https://orcid.org/0000-0001-6877-8650
Figures
Abstract
Objectives
To examine whether there is a relationship between anxiety and/or depression and wound healing.
Data Sources
Searches were conducted on PsycINFO, MEDLINE, EMBASE, CINAHL and Web of Science on the 06-March-2023.
Methods
Eligible studies explored the effects of anxiety and/or depression on wound healing in adults. Healing outcomes included time to heal and complication rates. Anxiety and depression outcomes were considered separately.
Results
Fifty-five studies were included in the narrative synthesis (26,612,809 participants), and 26 studies in the meta-analysis. Studies utilised a range of observational and experimental designs. Wounds included in the review were: surgical, ulcer, burn and experimental wounds. The narrative synthesis gave mixed results, with some studies noting positive associations between increased anxiety or depression and wound healing, while others did not find an association. Results from the meta-analysis found no significant effect of anxiety on wound healing outcomes. However, depression was associated with significantly higher odds of delayed wound healing, OR = 2.10, [1.02, 4.33]; higher risk of wound complications, RR = 1.30, [1.11, 1.53] and increased risk of wound infection RR = 1.25, [1.09, 1.44].
Conclusion
These findings suggest depression negatively impacts wound healing. There is less evidence for an association with anxiety, but this may be due to less research in this area. Future studies should explore the mechanism of associations between depression and wound healing to inform clinical interventions.
Citation: O’Donovan F, Capobianco L, Taylor-Bennett J, Wells A (2025) Relationships between anxiety, depression and wound healing outcomes in adults: A systematic review and meta-analysis. PLoS One 20(5): e0309683. https://doi.org/10.1371/journal.pone.0309683
Editor: Francesco Savoia, IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori / Skin Cancer Unit, Romagna Institute for the Study of Cancer IRST IRCCS Dino Amadori, ITALY
Received: February 28, 2024; Accepted: February 20, 2025; Published: May 20, 2025
Copyright: © 2025 O’Donovan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data analysed in the study was based on previously published data. Data extracted from included studies and data used for analyses are on request to the corresponding author. Data is available on request from researchoffice@gmmh.nhs.uk
Funding: This review was conducted as part of a Clinical Psychology Doctorate (ClinPsyD) program at the University of Manchester and supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Wound healing is crucial in recovery from injury and surgical wounds. Wound management presents a significant clinical, economic, and social burden and in the UK costs the NHS an estimated £8.3 billion per year [1]. Delayed healing is associated with increased pain, psychological distress, reduced mobility and social isolation [2]. Wound healing is a complex, dynamic, multi-stage process influenced by multiple factors. While the physical health variables that influence healing are relatively well understood (e.g., age, wound type, chronic health conditions; [3]) there is a growing acknowledgement of the impact of psychological factors on healing [4].
Studies suggest common mental health difficulties, such as anxiety and depression may impact the wound healing process in a number of ways. Anxiety and depression can trigger the physiological stress response. This response activates the sympathetic-adrenal-medullary (SAM) and the hypothalamic-pituitary-adrenal (HPA) axes. The SAM axis triggers the release of catecholamines such as noradrenaline and norepinephrine, while the HPA axis secretes glucocorticoids such as cortisol [5]. There is considerable evidence from experimental studies (human and animal) that catecholamine and glucocorticoid production slows wound healing [4]. Moreover, neuropeptides oxytocin and vasopressin have been considered regulators of anxiety and depression symptoms [6], and have also been implicated in wound healing [7], therefore such neuropeptides might be a pathway through which psychological factors impact healing. However, it is also likely that psychological factors may impact through health behaviours. Individuals experiencing adverse emotional states such as anxiety or depression may be more likely to consume alcohol and tobacco, make poor dietary choices, experience poor sleep, and engage in low levels of exercise, all of which have been associated with slower wound healing [8–12].
An issue with existing research is that it often lacks specificity when exploring relationships between psychological factors and wound healing. For example, a previous systematic review looked at the effect of psychological stress defined as “any form of negative psychological state, condition, or experience” ([13] p. 254). While this definition was chosen to reflect the variability in the published literature, such a broad definition may mask differential effects of different psychological states and conflates the concept of stress with emotion.
Given such important limitations, we aimed to examine the effects specifically of negative emotions of anxiety and depression on wound healing, since these are common responses in physical health settings that might be managed through psychological treatment methods. Consequently, the aim of this review is to address the question: do anxiety and/or depression have an effect on wound healing?
Methods
Protocol details and reporting guidelines
The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; ID CRD42021269269). The paper is reported with reference to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) statement [14]. Please see S1 Table for the PRISMA checklist. No ethical approval was requested as the review utilised data from previously published studies in which informed consent was obtained by the primary investigators.
