Abstract
Introduction:
Chronic wounds are a significant source of patient morbidity, and ineffective treatment can lead to complications that are difficult and costly to manage. Given the limitations of current therapies, repurposing medications with well-studied safety and accessibility profiles offers a promising strategy for advancing wound care.
Methods:
A comprehensive review of the existing literature was conducted to evaluate the role of serotonin-modulating pharmacotherapy in wound healing.
Results:
Serotonergic signaling plays a multifaceted role in wound healing and evidence increasingly supports serotonin-modulating pharmacotherapy as having favorable angio-regulatory, immunomodulatory, and antimicrobial wound healing effects. Preclinical and clinical studies have demonstrated that topical administration of serotonin-modulating pharmacotherapy may improve wound healing outcomes.
Discussion:
findings of this study provide support for the use of serotonin-modulating pharmacotherapy, with a special focus on topical application, as an adjunctive treatment for chronic, non-healing wounds and highlight the need for further translational clinical investigation.
1 Introduction
Chronic non-healing wounds, such as neuropathic and vascular ulcers, cause significant disability and increase the risk of pain, infection, sepsis, amputation, and other morbidities (Zhao et al., 2016). In the United States, chronic wounds affect nearly 2.5% of the population and contribute to an economic burden surpassing $50 billion annually (Sen, 2019; Sen, 2021). Serotonin also known as 5-hyrdoxytryptamine (5-HT) is an extensively studied monoamine neurotransmitter that is also synthesized and used by peripheral cells (Malinin et al., 2004; ; Laberge et al., 1996; Nguyen et al., 2019). Tryptophan hydroxylase 1, a key peripheral serotonin-synthesizing enzyme, is expressed in lymphocytes, macrophages, mast cells, and T cells, while serotonin transporter (SERT) and 5-HT receptors are also present in macrophages, dendritic cells, and lymphocytes (Shah and Amini-Nik, 2017). In response to peripheral inflammation, both 5-HT and its receptors are upregulated, promoting key angiogenic and cellular wound healing pathways (Malinin et al., 2004; ; Laberge et al., 1996; Nguyen et al., 2019). At present, 5-HT is underappreciated in the wound healing literature, but its developing multifaceted involvement positions 5-HT signaling as a promising target for advanced wound care therapeutics.
2 Mechanistic basis and therapeutic rational for Serotonin/SSRIs in wound healing
2.1 Overview and clinical framing
5-HT plays regulatory roles in the four progressive, overlapping stages of wound healing: hemostasis, inflammation, proliferation, and remodeling (Figure 1) (; ). Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, citalopram, escitalopram, sertraline, and paroxetine, inhibit 5-HT reuptake at the synaptic cleft and are increasingly used across a broadening range of clinical applications including dermatologic diseases such as atopic dermatitis, contact dermatitis, and psoriasis, partially due to their well-documented downregulation of various proinflammatory cytokine signatures (; ; Kiecka and Szczepanik, 2022; Shah and Amini-Nik, 2017). Emerging evidence supports the use of SSRIs to improve wound healing outcomes via angio-regulatory, immunomodulatory, and antimicrobial mechanisms, which remain under-characterized and have not yet been comprehensively contextualized for cutaneous wound healing ().
FIGURE 1
2.2 Hemostasis and angiogenesis
Within minutes of cutaneous injury in the hemostasis stage, thrombin triggers 5-HT release from platelets and endothelial cells, activating 5-HT receptors on the same cell types and initiating G-protein–mediated extracellular signal–regulated kinases 1 and 2 phosphorylation in the mitogen-activated protein kinase signaling pathway (; Raote et al., 2007; Machida et al., 2013; Qin et al., 2013; Olszewska-Pazdrak and Carney, 2013; ; ; ; ; Tsopanoglou and Maragoudakis, 1999; ). This early 5-HT autocrine signaling amplifies downstream pro-angiogenic cascades by upregulating vascular endothelial growth factor (VEGF) receptors and promoting release of VEGF, CXCL12, and matrix metalloproteinases, to sustain VEGF and nitric oxide–driven neovascularization (; Lin et al., 2023; Olszewska-Pazdrak and Carney, 2013; ; ; Yang et al., 2005; ). SSRIs may be leveraged to attenuate dysregulated 5-HT signaling and to modulate the aberrant platelet and vascular responses in pathologic chronic wounds. For example, systemic SSRIs block SERT on platelets, preventing 5-HT uptake and causing a dose-dependent decrease, often exceeding 80%, in platelet 5-HT with greater effects seen after 6–12 weeks (Maguire et al., 1993; Kubera et al., 2001; Serebruany et al., 2001). Additionally, SSRIs lower plasma 5-HT, reduce key aggregation glycoproteins, and inhibit platelet signaling proteins involved in calcium mobilization release, which is a key step in platelet activation (Maguire et al., 1993; Kubera et al., 2001; Serebruany et al., 2001; Malinin et al., 2004). In contrast to CNS neurons which can synthesize 5-HT de novo via tryptophan hydroxylase, an enzyme which has enhanced expression in response to SSRIs, platelets cannot synthesize 5-HT and experience a depletion of intracellular stores to less than 2% of baseline after SSRI treatment (Shah and Amini-Nik, 2017). Relevant for poorly perfusing wounds, preliminary animal model studies have shown SSRIs may increase endothelial nitric oxide synthase activity and nitric oxide bioavailability (Pereira et al., 2015; Ofek et al., 2012). The platelet-inhibitory SSRI effects may also be particularly useful for targeting venous stasis ulcer disease processes as all classes of chronic venous insufficiency are linked to pathogenic platelet hyperactivity and increased platelet-monocyte and platelet-neutrophil aggregates, independent of whether a wound is present (Malinin et al., 2004).
