A Review of Chronic Wounds and Their Impact on Negative Affect, Cognition, and Quality of Life

ABSTRACT

Chronic wounds represent a substantial socioeconomic, financial, and psychological burden. We examine preclinical and clinical evidence assessing the impact of chronic wounds on negative affect, cognition, and quality of life and discuss potential mechanisms underlying the link between chronic wounds and negative affect and cognition. There is limited preclinical evidence examining negative affect and wounds, but anxiety‐related behaviour has been reported in a rat incisional wound model. The incidence of anxiety and depression in people with chronic wounds varies considerably. Potential mechanisms underlying the link between chronic wounds and negative affect include the immune system, pain, metabolic dysfunction, inflammation, and vascular damage. There is a paucity of both preclinical and clinical studies examining the effect of chronic wounds on cognition, highlighting a need for more studies in this area. Research suggests that there are deficiencies in the management of anxiety, depression, and cognitive impairment in people with chronic wounds, but developing and administering therapies that target these comorbidities may have a positive impact on quality of life and wound healing. Integration of mental health and cognition screening into wound care protocols would provide substantial benefits both socioeconomically and to individuals with chronic wounds.

Summary.

• We review preclinical and clinical studies investigating the impact of chronic wounds on negative affect, cognition and quality of life, and discuss potential mechanisms underlying the link between chronic wounds and negative affect and cognition.

• There are deficiencies in the management of anxiety, depression and cognitive impairment in people with chronic wounds.

• Therapies that target these comorbidities may have a positive impact on quality of life and wound healing.

• These comorbidities are an important area that warrants further research and we provide suggestions in this regard.

Abbreviations

BDNF

brain‐derived neurotrophic factor

DFU

Diabetic foot ulcer

EU

European Union

EWMA

European Wound Management Association

HIF‐1α

Hypoxia‐inducible factor 1‐alpha

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

SGLT2‐I

sodium‐glucose co‐transporter 2 inhibitor

VEGF

vascular endothelial growth factor

VLU

venous leg ulcer

1. Introduction

Chronic wounds are wounds that fail to progress through the normal process of wound healing in an orderly and timely manner to produce anatomic and functional integrity, or wounds that proceed through the repair process without establishing a sustained anatomic or functional result [1]. They have a global incidence rate of approximately 1% and represent a significant socioeconomic, psychological, and financial burden on both individuals with chronic wounds and on the global health system [2, 3]. Chronic wounds are often considered a comorbidity of conditions such as vascular insufficiency, tissue ischaemia, or diabetes, with risk factors for the development of chronic wounds including obesity, poor nutrition, smoking, cancer, immune disorders, or immunosuppression [4].

There is no current consensus on the nomenclature or wound duration required for a wound to be classified as ‘chronic’. Therefore, differing timeframes and definitions of chronicity have been used in the literature, potentially contributing to the variable results reported between studies. Chronic wounds are also known as non‐healing wounds, hard‐to‐heal wounds, or skin ulcers [4]. Attempts have been made to standardise the definition and nomenclature of chronic wounds, with one consensus statement proposing that chronic or hard‐to‐heal wounds are wounds that have not healed by 40%–50% after 4 weeks of standard care [4]. However, some studies define a wound as ‘chronic’ if it has not healed in 4 weeks, while others consider a wound as chronic if it has not healed after 3 months [5, 6].

There is a growing body of evidence highlighting a high incidence of comorbid anxiety, depression, and cognitive impairment in people with chronic wounds, and that these negatively impact on quality of life [7]. This review gives a brief overview of chronic wounds and reviews the current clinical and preclinical literature on the burden of chronic wounds and their impact on negative affect, cognition, and quality of life. Putative biological mechanisms that link chronic wounds with affective disorders and cognition are discussed. Finally, current and potential treatments for these comorbid psychological conditions are considered.

1.1. Chronic Wound Types

All chronic wounds share some common characteristics, such as chronic inflammation, cellular senescence and bacterial colonisation of the wound, that are independent of underlying aetiologies, by which they are usually classified into vascular ulcers (e.g., venous ulcers, arterial ulcers), diabetic ulcers and pressure ulcers [8, 9].

1.1.1. Venous Ulcers

Venous ulcers are the most common type of chronic wound, affecting almost 1% of the general population and encompassing around 70% of all leg ulcers [10, 11]. Venous ulcers arise from venous disease, where alterations in the structure of veins or valves and the resulting venous insufficiency can lead to the initiation of an inflammatory state and disruption of the skin barrier [12]. There are numerous risk factors for the development of venous ulcers, including family history of venous ulcers or chronic venous insufficiency, high blood pressure, physical inactivity, chronic obstructive pulmonary disease, deep venous thrombosis and age [13]. Venous ulcers have poor clinical outcomes, with approximately 57% of people with venous ulcers experiencing recurrent ulcerations [14].