Search strategy
A systematic review was conducted in March 2023 of the following electronic databases: PsycINFO, MEDLINE, EMBASE, CINAHL and Web of Science Search terms were agreed with the authors (FOD, LC, AW). The search strategy included terms relating to anxiety, depression and wound healing. The full search strategy is displayed in S2 Table. Further studies were identified from reference lists of related studies.
Eligibility criteria
Studies were eligible if they were published in a peer-reviewed journal, evaluated wound healing in adult humans and included a validated measure of anxiety and/or depression. Only English language quantitative studies were eligible for inclusion. Studies reported as abstracts in conferences, theses and book chapters were excluded. Similarly, reviews and meta-analyses were excluded.
For this review, a “wound” was defined as a ‘disruption of normal tissue structure and function’ [13]. This encompassed a range of wound types, including clinical wounds (e.g., burns injuries, ulcers, surgical wounds) and experimentally induced wounds (e.g., punch biopsy wound and suction blister). As the outcome of interest was rate of wound healing studies had to include an outcome on wound healing. This included time to heal or whether a wound is classified as healed or not by a time point. It also incorporated indirect measures of wound healing, such as rates of wound complications, wound infections, or wound dehiscence (when a surgical incision wound reopens post operatively).
Psychological factors of interest were anxiety and depression using self-report measures or diagnostic criteria. Anxiety included: anxiety symptoms, anxiety diagnoses, trait anxiety, state anxiety, worry and neuroticism. Depression included depressive symptoms, depression diagnoses, low mood and negative affect. Studies that only included measures of related but distinct concepts (e.g., general distress, stress, or quality of life) were excluded.
Selection process
Searches were saved to EndNote 20 to create a master file of all references. Duplicates were removed using the process described by Bramer and colleagues [15]. All titles and abstracts were screened by one reviewer (FOD) to determine potential eligibility. Full texts were then screened for eligibility by one reviewer (FOD). A second reviewer (JTB) independently screened 20% of the full texts to check for consistency. There was a moderate agreement between the two reviewers (k = 0.46).Disagreements were resolved by discussion.
Data collection process and data items
Data extraction was conducted by the first author. Study characteristics were extracted which included: study citation, year of publication, study location, setting, design, participant details (i.e., number of participants, gender and age), measure of anxiety and/or depression, details of wound (e.g., punch biopsy, surgical wounds), wound healing outcome, and key results. Any unclear or missing data was documented in the extraction form.
Quality appraisal
Risk of bias of included studies was assessed by the first author using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies [16]. This tool was selected because it has good reliability and validity and can be applied to different study designs [17]. Risk of bias was assessed at the study level. No studies were excluded based on their quality appraisal rating. No weighting was provided to studies based on quality ratings.
Data synthesis
All included studies were incorporated into a narrative summary and tabulation of findings. Tables were grouped by wound types. Narrative syntheses were grouped a) by psychological variable (anxiety or depression) and b) by wound outcome measure.
Where possible studies were included in a meta-analysis. Meta analyses were conducted on R [18] using the meta package [19], as guided by Harrer and colleagues [20]. All analytic code and data is available to view/download from Open Science Framework (https://osf.io/m9nre/). Studies were pooled and analysed using a random-effects (RE) model to obtain the summary effect estimates and forest plots were created. Heterogeneity between studies was explored through visual inspection of the forest plots and using the I2 statistic. When clarification on heterogeneous data was required, authors were contacted.
Meta-analyses were conducted separately for different wound healing outcomes (e.g., healing time combined separately from infection rate). Where possible data were converted to common metrics to be combined, except in cases where there was insufficient data or measures were conceptually distinct (i.e., studies using Hazard Ratios (HRs) or Odds Ratios (ORs); see Harrer et al [20]). In order to convert HRs and ORs to similar log scales and calculate standard error, the Revman Calculator function was used [21]. In addition, some studies calculated the odds of wound healing [22], whereas others calculated the odds of not healing [23]. In these scenarios, some of the ratios were inverted to facilitate meta-analytic synthesis.