2.3 Inflammation phase immunomodulation
The downregulatory effects of SSRIs on platelet 5-HT signaling may also modulate the inflammatory stage of wound healing where platelet-secreted 5-HT enhances recruitment and activation of neutrophils and macrophages, leading to unfavorable upregulation of key pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-ɑ) and interleukin-12 (IL-12) in chronic wounds (Maguire et al., 1993; Kubera et al., 2001; Serebruany et al., 2001; Shah and Amini-Nik, 2017). Synergistically, in vitro SSRI exposure has been shown to increase natural killer cell, a negative regulator of wound-microenvironment pro-inflammatory signaling, activity thereby reducing inflammation via two converging, complementary mechanisms (; ). Dendritic cells are also involved in the inflammatory stage and sequester 5-HT via SERT from activated T lymphocytes, subsequently presenting it to naïve T cells to promote their activation and adaptive immune response (Shah and Amini-Nik, 2017). In pathologic nonhealing wounds, T lymphocytes are elevated and exhibit dysfunctional signaling unresponsive to stimulation (Raziyeva et al., 2021; ; Shah and Amini-Nik, 2017). SSRIs may reduce T lymphocyte proliferation, cytokine production, and induce apoptosis in unresponsive, constitutively activated T lymphocytes preferentially compared to mature naïve T lymphocytes (Shenoy et al., 2013; ; Pállinger and Csaba, 2007; ). A persistent inflammatory phase may be associated with dysregulated monopoiesis and sustained elevation of proinflammatory macrophages, a key cell-type for transition to the proliferative stage which has upregulated phagocytosis and TNF-a in response to 5-HT (Li et al., 2021; Malinin et al., 2004). In an ex-vivo study, SSRIs significantly reduced the expression of CXCR4, CD4, and CCR5 on both monocyte-derived macrophages (MDM) and peripheral blood mononuclear cells compared to control, suggesting an inhibitory role of SSRIs for macrophage proinflammatory signaling (). Other studies have demonstrated SSRI-associated reductions in MDM proinflammatory cytokines, reactive oxygen species, and antigen presentation to immune cells, which may be dysregulated in pathologic wound healing (Nazimek et al., 2017).
2.4 Proliferation: keratinocyte and fibroblast responses
In regard to proliferative phase keratinocytes, topical 5-HT has been shown to enhance survival, migration, and wound area reduction in a dose-dependent manner, accelerating closure in both in vitro and in vivo models (Polanski et al., 1995; Sternberg et al., 1987; Nguyen et al., 2019; Sadiq et al., 2018; Lenz et al., 2001; Malinin et al., 2004; Seuwen et al., 1988; Rodriguez-Barucg et al., 2024). Improved keratinocyte scratch closure rates due to increased proliferation were reversed following treatment with ketanserin, a 5-HT receptor antagonist, supporting SSRI dependance on 5-HT keratinocyte signaling (Rodriguez-Barucg et al., 2024). This study also identified improved phosphorylation profiles and 350 differentially expressed genes in SSRI-treated keratinocytes with reactome analysis suggesting altered mitochondrial and ribonucleotide metabolism and thermogenesis (Rodriguez-Barucg et al., 2024). In fibroblasts, 5-HT promotes survival, activity, proliferation, and collagen production, while also synergizing with FGF-2 to enhance tissue proliferation (Polanski et al., 1995; Sternberg et al., 1987; Nguyen et al., 2019; Sadiq et al., 2018; Lenz et al., 2001; Malinin et al., 2004; Seuwen et al., 1988). These effects involve active transport, increased oxygen formation, protein phosphorylation, and 5-HT receptor–mediated mitogenesis, adhesion, and multiplication in culture (Polanski et al., 1995; Sternberg et al., 1987; Nguyen et al., 2019; Sadiq et al., 2018; Lenz et al., 2001; Malinin et al., 2004; Seuwen et al., 1988). The effects of SSRIs on certain chronic wound mechanism which have implicated 5-HT signaling remain unassessed; these include 5-HT-induced B-lymphocyte proliferation, afferent nerve ending stimulation and pain response and the potential of SSRIs to alter β-receptor function in wound cells, similar to SSRI-induced postsynaptic β-receptor downregulation in the brain (Malinin et al., 2004).