1.1.2. Arterial Ulcers

Arterial ulcers account for approximately 20% of all leg ulcers and develop from tissue ischemia due to arterial insufficiency caused by arterial disease or atherosclerosis [15]. Risk factors for the development of these vascular diseases include smoking, diabetes, hypertension, hypercholesterolemia and age [16]. Arterial ulcers are mostly found in the extremities, such as at the tips of or between the toes, but can also develop at pressure points from footwear, such as the heel or outer ankle, in comparison to venous ulcers, which are found in the gaiter area of the leg in over 95% of cases [17].

1.1.3. Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) affect approximately 19%–34% of people with diabetes during their lifetime [18]. They are associated with increased mortality, with 5% of people dying within 12 months of developing their first ulcer, and 42% of people with DFUs dying within 5 years after their first visit to a doctor or hospital for their DFU [19]. While DFUs are not usually the direct cause of mortality, they can act as a marker of patient health. Risk factors for developing foot ulcers include diabetic neuropathy, poor glycaemic control, and peripheral vascular disease (PVD) [20]. Ulcer recurrence is high, with a 1‐year ulcer recurrence rate of 31%, rising to 64% at 3 years, despite up to 77% of DFUs first achieving wound closure within 1 year [21, 22]. Thus, many people with DFUs that have achieved wound closure may be described as being in remission as opposed to having achieved complete wound healing [23].

1.1.4. Pressure Ulcers

Pressure ulcers are caused by a combination of prolonged pressure and shear, which lead to tissue ischemia, hypoxia, and necrosis [24]. The prevalence of pressure ulcers in hospitalised patients can vary from 5.2% at the time of admission to 12.3% at the time of discharge, with hospital incidence rates varying widely between 4.5% and 78.4% [25]. Most commonly found over bony prominences, most pressure ulcers are located on the sacrum, heel, or buttocks [26]. Risk factors for the development of pressure ulcers include age, length of stay in an intensive care unit, sedation, hypotension, and diabetes [27]. While most pressure ulcers occur in people over the age of 60, they can also occur in neonates and young children, with ulcer pressure rates of around 20% in some neonatal intensive care units [28]. The high incidence of pressure ulcers in care settings highlights the need to implement preventative measures for patients at risk of pressure ulcer formation, which can include regular repositioning and providing pressure relief [29].

1.1.5. Other

Chronic wounds can also occur due to types of traumatic injuries (e.g., lacerations, stab wounds, burn wounds and gunshot injuries), skin disease conditions (e.g., sarcoidosis), autoimmune conditions (e.g., scleroderma) and as a complication of other diseases such as melanoma [8]. Up to 6.6% of people with metastatic cancer also have a malignant fungating wound [30]. Independent of their underlying aetiology, chronic wounds can have a profound impact on those directly affected by chronic wounds and the wider society.

2. Chronic Wound Burden

Chronic wounds represent a significant economic and financial burden to both individuals with chronic wounds and to national health systems. Chronic wounds contribute to healthcare and hospital costs, with treatment costs for a patient with chronic wounds estimated to account for approximately 1%–3% of total healthcare expenditure in developed countries [3]. In the United Kingdom, it is estimated that between 70 000 and 190 000 individuals suffer from venous leg ulcers (VLUs) at any one time [31]. The cost of managing chronic wounds averages £1727 (~€2000) per patient per year in Wales, amounting to £328 (~€380) million or 5.5% of the total healthcare expenditure of the country [32]. These costs can increase to greater than £8500 (~€9900) for patients with wounds requiring more dressing changes or more frequent healthcare visits [33]. These figures account for direct costs associated with chronic wounds (e.g., GP visits, dressing changes and outpatient and inpatient appointments) but few studies account for indirect costs associated with factors such as common comorbid conditions (e.g., hypertension, anxiety and depression), reduction in quality of life, inability to work, and wound‐related complications (e.g., amputations). A study from Tan et al. found that annual indirect costs amounted to 3600 Singapore Dollars (~€2500) per chronic wound patient [34].

Chronic wounds are a significant socioeconomic burden due to their chronicity and high recurrence rate. Only 50%–75% of chronic wounds achieve closure within 6 months of ulcer onset [35], while over half of VLUs can recur within 3 years of wound closure, highlighting the importance of including both wound closure and ulcer recurrence as outcome measures in clinical trials of potential therapies for chronic wounds [36]. Given the increasing prevalence of risk factors for chronic wounds in the general population, in particular obesity, diabetes, and an ageing population, the incidence and burden of chronic wounds are expected to grow substantially [37].