A number of included studies analysed data from the same large-scale databases, albeit using different time windows. In this scenario, both studies were described in the narrative synthesis. However, in the meta-analyses if more than one study reported data from the same database, examining the same wound type, only the study with the largest sample size was included in the meta-analytic synthesis, to avoid double counting of participants. See comment by Tarp et al., for a brief discussion on analytical issues presented when combining multiple analyses of the same database [24]
Results
Study selection
A flow diagram outlining the study selection process is outlined in Fig 1. From the database searches and journal hand searching, 7,479 records were identified. Duplicates were removed, leaving 6,568 records remaining. Following title and abstract screening, 6,352 records were excluded, and 216 records remained for full text screening. All except one full text were obtained. Fifty-five studies were included in the review, seven of which explored the impact of anxiety only, 34 examined the effects of depression only, and 14 looked at the impact of both anxiety and depression. Of the 55 studies included in the review, 26 were included in the subsequent meta-analyses. Wherein published papers included reports of multiple samples, the sample relevant to the current research question were described [25]. Likewise, features of the design that are relevant to the current research question were described. For example, Monami [26] and colleagues describe a study that has an overall follow up time of 12 months, however, only a 6-month follow-up period was used for their analysis on wound healing, therefore the study is described using a 6-month follow up period throughout the review. Some studies employed interventions in certain groups of participants but analysed the association between psychological factors and wound healing for the whole study population. These studies were considered eligible for inclusion [27–29]. One study that was initially selected reported unusual results of no wound complications in large samples of anxiety (n = 139,267) or depression (n = 342,769) patients following surgery [30]. The authors were contacted, and they explained that their study only assessed complications at time of surgery and not follow up and they explained that their study did not assess wound healing [30]. Therefore, the study in question was not included in the present review.
Description of included studies
The studies included various types of wounds. Thirty studies examined healing of surgical wounds including: ankle surgery [31,32], knee or hip arthroplasty [33–39], total shoulder arthroplasty [40,41], spinal surgery [42–44], dental procedures [45–47], cardiac surgeries including Coronary Artery Bypass Graft (CABG, [48–52]) or other mixed surgeries [53–60]. Fourteen studies examined healing of various types of ulcers, namely: leg ulcers [61–67], foot ulcers [22,26], duodenal ulcer [25,68], or mixed ulcers [23,69,70]. Two studies looked at healing in burn wounds [71,72]. Nine studies created wounds experimentally to track healing, these wounds included suction blister wounds on participants’ forearms [27,73,74], punch biopsy wounds on participants’ arms [28,75,76], a circular wound created on participants’ oral hard palate [77] and a tape stripping paradigm wherein skin barrier function was disrupted using tape stripping procedure on participants” arms. Rate of recovery was then measured using Transepidermal Water Loss (TEWL; [29,78]). TEWL provides a measure of the skin’s ability to prevent water loss. TEWL decreases as the skin barrier is restored, thereby giving an objective measure of skin barrier recovery rate following skin disruption/wounding.
Twenty-seven of the studies utilised prospective designs and monitored healing for a period of time ranging from 2-hour follow up of experimentally induced skin injury [29,78] to tracking ulcer healing for up to 1.5 years [70,79]. Nineteen of the studies employed retrospective cohort designs. Two studies used retrospective chart reviews and a single study utilised a retrospective case control design [71]. Three of the included studies were cross sectional and three were randomised controlled trial (RCT) designs.
Study sample sizes ranged from 17 to 8,710,630 participants. Across all studies, there was a total sample size of 26,612,809. However, it is not possible to verify that these are all unique individuals. Various studies used large scale databases such as the Truven Marketscan database (albeit using different time windows) therefore it is possible that some participants could be double counted. Not all studies reported the ratio of participants’ gender, but of those that did, across all studies 58.18% of participants were female. Similarly, not all studies reported mean age of participants, but in studies that did report this, the mean age range per study was 20.1 [78] to 79.7 [44].
Further detail on the characteristics and results of included studies are displayed in Table 1 for surgical wounds, Table 2 for ulcer and burn wounds, and Table 3 for experimental wounds.
Quality appraisal
Overall results of the quality appraisal are displayed in Tables 1–3. Eighteen of the included studies were rated as strong, 26 as moderate and 11 were rated as weak. Over half (16 out of 26) of the studies on surgical wounds were rated as strong. This is because several of them utilised population-based cohort study designs, meaning that selection bias was likely to be low and data collection methods were largely deemed as valid and reliable (see Table 1). More than half of the studies on experimental wounds (five out of nine) were rated as weak, this is largely because participants self-referred to these studies, meaning that selection bias may have been an issue and because there was not extensive control of confounding variables (see Table 3). Full quality ratings for each of the components of the appraisal tool are displayed in S3 Table.
Anxiety and wound healing: Narrative synthesis
Twenty-one of the included studies examined associations between anxiety and healing in various types of surgical, clinical, and experimental wounds [22,25,27,37,39,43,45–47,51,52,54,56,57,59,64,67,68,70,72,79]. The studies employed a range of study designs including retrospective cohort, prospective, cross-sectional and RCT designs. The studies utilised various measures of anxiety including the presence or absence of a diagnosed anxiety disorder as recorded in clinical notes [37,39,43,52], trait anxiety measures [45,46] or validated anxiety symptom measures [22,27,56,57,59,64,67,70,72]. Other studies devised or adapted anxiety measures for the study [45,68]. Two studies utilised visual analogue scales to quantify worry/anxiety prior to surgery [47,54]. Two studies examined the impact of neuroticism [25,51], while one study explored the effect of attachment anxiety, which was described by the researchers as the degree to which individuals worry about rejection or loss of closeness in a romantic relationship [79].