2.5 Selective serotonin reuptake inhibitors and wound microbiome
Recurrent or chronic infection is a known contributor to impaired wound healing and, in a retrospective analysis of 2963 patients, it was found that the predominant bacterial species in chronic wounds were S. epidermidis, S. aureus, Corynebacterium, and Pseudomonadaceae (Kiecka and Szczepanik, 2022). Biofilms, which hinder antibiotic treatment by using extracellular polymeric substance barriers and efflux pumps, are associated with delayed healing and increased infection risk in chronic wounds (; Wall et al., 2019; Pereira et al., 2021). Polymicrobial interactions, involving species like Staphylococcus aureus and Pseudomonas aeruginosa may enhance biofilm pathogenicity via exchange of antibiotic resistance genes, like those producing antibiotic-degrading enzymes (Ponde et al., 2021; ; Orazi and O'Toole, 2019).
Among SSRIs, fluoxetine and sertraline have the strongest antimicrobial effects; these SSRIs are more hydrophobic than others and may diffuse more easily across the phospholipid membrane to interact with cellular machinery (Kiecka and Szczepanik, 2022). These SSRIs, at sub-minimum inhibitory concentrations, have been shown to prevent biofilm production via ALS3 protein-binding and reduce mature biofilm metabolism (Oliveira et al., 2018; ; Rodrigues et al., 2023). Fluoxetine has been shown to have in vitro effect against multi-resistant S. aureus, E. faecalis, S. epidermidis, E. coli and P. aeruginosa and decreases biofilm formation of S. aureus clinical isolate UAMS-1 (). There is also evidence suggesting fluoxetine synergizes polymyxin B bactericidal effects in 80% of gram-negative isolates, outperforming fosfomycin and meropenem combinations (). Fluoxetine topical application to infected wounds may also decrease purulence and hinder hematogenous bacterial invasion (). Fluoxetine has also shown effectiveness against fluconazole-resistant Candida strains, and its administration leads to significant dose-dependent reductions in biofilm metabolism, 96% for C. krusei, and biomass, 82% for C. glabrata (). Sertraline inhibits the growth of S. aureus, E. coli, P. aeruginosa, and other Gram-positive bacteria such as S. epidermidis and E. faecalis, and shows synergy with antibiotics, including reductions in mimimum inhibitory concentration of tetracycline and ciprofloxacin against C. urealyticum and quinolone-resistant strains (). While generally less effective against Gram-negative species, it demonstrates activity against H. influenzae, M. catarrhalis, C. jejuni, Acinetobacter spp., and can inhibit biofilm production in coagulase-negative staphylococci (). In addition to the immunomodulatory properties of SSRIs, the antimicrobial properties of SSRIs make them promising adjuncts for difficult-to-treat wound bacterial and fungal infection.
3 Topical selective serotonin reuptake inhibitors and wound healing studies
3.1 Pre-clinical studies
Evidence from preclinical studies suggest topical SSRI application may improve wound healing. An in vivo study of diabetic mouse wound models revealed topical fluoxetine treatment promoted re-epithelialization, with significant decreases in wound area and exudate. Topical fluoxetine treatment also increased angiogenesis, suggested by higher CD31+ endothelial cell counts and visible small vessels, while reducing inflammatory macrophages and shifting their phenotype towards a pro-reparative state (Nguyen et al., 2019). In another study where wounds were created in rats, chronic topical fluoxetine administration improved mean wound lengths compared to acute administration in the initial 4 days; wounds in both chronic and acute fluoxetine treatment groups healed completely by day 10, while the placebo group did not fully heal by the study’s conclusion () In rats subjected to stress which decreased wound healing rate, topical fluoxetine treatment increased healing rate, leukocyte healing response, and normalized epithelialization and epithelial cell structure (). Bioelectronic delivery of topical fluoxetine in a murine punch wound model increased re-epithelialization by nearly 40% compared to control; this was accompanied by anti-inflammatory M2 macrophage infiltration without pro-inflammatory M1 presence, leading to a reduced M1/M2 ratio over time, indicative of accelerated transition to the reparative phase of wound healing (Li et al., 2024; ). In a porcine model also using bioelectronic delivery, topical fluoxetine produced similar re-epithelialization improvements, also with corresponding improvements in the wound macrophage and cytokine profile (Li et al., 2025).There is an advantage to topical, as opposed to systemic, administration: preclinical data indicate that topical fluoxetine application leads to plasma fluoxetine concentrations that are twofold lower than those achieved with oral fluoxetine at therapeutic neurological doses. Importantly, topical fluoxetine treatment does not affect plasma levels of 5-HT, highlighting its potential for localized therapy with minimal systemic impact (Nguyen et al., 2019).
3.2 Clinical studies
In view of the pro-reparative outcomes noted with agonists of the 5-HT receptors, it may be counterintuitive to propose that antagonists may have a similar result. However, existing clinical studies have investigated ketanserin. Although ketanserin does not increase serotonin levels, its wound healing effects are thought to result from its antiplatelet properties and ability to improve microvascular perfusion, rather than through direct serotonergic signaling (Malinin et al., 2004; ). Separately, iproniazid (an irreversible monoamine oxidase inhibitor that limits the breakdown of serotonin) may promote reparative effects by increasing extracellular 5-HT and enhancing downstream receptor activation (). There are no ongoing or previous clinical trials investigating topical SSRIs for the treatment of chronic wounds (ClinicalTrials.gov).