3. Chronic Wounds and Negative Affect

3.1. Evidence From Clinical Studies

Anxiety and depression are two of the most common comorbidities of individuals with chronic wounds [38]. An assessment of the psychological burden of skin diseases found that people with chronic leg ulcers had the highest rate of depression among all skin diseases, with a depression rate of 24% [7]. 17.5% of leg ulcer outpatients also had anxiety, which was the third highest rate among all skin diseases examined in this study behind psoriasis and eczema (atopic and hand). There is variability in the reported rates for anxiety and depression in people with chronic wounds (Table 1), with some studies reporting rates of depression as high as 72.9% [41]. Most studies report more modest incidences, with Zhou et al. reporting that 45.6% of chronic wound patients have moderate to severe depressive symptoms [47]. Over half of DFU and 44% of individuals with a leg ulcer reported symptoms of depression, which is associated with poorer health‐related quality of life [40, 46]. While most studies have reported a higher incidence of depression in people with chronic wounds compared to control groups, evidence indicating no difference in the incidence of depression has also been reported [38]. The incidence of anxiety in people with chronic wounds also varies considerably, between 26% and 63% [6, 43]. 30% of individuals with VLUs scored as anxious, while patients with DFUs had an anxiety rate of 40% [48]. A study of psychological factors in leg ulceration found that there was no difference in anxiety scores between people with leg ulcers and controls, but people with leg ulcers had significantly greater levels of depression than controls [42]. This concurs with a systematic review of observational studies that profiled patients with VLU, with between 4% and 30% of patients with leg ulcers reporting high levels of depression [52]. This review also indicated poor reporting of mental health issues in people with VLUs and a lack of comprehensive profiling of people with chronic wounds that would aid in the improvement of patient outcomes.

TABLE 1.

Incidence of anxiety and depression in people with chronic wounds.

Chronic wound Type	Sample size	Assessment scale	Depression	Anxiety	References
Chronic lower leg wounds	53	HADS	24.5% of patients had depression	30.2% of patients had anxiety	[39]
Venous leg ulcers (VLU)	190	HADS	27% of patients scored as depressed	26% scored as anxious	[6]
VLU	94	BDI	25% of patients with VLUs had mild depression, 11% had moderate depression and 6% had severe depression.	—	[40]
Venous ulcer	77	GDS	Mild depression was reported in 43.2% of patients with ulcers, compared to 10.5% of control patients without ulcers. Severe depression was reported in 29.7% of patients with ulcers, compared to 2.6% of control patients without ulcers	—	[41]
Chronic leg ulcers (venous, arterial or mixed ulcers)	102	HADS	There was no significant difference in HADS‐D depression subscale between individuals with a leg ulcer and healthy controls	Individuals with a leg ulcer had a significantly higher HADS‐total and HADS‐A anxiety subscale compared to healthy controls	[38]
Leg ulcers	95	HADS	HADS‐D scores were significantly higher for patients compared to age‐ and gender‐matched controls	There was no significant difference in HADS‐A scores between patients and age‐ and gender‐matched controls	[42]
Leg ulcers	62	Qualitative interview	During the interview, 63% of patients reported feelings of depression	76% said they had a feeling of worry due to their ulcer	[43]
DFU	179	HADS	42.5% of patients presented with clinically significant symptoms of depression	63.7% of patients presented with clinically significant symptoms of anxiety	[44]
Chronic wounds (DFU, venous leg ulcer, surgical wound, pressure injury)	216	SAS SDS	37% of people with chronic wounds showed depressive symptoms (17.6% with mild depression, 3.7% with moderate depression and 15.7% with severe depression)	36.6% of hospitalised patients with chronic wounds presented with symptoms of anxiety (20.4% with mild anxiety, 8.3% with moderate anxiety and 7.9% with severe anxiety)	[45]
DFU	60	PHQ	51.6% had depressive symptoms (23.3% reported mild symptoms of depression, 28.3% reported moderate to severe depressive symptoms)	—	[46]
Chronic wounds (VLU and non‐VLU)	222	PHQ	81.6% had depressive symptoms (36% mad minimal depressive symptoms, 23.4% of patients reported mild depression severity, 22.2% reported moderate to severe depression)	—	[47]
VLU	30	HADS	40% of patients scored as depressed	30% of patients scored as anxious	[48]
DFU	260	GADS PHQ	39.6% of patients scored as depressed	37.7% of patients scored as anxious	[49]
Venous ulcers	60	BDI	91.7% had symptoms of depression (65% had mild to moderate depression, 11.7% of patients scored as moderate to severe, 15% scored as severe depression)	—	[50]
Leg ulcers	41	QIDS‐SR16	43.9% of patients had moderate depressive symptoms, 22% had severe depressive symptoms	—	[51]

Abbreviations: BDI: Beck Depression Inventory, GADS: Generalised Anxiety Disorder Scale, GDS: Geriatric Depression Scale, HADS: Hospital Anxiety and Depression Scale, PHQ: Patient Health Questionnaire, QIDS‐SR16: Quick Inventory of Depressive Symptomatology‐Self Report, SAS: Self‐rating Anxiety Scale (SAS), SDS: Self‐rating Depression Scale.