Associations between anxiety and rate of wound healing.
Eight studies examined whether there was an association between anxiety and time for (ulcer, burn or surgical) wounds to heal, with mixed results [22,25,59,64,67,68,70,72]. The majority of these studies were rated as moderate (k = 5) in the quality appraisal, two were rated as strong and one was rated as weak. Four studies found that self-report anxiety was associated with incomplete healing (OR = 1.03; 67), delayed healing (Mann Whitney test Z: 1.98; 63), healing time (r = -0.315; 58) or reduced likelihood of spontaneous healing (p < 0.05, Jonckheere-Terpstra test for trend; 25) of ulcers. In contrast, four studies found that self-report anxiety was not predictive of time required to heal for leg ulcer, foot ulcer or burn wounds [22,67,70,72].
Effect of anxiety on change in wound surface area over time.
Two studies evaluated whether anxiety predicted change in ulcer area over time [22,67]. In studies that were rated as moderate and strong respectively, it was found that anxiety did not predict changes in wound surface area for diabetic foot ulcers (F = 1.297, p = .281; [22]) or venous leg ulcers (β = -0.18, p = .53; [67]).
Associations between anxiety and clinician rating of healing status.
Three studies, rated as weak to moderate in quality, explored associations between self-report anxiety and clinicians’ assessment of healing from dental surgery/treatment using novel rating scales [45–47]. Kloostra and colleagues [46] found a negative moderate correlation (r = -.316) between trait anxiety and wound healing but no other significant correlations were found (correlation coefficients range: -.226 to.12; [45,47]).
Anxiety and rates of wound complications including infections.
Seven studies explored the influence of anxiety on wound complications and infections [37,39,43,51,52,56,57].
Four studies, rated as moderate to strong in quality, explored whether anxiety was related to rates of wound complications and related outcomes post-surgery. In one study, rates of wound complications were slightly higher in patients with anxiety (2%) compared to patients with no psychiatric disorder (1.7%) however whether this difference was statistically significant was not reported [43]. In the three other studies anxiety was not associated with significantly higher rates of post-surgical wound dehiscence or re-hospitalisations due to wound infection [37,39,51].
Three studies, rated as moderate, explored whether anxiety was associated with rates of surgical wound infection. They found no association between anxiety and rates of local wound infection [56], infection at the surgical site [57] or deep sternal wound infection [52].
Anxiety and rate of recovery of skin function.
Two studies, rated as moderate and weak in quality respectively, examined the rate of skin barrier recovery following experimental wounding/skin disruption, as measured by TEWL [27,79]. Gouin and colleagues [27] found that anxiety, did not predict the rate of healing of suction blisters. While Robles and colleagues [79] found that, across two laboratory visits, attachment anxiety predicted faster skin barrier recovery in women (β = 0.13, p = .006), but not in men (β = -0.11, p = .06) following skin disruption using tape-stripping.
Anxiety and biomarkers of wound healing.
Broadbent and colleagues [54] examined wound healing by tracking cytokine levels in wound fluid post-surgery, in a study rated as moderate in quality. They found that anxiety predicted lower levels of metalloproteinase-9 (β = −.38, p = .03) but did not predict levels of interleukin-1 or interleukin-6.
Meta-analytic synthesis: Anxiety and wound healing
Five studies were included in two meta-analytic syntheses exploring the associations between anxiety and wound healing [39,43,45–47].
Correlations between anxiety and clinicians’ rating of wound healing.
Three studies, which evaluated the correlations between anxiety and clinician rated healing in dental procedures were synthesised in a meta-analysis. Two studies measured trait anxiety using either a novel two question scale [45] or the State-Trait Anxiety Inventory (STAI; [46, 88]), while one study measured preoperative anxiety using a visual analogue scale [47]. The quality appraisal rated them as weak [45,47] to moderate in quality [46]. The statistical synthesis did not indicate a significant correlation between anxiety and wound healing ratings, r = -0.13, 95% CI [-0.58, 0.38], see Fig 2.
Anxiety and risk of wound complications/dehiscence
Two studies that explored the relationship between a recorded anxiety diagnosis and rates of wound complications following spinal surgery [43] or wound dehiscence following knee or hip arthroplasty [39] were included in a meta-analytic synthesis. The studies were classified as strong [39]and moderate [43] in the quality appraisal. In the pooled analysis, a diagnosis of anxiety did not significantly increase the risk of wound complications/dehiscence RR = 1.19, 95% CI [0.80, 1.76], see Fig 3.