In a double-blind placebo-controlled clinical trial of various chronic wounds, topical ketanserin 2% BID application was associated with greater re-epithelialization, granulation tissue formation, and wound area reduction rate (). Other studies of topical ketanserin 2% BID for VLUs and DFUs showed similar improvements in wound healing measures in addition to reductions in transudate and erythema (Roelens, 1989). In a double-blind intra-individual comparative study, diabetic participants with ≥2 chronic leg ulcers were randomized to receive topical 2% ketanserin BID on one ulcer and placebo on another ulcer for 8 weeks, in adjunct to SOC. The mean weekly reduction in wound area was significantly greater for ketanserin-treated ulcers (10.25%) compared to placebo-treated ulcers (2.5%) (Quatresooz et al., 2006). One trial investigating topical 10% iproniazid BID for 2 weeks for the treatment of chronic ulcers showed significantly increased rates of healing throughout the trial compared to placebo control (). These studies are summarized in Table 1.
TABLE 1
| Treatment | Participants (n) | Ulcer etiology | Findings | Reference |
|---|---|---|---|---|
| 2% Ketanserin BID | 72 | VLU, Decubitus, or Ischemic | Ketanserin significantly improved granulation (p < 0.05), epithelialization, and reduced wound area faster than placebo, with 36% complete healing by week 8 | |
| 2% Ketanserin BID | 23 | VLU | Ketanserin significantly improved granulation tissue formation compared to placebo (p < 0.05) and showed better epithelialization and healing (p < 0.01) | Roelens (1989) |
| 2% Ketanserin BID | 12 | DFU | Ketanserin significantly reduced ulcer area by 94% (p < 0.001) and improved relative wound area and healing index values from week 4 onward (p < 0.05) | Quatresooz et al. (2006) |
| 2% Ketanserin BID | 140 | DFU | At 12 weeks, ketanserin reduced ulcer area by 87% vs. 63% for placebo, significantly accelerating wound healing | Martínez-de Jesús et al. (1997) |
| 10% Iproniazid BID | 28 | Decubitus or Traumatic | After 1 week, iproniazid-treated lesions healed 52% vs. 27% for saline (p < 0.05), and differences remained significant after 2 weeks |
Clinical studies investigating topical serotonin-modulating medications and chronic wound healing.
4 Selective serotonin reuptake inhibitor-associated cutaneous adverse drug reactions
Oral SSRI-associated cutaneous adverse drug reactions (CADRs) have been reported in the literature. One systematic review of 173 cases found fluoxetine is the most commonly reported SSRI with CADRs, followed by sertraline and paroxetine. CADRs were frequently petechiae, ecchymoses, alopecia, and photo-dermatoses (Masuka et al., 2022). SSRI-related petechiae and ecchymoses may be attributed to SSRI-induced platelet inhibition; however, a study of oral fluoxetine found no significant difference in cutaneous microcirculation compared to control (; ; Mück-Weymann and Rechlin, 1996). Notably, there are no reports of adverse drug reactions for topical SSRI administration. Therefore, topical delivery of SSRIs for the treatment of chronic wounds or wound infections is preferred, to maximize concentrations of the drug at the wound while minimizing systemic absorption. Indeed, these approaches are under investigation, including delivery via hydrogels, microparticles, nano capsules, or bioelectronic delivery devices (Josino et al., 2021; ). Topical use would be expected to minimize serotonergic effects; although, patients on dual antiplatelet therapy or anticoagulation should still be monitored clinically.
5 Conclusion
With their immunomodulatory and antimicrobial properties, repurposing 5-HT modulating pharmacotherapy, including SSRIs, for topical administration may offer significant benefits in treating chronic wounds, as supported by both preclinical and clinical evidence. Further clinical research and pharmacokinetic studies are essential to fully evaluate the potential of SSRIs in improving wound healing outcomes and to establish their role as a viable adjunctive therapeutic option in chronic wound care.
Statements
Author contributions
AB: Conceptualization, Writing – review and editing, Project administration, Writing – original draft, Methodology. AM: Project administration, Writing – original draft, Methodology, Writing – review and editing, Conceptualization. JG-K: Writing – review and editing, Writing – original draft. JDP: Writing – review and editing. CH-V: Writing – review and editing, Writing – original draft. LA: Writing – review and editing, Writing – original draft. SD: Supervision, Conceptualization, Writing – review and editing. RRI: Writing – review and editing, Supervision, Conceptualization.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
This manuscript includes adapted and modified versions of the following icons by Servier Medical Art: “skin-normal,” “platelet-2,” “b-lymphocyte,” “macrophage,” “neutrophil-granulocyte-1,” “lymphoid-stem-cell,” “fibroblast-1,” “keratinocyte-1,” “angiogenesis,” and “collagen-3d.” All original images are available at https://smart.servier.com and are licensed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). The modified versions are published under the same license, with appropriate attribution.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
AhmedS. A.JordanR. L.IsseroffR. R.LenhardJ. R. (2024). Potential synergy of fluoxetine and antibacterial agents against skin and soft tissue pathogens and drug-resistant organisms. Antibiot. (Basel)13, 1165. 10.3390/antibiotics13121165
2
AlmalkiS. G.AgrawalD. K. (2017). ERK signaling is required for VEGF-A/VEGFR2-induced differentiation of porcine adipose-derived mesenchymal stem cells into endothelial cells. Stem Cell Res. Ther.8, 113. 10.1186/s13287-017-0568-4
3
AlstergrenP.ErnbergM.KoppS.LundebergT.TheodorssonE. (1999). TMJ pain in relation to circulating neuropeptide Y, serotonin, and interleukin-1 beta in rheumatoid arthritis. J. Orofac. Pain13, 49–55.