There are several potential contributing factors to the variability observed in the incidence of anxiety and depression in people with chronic wounds. These include different wound aetiologies, contrasting patient cohorts (e.g., inpatient vs. outpatient) and different methods of assessing anxiety and depression. The studies outlined in Table 1 assess anxiety and/or depression in a range of individuals with chronic wounds, with some studies combining chronic wounds of different aetiologies, while others stratify cohorts by wound aetiology or location. The results outlined in Table 1 indicate that there may be different incidences of anxiety and depression depending on the wound aetiology, which should be investigated further and may be contributing to variance in the reported incidence of anxiety and depression in people with chronic wounds. Furthermore, differing chronic wound durations at the time of assessment may also influence negative affect, with increased rates of anxiety and depression associated with DFUs present for more than 7 months [53]. Confounding factors, such as comorbid conditions and wound odour, may also contribute to the variable rates of anxiety and depression and should also be accounted for in data analysis. 67.1% of patients with wound odour report anxiety, with only 32.8% of patients without wound odour reporting anxiety. Similarly, 59.2% of patients with wound odour present with symptoms of depression, whereas only 18.6% of people with chronic wounds without odour report depression [45]. Discrepancies in reported incidences of anxiety and depression may also be due to different assessment tools. The Hospital Anxiety and Depression Scale (HADS) was the most frequently used method of assessing negative affect in individuals with chronic wounds, but other questionnaires, such as the Beck Depression Inventory (BDI), Self‐rating Anxiety Scale (SAS) and standardised interviews, have also been employed. HADS has shown good concurrent validity with other commonly used questionnaires for anxiety and depression, such as Beck's Depression Inventory (BDI) and the General Health Questionnaire (GHQ) but may still account for some of the variability in reported anxiety and depression [54].

3.2. Other Comorbidities and Chronic Wounds

The direct impact of chronic wounds on negative affect is difficult to ascertain due to confounding factors such as other comorbidities and the differing underlying chronic wound aetiologies. Other common comorbidities of people with chronic wounds include hypertension, obesity, diabetes and dyslipidaemia, which can influence quality of life and negative affect independently of the presence of a chronic wound [55]. High incidences of anxiety and depression in patients with arterial hypertension have also been reported, with a literature review finding that the prevalence of anxiety in hypertension patients is between 7.5% and 53%, while the prevalence of depression varied between 19% and 51% [56]. People with diabetes have a higher incidence of both anxiety and depression than the general population, with 32% of patients exceeding the HADS score for mild to severe anxiety and 22.4% exceeding the score for mild to severe depression [57]. A history of DFU is associated with more depressive symptoms and poorer psychological well‐being compared to a non‐diabetic control group [58]. However, levels of anxiety, depression, and psychological wellbeing were not significantly different between patients with a history of DFUs and patients with diabetes without a history of DFUs. This suggests that in this sample, diabetes, but not DFUs, was the main driver of depression symptoms in both people with and without a history of DFUs. However, this study did not discriminate between participants that actively had an ulcer and those who had an ulcer that had healed prior to the commencement of the study. Large‐scale studies examining the contribution of chronic wounds and other comorbidities on anxiety, depression, and quality of life of people with different types of chronic wounds are warranted, with emphasis on using correct controls and accounting for potentially confounding variables in statistical analysis.

3.3. Influence of Negative Affect on Chronic Wounds

While the presence of a chronic wound influences negative affect, conversely, psychological state influences wound healing. Higher scores on the HADS are associated with delayed healing of chronic wounds in the lower leg [39]. Individuals with a chronic leg ulcer scoring in the top 50% of HADS scores were found to be four times as likely to have delayed wound healing as those scoring in the bottom 50% of HADS scores. This may also be the case for acute wound healing, with a small study of 26 people indicating that people under increased psychological stress have slower wound healing [59]. HADS scores were found to be significantly higher in people with chronic wounds that had not healed within 30 or 90 days, indicating an association between anxiety and depression with wound duration and healing [60]. A review of the literature examining risk factors for delayed wound healing in people with VLUs found that there is a lack of studies examining the effect of psychosocial factors on chronic wound healing, but does note the profound effects of chronic wounds on anxiety, depression, and quality of life [61]. A position document from the European Wound Management Association (EWMA) in 2008 acknowledged that anxiety, depression, pain and social isolation are key psychosocial factors associated with delayed wound healing, and highlighted the lack of high‐quality evidence of the mechanisms underlying the relationship between chronic wound healing and negative affect [62].