Depression and wound healing: Narrative synthesis
Forty-eight of the included studies explored associations between depression and wound healing outcomes, utilising a range of wound types including surgical, ulcer, burn and experimental wounds [22,23,26–29,31–44,46,48–53,55,58–74,76–78]; see Tables 1–3). These studies utilised various research designs including: retrospective cohort, prospective, cross-sectional, retrospective chart review, retrospective case controlled and RCTs. Depression was identified/quantified in several ways. Twenty-three studies compared wound healing outcomes in participants with a diagnosis of depression versus participants with no psychiatric diagnosis (e.g., [37,42,53]). Other studies utilised validated measures of depression symptomology (e.g., [37,42,53]), such as the Geriatric Depression Scale (GDS; [90]), the Beck Depression Inventory (BDI; [89]) or the Centre for Epidemiologic Studies Depression Scale (CES-D; [81]). Other studies assessed the level of negative affect using the Positive and Negative affect Schedule (PANAS; [96]; e.g., [73,76]). One study created a novel composite depression measure [68].
Association between depression and rate of wound healing.
Seventeen studies explored the relationship between depression and rate of wound healing, with mixed results [22,23,26,28,34,59,63–68,70–72,76,78]). Twelve of these studies were rated as moderate in the quality appraisal, four were rated as strong, and one was rated as weak [64], see Tables 1–3.
Two studies found that depressive symptoms were associated with delayed healing of leg ulcers [64, 65]. However, four studies found no association between depression and healing time for duodenal or foot/leg ulcers, or surgical wounds [59,67,68,70]. In burns patients, Wilson and colleagues [72] found a small positive correlation (ρ = .28) between depressive symptoms and healing time, whereas Tarrier and colleagues [71] found that patients with depression did not differ from matched controls in time taken for burns to heal. In experimentally induced wounds, one study found that individuals with high self-report depressive symptoms were over 3.5 times more likely that those with low depressive symptoms to exhibit slower than median healing rate of a wound on the oral hard palate (OR = 3.68, 95% CI [1.37, 9.89]; [78]). However, two further studies found no association between depressive symptoms and healing time for punch biopsy wounds [28,76].
Six studies examined whether there was an association between depression and whether an ulcer was classified as healed or unhealed by the end of the study follow-up period. Two of these studies found that patients with higher depressive scores had higher risk of leg (HR = 0.47, 95% CI [0.23, 0.96]; [65]) or foot ulcers (HR = 2.00, 95% CI [1.131, 3.542]; [26]) at 6-month follow-up. None of the other four studies found a significant association between depression and ulcer healing in studies with 6-month [22,23,63] or 12-month follow-up [66]. One study found that patients with depressive disorder had higher odds of surgical wounds not being healed by 90 day follow up [34].
Depression and change in wound surface area over time.
Three studies, which were rated as moderate [22,78] to strong [67] in quality, explored whether depression was associated with change in wound surface area over time. All three demonstrated an effect of depression: Depression had a small effect on wound size (F(8,166) = 2.51; p = .01) in an experimental wound model [78] and had a moderate effect on changes in ulcer diabetic foot size over time (d = 0.31; [22]). Furthermore, depression significantly predicted change in wound area per week in venous leg ulcers (β= -0.514, p = .039; [67]).
Association between depression and clinician rated healing status.
One study, which was rated as moderate in the quality appraisal, investigated an association between depression and clinician ratings of wound healing following periodontal treatment [46]. Preoperative depression was not significantly associated with dentist rating of wound healing (r = -.256, p = .094), wound epithelialization (r = -.294, p = .053), or wound integrity (r = -.288, p = .064).
Depression and wound complications including infections.
Overall, 24 of the included studies examined the association between depression and wound complications [31–33,35–43,48,49–53,55,58–62]. All of the studies related to surgical or ulcer wounds.
Nine studies explored the association between depression and overall wound complication rate post-surgery, all of which were rated as moderate to strong in the quality appraisal. Five studies found that patients with depression had higher odds of wound complications than non-depressed patients following ankle surgery (OR = 1.13; 95% CI [1.00, 1.28]; [31]), total ankle arthroplasty (TAA; OR = 1.59, 95% CI [1.11, 2.29]; [32]), total shoulder arthroplasty (TSA; OR = R = 1.41, 95% CI [1.04–1.90]; [40]), breast reconstruction following mastectomy (OR = 1.6, 95% CI [1.41, 1.8]; [55]), or CABG (OR = 3.71, 95% CI [1.15, 12.0]; [50]). Menendez and colleagues [43] reported that depressed patients had higher rates of wound complications (1.9%) that non-depressed (1.7%) patients but did not report a statistical comparison of the groups. Britteon and colleagues [53] found that previously diagnosed depression was not associated with odds of hospital-reported wound complications (OR = 0.96, 95% CI [0.69, 1.33] but, was associated with higher odds of readmission rates for surgical wound complication (OR = 1.37, 95% CI [1.11, 1.69]). Two studies found that no difference in odds of wound complications between depressed and non-depressed patients following total knee arthroplasty (TKA; OR = 0.807, 95% CI [0.317, 2.053]; [36]) or total hip arthroplasty (THA; OR = 0.98, 95% CI [0.85, 1.15]; [38]).