4
AndradeC.SandarshS.ChethanK. B.NageshK. S. (2010). Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J. Clin. Psychiatry71, 1565–1575. 10.4088/JCP.09r05786blu
5
AsefifeyzabadiN.NguyenT.LiH.ZhuK.YangH. Y.BaniyaP.et al (2024). A pro-reparative bioelectronic device for controlled delivery of ions and biomolecules. Wound Repair Regen.32, 709–719. 10.1111/wrr.13191
6
BrodyD. J.GuQ. (2020). Antidepressant use among adults: united States, 2015-2018 NCHS data brief. MD: Hyattsville. code data-end=”628” data-start=”611.
7
BrubakerA. L.SchneiderD. F.KovacsE. J. (2011). Neutrophils and natural killer T cells as negative regulators of wound healing. Expert Rev. Dermatol6, 5–8. 10.1586/edm.10.66
8
CeradiniD. J.KulkarniA. R.CallaghanM. J.TepperO. M.BastidasN.KleinmanM. E.et al (2004). Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med.10, 858–864. 10.1038/nm1075
9
CheongJ. Z. A.JohnsonC. J.WanH.LiuA.KernienJ. F.GibsonA. L. F.et al (2021). Priority effects dictate community structure and alter virulence of fungal-bacterial biofilms. ISME J.15, 2012–2027. 10.1038/s41396-021-00901-5
10
Costa SilvaR. A.Da SilvaC. R.De Andrade NetoJ. B.Da SilvaA. R.CamposR. S.SampaioL. S.et al (2017). In vitro anti-candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates. Microb. Pathog.107, 341–348. 10.1016/j.micpath.2017.04.008
11
DafinoneM. E.LyleR. E.LeeC.MehtaA.DahleS. E.IsseroffR. R. (2025). Non-antibiotic approaches to mitigating wound infections: potential for SSRIs and adrenergic antagonists as emerging therapeutics. Wound Repair Regen.33, e13240. 10.1111/wrr.13240
12
Di RossoM. E.PalumboM. L.GenaroA. M. (2016). Immunomodulatory effects of fluoxetine: a new potential pharmacological action for a classic antidepressant drug?Pharmacol. Res.109, 101–107. 10.1016/j.phrs.2015.11.021
13
Dos SantosS. B. F.PereiraS. A.RodriguesF. A. M.Da SilvaA. C. C.De AlmeidaR. R.SousaA. C. C.et al (2020). Antibacterial activity of fluoxetine-loaded starch nanocapsules. Int. J. Biol. Macromol.164, 2813–2817. 10.1016/j.ijbiomac.2020.08.184
14
DuerschmiedD.SuidanG. L.DemersM.HerrN.CarboC.BrillA.et al (2013). Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood121, 1008–1015. 10.1182/blood-2012-06-437392
15
EdinoffA. N.RaveendranK.ColonM. A.ThomasB. H.TrettinK. A.HuntG. W.et al (2022). Selective serotonin reuptake inhibitors and associated bleeding risks: a narrative and clinical review. Health Psychol. Res.10, 39580. 10.52965/001c.39580
16
EnochS.LeaperD. J. (2008). “Basic science of wound healing,”, 26. Oxford, 31–37. 10.1016/j.mpsur.2007.11.005Surgery
17
EskelandS.HalvorsenJ. A.TanumL. (2017). Antidepressants have anti-inflammatory effects that may be relevant to dermatology: a systematic review. Acta Derm. Venereol.97, 897–905. 10.2340/00015555-2702
18
FarahaniR. M.SadrK.RadJ. S.MesgariM. (2007). Fluoxetine enhances cutaneous wound healing in chronically stressed wistar rats. Adv. Skin. Wound Care20, 157–165. 10.1097/01.ASW.0000262710.59293.6b
19
FlaumenhaftR.De CeunynckK. (2017). Targeting PAR1: now what?Trends Pharmacol. Sci.38, 701–716. 10.1016/j.tips.2017.05.001
20
FrankM. G.HendricksS. E.JohnsonD. R.WieselerJ. L.BurkeW. J. (1999). Antidepressants augment natural killer cell activity: in vivo and in vitro. Neuropsychobiology39, 18–24. 10.1159/000026555
21
GillmanP. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br. J. Anaesth.95, 434–441. 10.1093/bja/aei210
22
GobinV.Van SteendamK.FeveryS.TillemanK.BilliauA. D.DenysD.et al (2013). Fluoxetine reduces murine graft-versus-host disease by induction of t cell immunosuppression. J. Neuroimmune Pharmacol.8, 934–943. 10.1007/s11481-013-9463-7
23
GoldsteinH. S.WolcottM. W.RosensteinI. N. (1962). Iproniazid in healing of chronic topical ulcers. Arch. Surg.85, 1011–1015. 10.1001/archsurg.1962.01310060147026
24
GompelmanM.Van AstenS. A. V.PetersE. J. G. (2016). Update on the role of infection and biofilms in wound healing: pathophysiology and treatment. Plast. Reconstr. Surg.138, 61S-70S–70S. 10.1097/PRS.0000000000002679
25
Gonzalez De ValdiviaE.BroselidS.KahnR.OldeB.Leeb-LundbergL. M. F. (2017). G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms. J. Biol. Chem.292, 9932–9943. 10.1074/jbc.M116.765875
26