3.4. Evidence From Preclinical Studies

Despite clinical evidence indicating a high prevalence of comorbid anxiety and depression in people with chronic wounds, there is a paucity of preclinical studies exploring negative affect and chronic wounds, as well as the mechanisms underlying these comorbidities (Table 2).

TABLE 2.

Anxiety‐ and depression‐related behaviour in preclinical wound models.

Model	Species/strain	Behavioural tests	Key behavioural findings	Effect on anxiety‐related behaviour	Effect on depression‐related behaviour	References
Hind paw incision	Male SD rats	Light–dark box test	Reduced time spent in light side post‐incision days (PIDs) 1 and 3	↑	—	[63]
		Elevated plus maze	Reduced time spent in open arms on PID 8
		Open field	No effect of incision on locomotor activity up to PID 4
Hind paw incision	Male SD rats	Open field test	Reduced entries into the centre zone and reduced distance moved compared to shams 10 weeks post‐incision	↑	No effect	[64]
		Tail suspension test	No difference in time spent struggling between sham and incision groups 10 weeks post‐incision
Hind paw incision	Male Wistar rats	Elevated plus maze	Reduced % time spent in open arms 1 h, 3 h, 6 h, 1 day, 3 days, and 5 days post‐incision	↑	—	[65]
		Open field test	Reduced time spent in centre square compared to sham 1 h post‐surgery
Hind paw incision	Male SD rats	Elevated plus maze	Reduced time spent in the open arm 1 h and 5 days after surgical incision compared to shams	↑	—	[66]
		Open Field test	Reduced time spent in the inner area compared to shams 5 days post‐incision

Abbreviations: —: not investigated, ↑: increased, PID: post‐incision day, SD: Sprague–Dawley.

To our knowledge, anxiety‐ and depression‐related behaviour in preclinical wound models has only been assessed in the plantar incision model. Rats subjected to a plantar incisional wound display anxiety‐related behaviour up to 8 days post‐incision [63]. Anxiety‐related behaviour has been observed in male rats with a paw incision up to 10 weeks after surgery [64]. Two other preclinical studies have also provided evidence that an incision in the hind paw can induce anxiety‐related behaviour [65, 66]. While anxiety‐related behaviour has been characterised in the paw incision model, there is a lack of studies investigating the molecular mechanisms underlying this behaviour. Only one study has investigated the effect of incision on depression‐related behaviour, with no depression‐related behaviour observed 10 weeks after incision [64]. However, the plantar incision model is often used as a model of postoperative pain and does not capture the aetiology, wound healing state, or duration of chronic wounds [67]. Other models of wounds and chronic wounds have been established in several different species (e.g., murine, rat, lapine and porcine models) that model some of the features of chronic wounds. Porcine models are commonly used in wound healing studies due to their similarity with human skin, but difficulties assessing behaviour and the cost‐effectiveness of studies make other species more attractive in preclinical research. Rodent models such as the ischemic flap model, that can imitate the ischemic state that can underlie the formation of chronic wounds, and the murine magnet pinch model, that models ischemic pressure ulcers, are other widely used wound models [68]. However, anxiety‐ and depression‐related behaviour has not been characterised in any wound model except the plantar incision model in the published literature.

Furthermore, current preclinical studies investigating anxiety‐and depression‐related behaviour in wound models are limited by the use of only male rats. Development and characterisation of preclinical wound models that display these comorbidities will aid in the understanding of the mechanisms underlying chronic wounds and negative affect, and the development of potential therapeutics to treat these comorbidities. Future studies should aim to develop and characterise a clinically relevant chronic wound model that exhibits anxiety‐ and depression‐related behaviour, taking into account factors such as wound aetiology and sex to improve the translational relevance of the model.

4. Chronic Wounds and Quality of Life

Chronic wounds have a profound negative impact on patients' daily life and quality of life [38] As outlined in Table 3, chronic ulcers affect self‐esteem, sleep quality and quantity, and increase loneliness and social isolation [38, 40]. Individuals with a leg ulcer were found to have a poorer quality of life in all six domains of the Nottingham Health Profile (energy, pain, emotion, sleep, social isolation and mobility) compared to age‐ and gender‐matched controls [42]. A qualitative review of 13 people with a history of chronic wound pain found that their pain was poorly managed and contributed to a poorer quality of life [70]. A systematic review of the impact of leg ulceration on patients' quality of life examined 24 research articles published between 1990 and 2006, and found that pain was the most debilitating aspect of having an ulcer [71]. Wound malodour was also found to negatively influence quality of life, as it is associated with increased anxiety, depression, social isolation and lower life satisfaction. VLUs negatively impact all areas of daily life, with pain, exudate, malodour and reduced mobility having the most profound effect on quality of life [72]. The degree of impact of chronic wounds on quality of life is dependent on the type of chronic wound, with arterial ulcers having the greatest negative impact on health‐related quality of life compared to other wound aetiologies [69]. Few studies examine sex differences in psychosocial characteristics within individuals with chronic wounds, but limited evidence suggests that females with chronic leg ulcers have significantly higher anxiety and social isolation scores, and worse overall quality of life than males with chronic leg ulcers [38].