Four studies, rated as moderate to strong in the quality appraisal, explored rates of wound dehiscence in depressed versus non depressed patients post-surgery, with mixed findings. Zalikha and colleagues [39] found that depressed patients had significantly higher odds of experiencing wound dehiscence compared to patients with no psychiatric diagnosis following THA or TKA (OR = 1.21, 95% CI [1.05, 1.40]. On the other hand, three studies found no difference between depressed and non-depressed patients’ rates of wound dehiscence following TAA (OR = 1.58, 95% CI [0.93, 2.58]; [32]), (TKA (0.1% versus 0.07% respectively; [37]) or TSA (0.04% versus 0.02% respectively, p = .908; [40]). Further, Mollon and colleagues [40] found no differences between depressed and non-depressed patients in rates of wound haematoma or seroma following TSA (0.04% vs 0.02% respectively, p = .653).
Studies exploring the association between depression and wound infection also generated mixed results and were rated as moderate to strong in the quality appraisal. Diagnosed depression was associated with a higher risk of infection in chronic leg ulcers in a cross-sectional study (β = 1.02, p = .035; [61]), but this finding was not replicated in a subsequent longitudinal study by the same research group (β = 0.58, p = .062; [62]). Depression was associated with a higher risk of wound infection in colectomy (OR = 1.08, 95% CI; [1.03, 1.12]) and proctectomy (OR = 1.19, 95% CI [1.05, 1.35]) patients [58] and patients with high depressive symptoms were more likely to be re-hospitalised for sternal wound infection following CABG (OR = 5.38, 95% CI [1.67, 17.37]; [51]). However, three studies did not find a statistically significant effect of depression on risk of wound infection following CABG (OR = 1.99, 95% CI [0.99, 1.46]; [48,49]) or colectomy (OR = 1.05, 95% CI [0.96, 1.14]; [60]).
In the context infection characteristics, two studies found that rates of superficial surgical site infection (SSI) were higher in depressed patients ([32,35], while three others did not [38,42,44]). Two studies found no impact of depression on rates of deep wound infections [42,53]. The association between a diagnosis of depression and prosthetic joint infections was explored in five studies. Studies led by Bozic [33], Lunati [40] and Wilson [72] found that depressed patients had greater risk/odds of prosthetic joint infections following TKA (HR = 1.28, 95% CI [1.08, 1.51]), TSA (OR = 1.41, 95% CI [1.04, 1.90]), and TAA respectively (OR = 1.82, 95% CI [1.06, 3.15]). On the other hand, two other studies found that depressed patients did not differ from non-depressed patients in rates of prosthetic joint infections following TKA (OR = 0.762, 95% CI [0.366, 1.589]; [36]) or THA (OR = 1.17, 95% CI [0.99, 1.39]; [38]).
One study took a slightly different approach and explored the relationship between depressive symptoms and the rate of requiring local medical treatment for peripheral arterial disease limb lesion wounds [69]. The requirement of additional treatment was within a 6 month period following the initial treatment or hospitalisation and taken to indicate poor wound healing. This study, which was rated as weak in the quality appraisal, found that depression was not related to the rate of requiring medical treatment as identified in medical notes.
Depression and rate of recovery of skin function.
Three studies, that were rated weak to moderate in the quality appraisal, utilised the TEWL method to explore associations between depressive symptoms and rate of recovery of skin function. Depression did not predict healing in suction blister wounds [27], punch biopsy wounds (β = -0.131, p = .318; [77]), nor tape stripping (β = 2.03, SE = 4.21; [29]).
Depression and biomarkers of wound healing.
Two studies explored the relationship between depressive symptoms and biomarkers of wound healing in experimentally created suction blister wounds [73,74]. Both studies were rated as weak in the quality appraisal. Yang and colleagues [74]) found that depressive symptoms were not related to the expression of healing biomarkers in wound fluid. On the other hand, Glaser and colleagues [73] found that negative affect was higher in subjects who had low levels of interleukin-1 alpha and interleukin -8 in blister chamber wound fluid, compared to those with high levels of these proinflammatory cytokines (F(1, 27) = 5.26, p = .03).