GreesonJ. M.GettesD. R.SpitsinS.DubéB.BentonT. D.LynchK. G.et al (2016). The selective serotonin reuptake inhibitor citalopram decreases human immunodeficiency virus receptor and coreceptor expression in immune cells. Biol. Psychiatry80, 33–39. 10.1016/j.biopsych.2015.11.003
27
GuoP.TaiY.WangM.SunH.ZhangL.WeiW.et al (2022). Gα12 and Gα13: versatility in physiology and pathology. Front. Cell Dev. Biol.10, 809425. 10.3389/fcell.2022.809425
28
HavranW. L.JamesonJ. M. (2010). Epidermal T cells and wound healing. J. Immunol.184, 5423–5428. 10.4049/jimmunol.0902733
29
HednerT.PerssonB. (1988). Effects of a new serotonin antagonist, ketanserin, in experimental and clinical hypertension. Am. J. Hypertens.1, 317S-323S–323S. 10.1093/ajh/1.3.317s
30
HuangZ.MiaoX.LuanY.ZhuL.KongF.LuQ.et al (2015). PAR1‐stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4‐stimulated platelet releasate. J. Thrombosis Haemostasis13, 465–476. 10.1111/jth.12815
31
IwabayashiM.TaniyamaY.SanadaF.AzumaJ.IekushiK.KusunokiH.et al (2012). Role of serotonin in angiogenesis: induction of angiogenesis by sarpogrelate via endothelial 5-HT1B/Akt/eNOS pathway in diabetic mice. Atherosclerosis220, 337–342. 10.1016/j.atherosclerosis.2011.10.042
32
JanssenP. A. J.JanssenH.CauwenberghG.DonckerP. D.BeuleK. D.LewiP.et al (1989). Use of topical ketanserin in the treatment of skin ulcers: a double-blind study. J. Am. Acad. Dermatology21, 85–90. 10.1016/s0190-9622(89)70153-5
33
JosinoM. A. A.Rocha Da SilvaC.De Andrade NetoJ. B.BarrosoF. D. D.Juvêncio Da SilvaL.CavalcantiB. C.et al (2021). Development and in vitro evaluation of microparticles of fluoxetine in galactomannan against biofilms of S. aureus methicilin resistant. Carbohydr. Polym.252, 117184. 10.1016/j.carbpol.2020.117184
34
KieckaA.SzczepanikM. (2022). The potential action of SSRIs in the treatment of skin diseases including atopic dermatitis and slow-healing wounds. Pharmacol. Rep.74, 947–955. 10.1007/s43440-022-00423-7
35
KuberaM.LinA. H.KenisG.BosmansE.Van BockstaeleD.MaesM. (2001). Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J. Clin. Psychopharmacol.21, 199–206. 10.1097/00004714-200104000-00012
36
LabergeS.CruikshankW. W.BeerD. J.CenterD. M. (1996). Secretion of IL-16 (lymphocyte chemoattractant factor) from serotonin-stimulated CD8+ T cells in vitro. J. Immunol.156, 310–315. 10.4049/jimmunol.156.1.310
37
LenzG.GonçalvesD.LuoZ.AvruchJ.RodnightR.NearyJ. T. (2001). Extracellular ATP stimulates an inhibitory pathway towards growth factor-induced cRaf-1 and MEKK activation in astrocyte cultures. J. Neurochem.77, 1001–1009. 10.1046/j.1471-4159.2001.00299.x
38
LiM.HouQ.ZhongL.ZhaoY.FuX. (2021). Macrophage related chronic inflammation in non-healing wounds. Front. Immunol.12, 681710. 10.3389/fimmu.2021.681710
39
LiH.YangH.-Y.AsefifeyzabadiN.BaniyaP.LopezA. M.GallegosA.et al (2024). Programmable delivery of fluoxetine via wearable bioelectronics for wound healing in vivo. Adv. Mater. Technol.9, 2301115. 10.1002/admt.202301115
40
LiH.AsefifeyzabadiN.SchorgerK.BaniyaP.YangH.-Y.TebyaniM.et al (2025). Remote-controlled wireless bioelectronics for fluoxetine therapy to promote wound healing in a porcine model. Adv. Mater. Technol.10, 70039. n/a. 10.1002/admt.202500040
41
LinP. K.KollerG. M.DavisG. E. (2023). Elucidating the morphogenic and signaling roles of defined growth factors controlling human endothelial cell lumen formation versus sprouting behavior. Am. J. Pathol.193, 2203–2217. 10.1016/j.ajpath.2023.08.009
42
MachidaT.IizukaK.HirafujiM. (2013). 5-hydroxytryptamine and its receptors in systemic vascular walls. Biol. Pharm. Bull.36, 1416–1419. 10.1248/bpb.b13-00344
43
MaguireK.TuckwellV.PereiraA.DeanB.SinghB. (1993). Significant correlation between 14C-5-HT uptake by and 3H-paroxetine binding to platelets from healthy volunteers. Biol. Psychiatry34, 356–360. 10.1016/0006-3223(93)90179-h
44
MalininA.OshrineB.SerebruanyV. (2004). Treatment with selective serotonin reuptake inhibitors for enhancing wound healing. Med. Hypotheses63, 103–109. 10.1016/j.mehy.2003.10.021
45
Martínez-De JesúsF. R.Morales-GuzmánM.CastañedaM.Pérez-MoralesA.García-AlonsoJ.Mendiola-SeguraI. (1997). Randomized single-blind trial of topical ketanserin for healing acceleration of diabetic foot ulcers. Arch. Med. Res.28, 95–99.