TABLE 3.

Effect of chronic wounds on quality of life.

Type of chronic wound	Sample size	Scale(s)	Quality of life	References
VLU	94	CSEI MMSE RCPM	28% of patients with non‐healed venous ulcers scored as having low self‐esteem using the CSEI. There was no significant difference in CSEI, MMSE and RCPM scores between VLU patients with healed vs. non‐healed wounds.	[40]
Chronic leg ulcers (venous, arterial, and mixed venous and arterial ulcers)	102	RSES UCLA Loneliness Scale DLQI	There was no significant difference in RSES scores between individuals with a chronic leg ulcer and healthy controls. Individuals with a leg ulcer scored significantly higher than healthy controls on the UCLA Loneliness scale The mean DLQI score for patients was 13.38; indicating ulcers had a large effect on their quality of life. Females with an ulcer scored significantly higher than their male counterparts in the DLQI, HADS‐anxiety and UCLA Loneliness Scale	[38]
Leg ulcers	95	Nottingham Health Profile	Individuals with a leg ulcer had significantly poorer quality of life in all six domains (energy, pain, emotion, sleep, social isolation and mobility) compared to age‐ and gender‐matched controls	[42]
Leg ulcers	62	Qualitative interview	Leg ulcers were found to impact several areas of quality of life, including mobility, pain, working capacity, financial domain, and psychological impact	[43]
Chronic wounds (venous ulcer, arterial ulcer, mixed ulcer, DFU, atypical hard‐to‐heal wounds)	233	EuroQol Dimension (EQ‐5D‐5L)	Arterial ulcers had the highest mean score for health‐related quality of life (HRQoL) and lowest visual analogue scale (VAS) scores compared to wounds of other aetiologies, indicating the greatest impact on health‐related quality of life.	[69]
Leg ulcers	41	DLQI	26.8% of patients reported that chronic wounds had a moderate/high impact on their quality of life	[51]

Abbreviations: CSEI: Coopersmith Self‐Esteem Inventory, DLQI: Dermatology Life Quality Index, EQ‐5D‐5L: EuroQol Dimension, MMSE: Mini‐Mental State Examination, RCPM: Raven's Coloured Progressive Matrices, RDES: Rosenberg's Self‐Esteem Scale.

5. Chronic Wounds and Cognition

5.1. Evidence From Clinical Studies

The effect of chronic wounds on cognitive processes such as learning and memory is another under‐researched area in chronic wounds. To date, there is very limited clinical and preclinical evidence exploring the relationship between chronic wounds and cognition in different types of chronic wounds.

5.1.1. Diabetic Foot Ulcers

Up to 40% of individuals with DFUs have global cognitive dysfunction across several cognitive domains, including memory, executive function, processing speed and abstract reasoning [73, 74]. Individuals with DFUs and type 2 diabetes controls found that people with DFUs had lower cognitive scores than those with diabetes alone, even when adjusted for factors including HbA1c levels (a measure of blood glucose control), macrovascular disease, smoking and depression [75, 76]. Deficits were reported in all cognitive domains that were tested (memory, attention and concentration, psychomotor efficiency, reaction time, executive function and problem solving) [75]. Another study indicated that 21.3% of individuals with DFUs had cognitive impairment as assessed by the Mini Mental State Examination (MMSE), while 70.2% of patients had impairment of executive function and attention in the Trial Making Test A and B (TMT‐A and TMT‐B) [77]. Another study found that individuals with a DFU have lower average scores than age‐matched controls from the general population in the Montreal Cognitive Assessment (MoCA) [78]. However, diabetes itself may cause cognitive impairment, making it a confounding factor in this study [79].

Evidence indicating that DFUs do not influence cognition has also been reported, with no differences in MMSE or MoCA scores found between outpatients with type 2 diabetes and foot ulcers and outpatients with type 2 diabetes and no foot ulcer, even after adjustments for factors including blood glucose and HbA1c levels [80]. However, in this study, individuals with DFUs reported better glycaemic control, less depression, and reported greater adherence to foot self‐care than the control group with diabetes. Some studies that have reported deficits in cognitive impairment in individuals with DFUs have reported worse glycaemic control in the DFU groups compared to controls with diabetes, which may account for the conflicting evidence [75, 76].

