Does fluoxetine (selective serotonin reuptake inhibitor) or serotonin exacerbate leukocytoclastic vasculitis?

From the Guidelines

Fluoxetine or serotonin is not explicitly mentioned as a factor that worsens alternating vasculitis in the provided evidence, and therefore, its impact on the condition remains unclear. The recent study by Hellmich et al. 1 published in 2024 in the Annals of the Rheumatic Diseases, focuses on the EULAR recommendations for the management of ANCA-associated vasculitis, but does not discuss the effects of fluoxetine or serotonin on vasculitis.

Key Points to Consider

• The study 1 provides recommendations for the management of ANCA-associated vasculitis, including the use of glucocorticoids, rituximab, and cyclophosphamide for induction of remission.
• There is no mention of fluoxetine or serotonin in the context of vasculitis management in the provided evidence 1.
• In clinical practice, when managing patients with vasculitis, it is essential to consider the potential effects of all medications, including fluoxetine, on the disease course.

Clinical Implications

• Patients with pre-existing vasculitis who are prescribed fluoxetine should be monitored for worsening symptoms.
• Healthcare providers should be aware of the potential for medication-related effects and evaluate whether dose adjustment or medication change is warranted if a patient with vasculitis experiences symptom exacerbation after starting fluoxetine.
• Decisions about continuing or discontinuing fluoxetine should be individualized, weighing the psychiatric benefits against potential vascular risks, although the current evidence 1 does not provide clear guidance on this matter.

From the Research

Evidence for Fluoxetine and Serotonin's Impact on Vasculitis

• There is evidence to suggest that fluoxetine, a serotonin reuptake inhibitor (SSRI), can have effects on the vasculature, including changes in vasomotor tone 2.
• A study found that chronic treatment with fluoxetine decreased sympathetic-mediated vascular responses by mechanisms that involve inhibition of norepinephrine release/reuptake and decreased Ca2+ stores 2.
• Another study reported a case of reversible cerebral vasoconstriction syndrome (RCVS) associated with fluoxetine, suggesting that serotonergic medications can be a potential cause of this syndrome 3.
• Research also suggests that chronic intake of fluoxetine can enhance atherosclerosis by increasing atherosclerotic lesion formation, vascular permeability, and chemokine-induced integrin-binding activity of circulating leukocytes 4.

Case Reports and Studies

• A review of the literature found 15 patients with RCVS associated with the use of serotonergic medications, including fluoxetine 3.
• A study found that fluoxetine treatment increased KCl-induced vasoconstriction, which was abolished by prazosin, suggesting that fluoxetine can affect vascular reactivity 2.
• Another study found that fluoxetine augmented vascular permeability and increased chemokine-induced integrin-binding activity of circulating leukocytes, which can contribute to atherosclerosis 4.

Mechanisms and Potential Risks

• The proatherogenic effect of fluoxetine is thought to occur independent of peripheral 5-HT depletion 4.
• Fluoxetine can directly promote β1 and β2 integrin activation in the presence of C-C motif chemokine ligand 5, which can contribute to atherosclerosis 4.
• The use of serotonergic medications, including fluoxetine, may increase the risk of acute cardiovascular events, particularly in older adults 5.