46
MasukaJ. T.MchunuN.MkhizeZ.ThandarY.MosamA. (2022). Selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor associated cutaneous adverse drug reactions: a systematic review of case reports and case series. Australas. J. Dermatol63, e13–e20. 10.1111/ajd.13780
47
Mück-WeymannM.RechlinT. (1996). Reflexes of the cutaneous microcirculation in amitriptyline and in fluoxetine treated patients. Psychopharmacol. Berl.124, 241–244. 10.1007/BF02246663
48
NazimekK.StrobelS.BryniarskiP.KozlowskiM.Filipczak-BryniarskaI.BryniarskiK. (2017). The role of macrophages in anti-inflammatory activity of antidepressant drugs. Immunobiology222, 823–830. 10.1016/j.imbio.2016.07.001
49
NguyenC. M.TartarD. M.BagoodM. D.SoM.NguyenA. V.GallegosA.et al (2019). Topical fluoxetine as a novel therapeutic that improves wound healing in diabetic mice. Diabetes68, 1499–1507. 10.2337/db18-1146
50
OfekK.SchoknechtK.Melamed-BookN.HeinemannU.FriedmanA.SoreqH. (2012). Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling. J. Cell Mol. Med.16, 2736–2744. 10.1111/j.1582-4934.2012.01596.x
51
OliveiraA. S.Martinez-De-OliveiraJ.DondersG. G. G.Palmeira-De-OliveiraR.Palmeira-De-OliveiraA. (2018). Anti-candida activity of antidepressants sertraline and fluoxetine: effect upon pre-formed biofilms. Med. Microbiol. Immunol.207, 195–200. 10.1007/s00430-018-0539-0
52
OpnejaA.KapoorS.StavrouE. X. (2019). Contribution of platelets, the coagulation and fibrinolytic systems to cutaneous wound healing. Thromb. Res.179, 56–63. 10.1016/j.thromres.2019.05.001
53
Olszewska-PazdrakB.CarneyD. H. (2013). Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia. J. Vasc. Res.50, 186–196. 10.1159/000348250
54
OraziG.O'tooleG. A. (2019). It takes A village: mechanisms underlying antimicrobial recalcitrance of polymicrobial biofilms. J. Bacteriol.202, e00530-19. 10.1128/JB.00530-19
55
PállingerE.CsabaG. (2007). Effect of serotonin-acting agents on the serotonin content of immune cells. A peculiar observation. Cell Biochem. Funct.25, 581–583. 10.1002/cbf.1329
56
PereiraC. A.FerreiraN. S.MestrinerF. L.Antunes-RodriguesJ.EvoraP. R.ResstelL. B.et al (2015). Chronic fluoxetine treatment increases NO bioavailability and calcium-sensitive potassium channels activation in rat mesenteric resistance arteries. Eur. J. Pharmacol.765, 375–383. 10.1016/j.ejphar.2015.09.002
57
PereiraR.Dos Santos FontenelleR. O.De BritoE. H. S.De MoraisS. M. (2021). Biofilm of candida albicans: formation, regulation and resistance. J. Appl. Microbiol.131, 11–22. 10.1111/jam.14949
58
PolanskiM.VermeulenM. W.WuJ.KarnovskyM. L. (1995). Muramyl dipeptide mimicry in the regulation of murine macrophage activation by serotonin. Int. J. Immunopharmacol.17, 225–232. 10.1016/0192-0561(94)00097-8
59
PondeN. O.LortalL.RamageG.NaglikJ. R.RichardsonJ. P. (2021). Candida albicans biofilms and polymicrobial interactions. Crit. Rev. Microbiol.47, 91–111. 10.1080/1040841X.2020.1843400
60
QinL.ZhaoD.XuJ.RenX.TerwilligerE. F.ParangiS.et al (2013). The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through Thrombospondin-1. Blood121, 2154–2164. 10.1182/blood-2012-07-443903
61
QuatresoozP.KharfiM.PaquetP.VroomeV.CauwenberghG.PiérardG. E. (2006). Healing effect of ketanserin on chronic leg ulcers in patients with diabetes. J. Eur. Acad. Dermatology Venereol.20, 277–281. 10.1111/j.1468-3083.2006.01422.x
62
RaoteI.BhattacharyaA.PanickerM. M. (2007). “Serotonin 2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways,” in Serotonin receptors in neurobiology. Editor AmitabhaC. (Boca Raton, FL: Taylor & Francis).