Meta-analytic synthesis: Depression and wound healing
Twenty-three studies were included in four meta-analytic syntheses investigating the relationship between depression and wound healing [22,23,26,31,32,35,36,38–44,48,50,52,55,58–60,65,78]. In order to further explore the results obtained, subgroup analyses were carried out on meta-analyses that contained at least 10 studies. The studies were grouped by type of surgery, the results of which can be found in S1 File. In addition, sources of herterogeneity were further explored using regression analyses, the results of which can be found in S1 File.
Depression and time to wound healing.
Three studies used Hazard Ratio’s (HRs) to explore whether depression influenced ulcer or [26,65] surgical wound healing [59]. All three studies identified depression using depressive symptom outcome measure scales. The studies were rated as strong [59,65] and moderate [26] in the quality appraisal. The pooled analysis did not indicate that depression was associated with increased time until wound healing HR = 0.67, 95% CI [0.40, 1.12], see Fig 4.
Depression and the likelihood of delayed wound healing.
Three studies examined if individuals with high versus low depression had different odds of experimental [78] or ulcer [22,23] wounds healing. Two studies utilized validated measures of depressive symptoms (BDI, [78]; HADS, [22]) while one study utilized diagnosis of depression [23]. All studies were rated as moderate in the quality appraisal. The pooled analysis revealed that individuals with depression/high depressive symptoms were twice as likely to display slower wound healing OR = 2.10, 95% CI [1.02, 4.33], see Fig 5.
Depression and risk of wound complications/dehiscence.
Data from ten studies were combined to look at the relationship between depression and rates of wound complications [31,32,36,38,40,43,50,55] or wound dehiscence in surgical wounds [39,41]. Surgeries included ankle surgery [31,32], TKA and/or THA [36,38,39], TSA [40,41], spinal surgery [43]), CABG [50] and breast reconstruction after mastectomy [55]. Eight studies compared individuals with or without a depression diagnosis, except the studies by Mollon and colleagues [41] who compared participant with or without a history of clinical depression and the study by Doering and colleagues [50] which categorised participants based on their depressive scores on the Multiple Affect Adjective Check List [82]. The studies contributing to this analysis were rated moderate and strong in the quality appraisal. Overall, depression was associated with a greater risk of wound complications/dehiscence, RR = 1.30, 95% CI [1.11, 1.53], see Fig 6.
Depression and risk of wound infection.
We examined the association between depression and rates of wound infection in 11 studies [32,35,36,38,40,42,44,48,52,58,60]. Studies were surgical and included a range of surgeries, including cardiac, spinal surgery, arthroscopy surgeries and proctectomy. Nine of the included studies classified participants based on whethre they had a current or historic diagnosis of depression, while two used depressive symptom outcome measures to categorise participants [44,48]. The types of infection outcomes contributing in this statistical synthesis include general wound infection [58,60], SSI ([32,35,38,42,44], PJIs [36,40], deep sternal wound infection [52] and leg wound infections [48]. The quality of the studies included were rated as moderate and strong. This meta-analysis revealed that individuals with depression had a significantly higher risk of developing wound infections, compared to those without depression, RR = 1.25, 95% CI [1.09, 1.44], see Fig 7.
Discussion
Anxiety and depression showed a mixed pattern of relationships with wound healing. Of the 21 studies that examined whether there was a relationship between anxiety and wound healing, four found an association, four showed mixed results while 13 demonstrated no significant relationship. The results of the meta-analyses did not indicate that anxiety was associated with slowed wound healing or increased the risk of wound complications (i.e., rate of complication, dehiscence, re-hospitalization).
Substantially more studies explored the relationship between wound healing and depression (k = 48). Nineteen studies found an association between depression and wound healing, 25 found no significant relationships and four found mixed results. Of the 19 studies that found an association between depression and wound healing outcomes, approximately half (k = 10) used diagnoses of depression and the other half (k = 9) used depressive symptom measures. One of the current meta-analytic outcomes indicated that depressed individuals did not have significantly longer time to heal, while, conversely, another meta-analytic outcome demonstrated that individuals with depression were more likely to experience delayed wound healing. Furthermore, depressed individuals overall had higher rates of wound complications and wound infections. Three studies indicated that depression was associated with slower changes in wound surface area (indicating slower healing). There was no evidence that depression was associated with clinician rating of healing status.
Findings from the narrative synthesis suggest more consistent results for depression than anxiety on wound healing outcomes. However, the results are mixed with approximately half of studies demonstrating an association between depression and poorer wound healing outcomes. The meta-analysis provide greater clarity. Whilst there were no significant effects for anxiety, significant effects were found for depression. Greater depression was associated with more wound complications, more infections and slower wound healing with significant but small effects observed.