5.1.2. Arterial Ulcers and VLUs

The effect of other chronic wound types on cognition is limited. Only 5% of people with leg ulcers have moderate to severe cognitive impairment; however, this study excluded people with severe cognitive impairment who would not be able to give consent nor had a significant other available to give consent [81]. This study used the Short Portable Mental Status Questionnaire to assess cognitive impairment and did not discriminate between cognitive domains. A study of leg ulcers of any aetiology in the elderly found that intellectual functioning was lower in people with leg ulcers compared to the non‐ulcer group, but there was no difference in cognitive functioning between groups [82]. Randomised, controlled studies with a large sample size are warranted to contribute high‐quality evidence on the incidence of cognitive impairment in different types of chronic wounds, including evidence on whether specific cognitive domains are affected.

5.2. Relationship Between Negative Affect and Cognition

The relationship between negative affect and cognition also warrants further investigation as it may be a confounding factor in studies. Over 42% of patients with anxiety and depression report problems with concentration and memory, compared to only 8% of controls [83]. A review of current literature on diabetes and cognitive function found that there were numerous risk factors for cognitive decline in diabetes and highlighted the reciprocal relationship between cognitive impairment and diabetes—while diabetes can cause cognitive impairment, conversely, reduced cognitive abilities can impair people's ability to care for and control their diabetes, resulting in poorer management of their condition [84]. People with more cognitive impairment were less likely to follow the recommended eating plan or exercise regularly compared to people with diabetes who were least cognitively impaired, indicating that cognitive impairment affected self‐care and adherence to treatment plans. This may also have a role in compliance with wound care plans [85]. Furthermore, DFUs can be considered an indicator of poorly controlled or severe diabetes, so people with DFUs may have a higher incidence of anxiety and depression due to the presence of more severe forms of the disease [58]. Despite this, cognitive function is not a predictor of DFU recurrence, but its influence in other chronic wound types needs to be investigated further [86].

5.3. Evidence From Preclinical Studies

There has been very little preclinical research to date on cognition and wounds. No difference in cognition‐related behaviour in the novel object recognition test was observed between naïve animals, rats that had undergone hind paw incision surgery on post‐natal day 3, and rats that had received hind paw incision surgery on post‐natal day 3 and again at 6 weeks old [87]. However, deficits in attention have been reported in male rats 16–20 weeks after paw incision surgery using a modified 5 choice titration variant paradigm [64]. Differing time points and behavioural tests may account for these conflicting findings. Further investigation of cognition in wound models is warranted.

6. Potential Mechanisms Underlying Chronic Wound‐Related Anxiety and Depression

6.1. Inflammation

While many clinical studies report a high incidence of anxiety and depression in people with chronic wounds, there is a paucity of studies examining the mechanisms underlying the link between chronic wounds and their comorbidities (Figure 1). One hypothesis is that chronic peripheral inflammation and immune activation can contribute to the development of negative affective states [88]. Local inflammation is an important feature of the wound healing process and functions to eliminate pathogens and clear debris from the wound site. Chronic wounds are characterised by being stuck in a self‐perpetuating, chronic inflammatory state and have increased levels of matrix metalloproteinases (MMPs) and reduced levels of tissue inhibitors of TIMPs compared to healing wounds [89]. The transition of pro‐inflammatory M1 macrophages to reparative M2 macrophages is also impaired in chronic wounds and contributes to persistent inflammation [90]. Systemic inflammation has been implicated in the pathophysiology of many brain disorders, including anxiety and depression [91]. Several autoimmune conditions are associated with an increased incidence of depression compared to the general population [92]. Furthermore, a meta‐analysis of cytokine levels in people with major depression found that there were significantly higher levels of tumour necrosis factor‐alpha (TNF‐alpha) and interleukin‐6 (IL‐6) in people with depression compared to controls [93]. Similar to people with depression, levels of IL‐6 and TNF‐alpha are elevated in people with anxiety compared to non‐anxious controls [94]. C‐reactive protein (CRP), a common marker of inflammation, is also elevated in anxious people [95]. While this provides evidence of a link between systemic inflammation and negative affect, the precise mechanisms underlying chronic wound inflammation and negative affect are yet to be elucidated. Another potential mechanism is the activation of the hypothalamus‐pituitary–adrenal (HPA) axis, where it has been suggested that stress‐induced activation of inflammation driven by the HPA axis may be involved in both anxiety and depression [91].

FIGURE 1.

Potential mechanisms underlying chronic wound‐related anxiety, depression and cognitive impairment. Poor quality of life, peripheral inflammation, and pain are potential mechanisms underlying anxiety and depression in people with chronic wounds, while inflammation, vascular damage, and metabolic dysfunction have been linked to cognitive impairment and may underlie chronic wound‐related cognitive impairment. Created using Biorender.com.