63
RaziyevaK.KimY.ZharkinbekovZ.KassymbekK.JimiS.SaparovA. (2021). Immunology of acute and chronic wound healing. Biomolecules11, 700. 10.3390/biom11050700
64
RodriguesD. S.CabralV. P. F.BarbosaA. D.SáL. G. D. A.MoreiraL. E. A.De Andrade NetoJ. B.et al (2023). Sertraline has in vitro activity against both mature and forming biofilms of different candida species. J. Med. Microbiol.72. 10.1099/jmm.0.001664
65
Rodriguez-BarucgQ.GarciaA. A.Garcia-MerinoB.AkinmolaT.Okotie-EbohT.FrancisT.et al (2024). Environmental fluoxetine promotes skin cell proliferation and wound healing. Environ. Pollut.362, 124952. 10.1016/j.envpol.2024.124952
66
RoelensP. (1989). Double-blind placebo-controlled study with topical 2% ketanserin ointment in the treatment of venous ulcers. Dermatologica178, 98–102. 10.1159/000248400
67
SadiqA.ShahA.JeschkeM. G.BeloC.Qasim HayatM.MuradS.et al (2018). The role of serotonin during skin healing in post-thermal injury. Int. J. Mol. Sci.19, 1034. 10.3390/ijms19041034
68
SenC. K. (2019). Human wounds and its burden: an updated compendium of estimates. Adv. Wound Care8, 39–48. 10.1089/wound.2019.0946
69
SenC. K. (2021). Human wound and its burden: updated 2020 compendium of estimates. Adv. Wound Care (New Rochelle)10, 281–292. 10.1089/wound.2021.0026
70
SerebruanyV. L.GurbelP. A.O'connorC. M. (2001). Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharmacol. Res.43, 453–462. 10.1006/phrs.2001.0817
71
SeuwenK.MagnaldoI.PouysségurJ. (1988). Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. Nature335, 254–256. 10.1038/335254a0
72
ShahA.Amini-NikS. (2017). The role of serotoninergic system in skin healing. Int. J. Drug Res. Technol.7, 80–106.
73
ShenoyA. R.DehmelT.StettnerM.KremerD.KieseierB. C.HartungH. P.et al (2013). Citalopram suppresses thymocyte cytokine production. J. Neuroimmunol.262, 46–52. 10.1016/j.jneuroim.2013.06.006
74
SternbergE. M.WednerH. J.LeungM. K.ParkerC. W. (1987). Effect of serotonin (5-HT) and other monoamines on murine macrophages: modulation of interferon-gamma induced phagocytosis. J. Immunol.138, 4360–4365. 10.4049/jimmunol.138.12.4360
75
TsopanoglouN. E.MaragoudakisM. E. (1999). On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J. Biol. Chem.274, 23969–23976. 10.1074/jbc.274.34.23969
76
WallG.Montelongo-JaureguiD.Vidal BonifacioB.Lopez-RibotJ. L.UppuluriP. (2019). Candida albicans biofilm growth and dispersal: contributions to pathogenesis. Curr. Opin. Microbiol.52, 1–6. 10.1016/j.mib.2019.04.001
77
YangS. X.ChenJ. H.JiangX. F.WangQ. L.ChenZ. Q.ZhaoW.et al (2005). Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem. Biophys. Res. Commun.335, 523–528. 10.1016/j.bbrc.2005.07.113
78
ZhaoR.LiangH.ClarkeE.JacksonC.XueM. (2016). Inflammation in chronic wounds. Int. J. Mol. Sci.17, 2085. 10.3390/ijms17122085
Summary
Keywords
wound healing, chronic wounds, serotonin, selective-serotonin reuptake inhibitor, serotonin-modulating pharmacotherapy
Citation
Budhiraja A, Mehta A, Ghebrehiwet-Kuflom J, Patel JD, How-Volkman C, Ali L, Dahle S and Isseroff RR (2025) Serotonin-modulating therapies for the management of chronic wounds. Front. Pharmacol. 16:1656302. doi: 10.3389/fphar.2025.1656302
Received
29 June 2025
Accepted
27 August 2025
Published
22 September 2025
Volume
16 - 2025
Edited by
Sujata Mohanty, All India Institute of Medical Sciences, India
Reviewed by
Igor Prudovsky, Maine Medical Center, United States
Updates
Copyright
© 2025 Budhiraja, Mehta, Ghebrehiwet-Kuflom, Patel, How-Volkman, Ali, Dahle and Isseroff.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Roslyn Rivkah Isseroff, rrisseroff@ucdavis.edu
† These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.