The mechanism by which depression may impact wound healing remains to be elucidated. It is possible that depression may exert direct effects on physiological processes underlying wound healing. Depression has been shown to impair the immune response through various cellular, molecular and immunological processes [97]. Importantly, inflammation and HPA axis hyperactivity have been identified as key factors in the neurobiology of depression [98] as well as key elements in the wound healing process [4]. A recent animal study explored the mechanism by which depression influences wound healing in rats [99]. This study found that depression had effects on inflammation and delayed wound healing and that antidepressant treatment counteracted these effects. Notably, alleviating the inflammatory response was one of the mechanisms by which the chosen antidepressant worked [99]. However, as the authors note, the effect of inflammation on wound healing is complex. Some level of inflammation is helpful and necessary for wound healing, however the level inflammation associated with depression may have a deleterious effect.
Another potential mechanism through which depression may impact wound healing is through cognitive processes. The perseverative cognition hypothesis [100] posits that worry (a feature of anxiety) and rumination (a feature of depression) are types of perseverative cognition that are relevant factors in somatic health. The authors present evidence that such cognitions have physiological sequelae that are associated with adverse health outcomes. Within such a model, perseverative cognition could be a moderator of the effect of emotion on bodily systems. Perseverative cognition prolongs stress-related psychological and physiological activation, by reactivating responses after a stressor has been experienced, slowing recovery, or intensifying short-term responses.
A further plausible mechanism by which depression may influence wound healing is through depression symptoms influencing health-related behaviours. Symptoms of depression include low levels of energy, insight, motivation, initiation, psychomotor slowing and disturbance of sleep and appetite [101]. Such symptoms could impact wound healing. For example, it has been shown that relatively modest sleep disturbance and nutritional deficiencies can impede, and delay wound healing [102,103].; On the other hand, exercise has been shown to accelerate wound healing [10], but activity levels can be reduced in depression. Furthermore, depressed patients are three times more likely than nondepressed patients to be noncompliant with medical treatment [104], meaning that patients with depression may not be engaging in recommended wound care procedures.
A better understanding of the mechanisms behind an association between depression and wound healing could help in developing integrated psycho-medical interventions. For example, medications could be used to target inflammation coupled with psychological interventions that target specific depressive symptoms/behaviours (e.g., increase exercise) or target depression and reduce perseverative cognitions (e.g., metacognitive therapy; [105]). There is evidence that a range of different psychological interventions can improve the rate of wound healing [106]. With the strongest effects seen in relaxation interventions for surgical wounds [106].
The quality of the studies included in this review was variable, as judged by the risk of bias assessments. The primary studies included employed different methods, research designs, and made different analytic decisions. For example, three of the included ulcer studies used the HADS [84] in different ways: one study classified anxiety or depression status using a cut-off score of 11 [22], another used a cut-off score of 9 to indicate caseness [64], while a third analysed HADS as a continuous variable [67]. Such variation in analytic decisions complicates interpretation of depression effects across studies.
The way in which results were reported limited statistical synthesis, with less than half of the studies in the narrative review contributing to the meta-analysis. This was largely due to insufficient statistical detail being reported. This raises important concerns over generalizability and increases the chance of bias. However, all outcomes relevant to the research question were included in the narrative and tabular synthesis, in an attempt to provide an accurate and rounded overview of the literature.
The strengths of this review include a comprehensive literature search and the consideration of distinct wound outcomes and psychological factors. By considering anxiety and depression separately, this review provides clarity on the impact of different psychological factors, rather than considering generic emotional or psychological variables such as stress. Limitations of this review include a restriction to papers published in academic journals, papers published in English and it did not include searches of grey literature, introducing the possibility that relevant reports may have been missed. A limitation of this review is that it did not explore the effects of different anxiety disorders (e.g., generalised anxiety versus obsessive compulsive disorder). Rather it considered the concept of anxiety more broadly (i.e., presence or severity of anxiety symptoms, or presence or absence of an anxiety disorder).
Overall, the present study demonstrated an association between depression and poorer wound healing outcomes. Relationships between wound healing and depression are likely to be complex and reciprocal in real world settings. There was less evidence to indicate a relationship between anxiety and wound outcomes, although fewer studies have investigated this relationship. Clinicians should be aware that patients with depression may be at higher risk for poorer wound healing outcomes. Future studies should investigate the mechanisms behind the associations between depression and wound healing in order to facilitate appropriate interventions.
Supporting information
S1 File. Subgroup and heterogeneity analyses.
https://doi.org/10.1371/journal.pone.0309683.s004
(DOCX)
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