepressants had no significantly increased risk for VTE (HR, 1.19; 95% CI, 0.95 - 1.49).

Although an inflammatory process is among key theories regarding the development of VTE, the mechanisms of a possible link to antidepressants are not clear.

The authors of the Million Women Study offered one hypothesis of the link between antidepressants and PE. They suggested that tricyclic antidepressants, in particular, may increase the risk, owing to chemical similarities with phenothiazines, a class of antipsychotic drugs.

These medications have been hypothesized to increase the risk for VTE by increasing "aggregation of platelets, the presence of anticardiolipin antibodies, and exacerbation of venous stasis as a result of the sedative effect," the authors note.

An Important Association

Numerous aspects of depression itself have been considered as potential mechanisms that may trigger VTE, including lack of mobility (a known risk factor for VTE), as well as greater platelet activation and increased procoagulant activity.

Depression is also linked to higher rates of hyperhomocysteinemia, which has also been proposed as a potential VTE risk factor. Still other factors of depression, including poor underlying health status, lifestyle, and diet, may contribute to increased VTE risk

The proposed mechanisms remain speculative, and the authors note that a causative role is not established in the analysis. However, the combined evidence suggests an important association that clinicians should be aware of and one that researchers should more rigorously investigate, Kunutsor said.

"Though the study could not prove cause and effect, it does show that a relationship exists between depression, antidepressant use, and venous thromboembolism," he said.

"Venous thromboembolism is a public health burden — its incidence doesn't seem to be on the decrease. It is associated with significant morbidity, mortality, as well as high health costs," he added.

"Prescribers and healthcare professionals therefore need to evaluate patients to determine their excess risk of venous thromboembolism during their management of depression or when prescribing antidepressants," he said.

"Puzzling" Results

Commenting on the study for Medscape Medical News, Philip R. Muskin, MD, professor of clinical psychiatry at Columbia University College of Physicians and Surgeons in New York City, said the findings are somewhat perplexing and in some ways counter concerns about antidepressants and bleeding.

"At least with SSRIs, the thing we tend to worry about is a bleeding risk, particularly gastrointestinal and intracranial, or bruising. So I tell patients if they need surgery to make sure to tell the surgeon they are on antidepressants," said Muskin, who is also chief of consultation-liaison psychiatry at the Columbia University Medical Center of the New York–Presbyterian Hospital.

Muskin noted that findings from the Fluoxetine for Motor Recovery After Acute Ischaemic Stroke (FLAME) randomized controlled trial showed benefits of the SSRI fluoxetine in motor recovery after acute ischemic stroke.

He said some important limitations of the current meta-analysis include relatively small overall RRs in many measures and the fact that data on the length of time participants were treated with antidepressants appear lacking.

"That's important, because if someone was treated for a month and had the same risk as someone treated for a year, that suggests something about the role of the drug," said Muskin.

He added that the finding of similar results across all antidepressant classes was especially notable.

"These drug classes are pharmacologically different and don't all affect serotonin. So the findings are frankly puzzling," he said.

"But we don't ignore puzzling — what we say is, okay, so this is a signal, and what does it mean? And the answer is, we don't know what it means, but we shouldn't ignore it. We shouldn't [overreact], but we should keep it in mind.

"I would suggest perhaps informing patients that there have been these reports, and if you develop pain in your calf, for instance, or some other symptom of a thrombosis, then I need to hear about it," Muskin concluded.

The study received support from the National Institute for Health Research Biomedical Research Center at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The authors and Dr Muskin have disclosed no relevant financial relationships.

Ann Med. Published online July 12, 2018. Abstract

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