6.2. Pain

Evidence that chronic pain can influence negative affect [96, 97] provides a potential mechanism by which chronic wound‐related pain may induce anxiety and depression in people with chronic wounds. People with an odorous wound or more severe wound‐related pain have a higher prevalence of anxiety and depression [6, 45], with pain reported to be the most challenging aspect of living with a chronic wound [98]. Approximately 72% of people with chronic wounds experience some level of pain associated with their chronic wounds, with one study finding that 65% of individuals with leg ulcers had severe pain [6, 43]. The average incidence of anxiety and depression in people with chronic pain conditions is as high as 45% and 52% respectively [99, 100, 101]. Changes in monoamine neurotransmitters, inflammatory factors, glutamate and their associated receptors in the brain have all been implicated in both chronic pain and depression [102]. Activation of serotonergic projections from the dorsal raphe nuclei to the interneurons in the central nucleus of the amygdala by both pharmacological and optogenetic techniques reduced depression‐like behaviour in a male mouse model of chronic pain, while inhibition of this pathway induced depression‐like behaviour [103]. This pathway is translationally relevant in humans, where people with chronic pain and comorbid depressive symptoms had reduced functional connectivity between the centromedial amygdala and the dorsal raphe nucleus compared to healthy controls, while patients with chronic pain without comorbid depressive symptoms did not [103]. An overlap of pathways involved in chronic pain and anxiety has also been established, with alterations in circuits within many brain regions including the amygdala, hippocampus, prefrontal cortex, nucleus accumbens, and recently in the bed nucleus of the stria terminalis, where chronic pain‐induced neural plasticity in this region was shown to induce anxiety‐related behaviour [104].

7. Potential Mechanisms Underlying Chronic Wound‐Related Cognitive Impairment

7.1. Inflammation

Potential pathophysiological pathways between complications of diabetes and cognitive impairment in people with DFUs have been suggested and include chronic hyperglycaemia, metabolic dysregulation, insulin dysregulation, and inflammation; therefore, people with DFUs may experience cognitive impairment due to these factors, independent of their chronic wound [105]. However, chronic inflammation is a characteristic of chronic wounds, which may be a mechanism by which chronic wounds themselves affect cognition. Evidence for the link between peripheral inflammation and cognition is conflicting, with a systematic review of peripheral inflammatory biomarkers in adults over the age of 55 finding that some studies indicated that higher CRP levels were associated with cognitive impairment, while another study has found that higher plasma CRP levels were associated with slower cognitive decline [106]. Similarly, limited evidence suggests a link between inflammatory markers and cognition in people aged 24 years, although this relationship in older adults is not investigated in this study [107]. The link between inflammation due to chronic wound and its potential effect on cognition requires further research to ascertain any potential relationship between these factors.

7.2. Metabolic Dysfunction

Dysfunctional glucose metabolism in the brain has been proposed as a potential mechanism of cognitive impairment in both diabetes and Alzheimer's disease [108, 109]. Insulin sensitivity is linked to deficits in speech production in non‐diabetic people over the age of 70, but there is no correlation between insulin sensitivity in cognitively impaired and diabetic subgroups [110]. Glucose metabolism has been targeted as a potential therapy to improve cognition, with intranasal insulin administration found to have beneficial effects on cognition in subjects with Alzheimer's disease [111]. Sodium‐glucose co‐transporter 2 inhibitors (SGLT2‐I), which reduce hyperglycaemia by preventing the reabsorption of glucose in the nephron, improved insulin sensitivity and ameliorated cognitive function in preclinical studies in obese and diabetic mice [112]. Translation to clinical studies has been less promising, with a clinical trial of 39 elderly people with type 2 diabetes not showing significant improvement in cognition after 12 months of treatment with the SGLT2‐I canagliflozin, despite improvements in high‐density lipoprotein cholesterol, with the authors citing a low sample size and short study duration as limitations of the trial [113]. Some evidence has indicated the potential cognitive benefits of SGLT2‐Is, with their use being associated with a lower risk of dementia [114]. However, the effect of SGLT‐Is on chronic wound‐related cognition remains to be elucidated.

7.3. Vascular Damage

Damage to the vasculature contributes to the development of arterial ulcers, venous ulcers, and DFUs. Vascular dysfunction and disease (e.g., chronic venous insufficiency in venous ulcers and peripheral arterial disease in DFUs and arterial ulcers) also contribute to the failure of these wounds to heal, with hypoxia of the chronic wound impairing angiogenesis, collagen deposition, and wound epithelialisation [115]. While acute hypoxia can stimulate angiogenesis by activating genes encoding vascular endothelial growth factor (VEGF) through the accumulation of hypoxia inducible factor 1‐alpha (HIF‐1α), a subunit of the HIF‐1 protein, sustained hypoxia can impair wound healing, with evidence that topical oxygen therapy can promote chronic wound healing [116, 117]. Similarly, vascular dysfunction can also contribute to cognitive decline and dementia, with vascular dementia accounting for over 20% of dementia cases globally, second to Alzheimer's disease [118]. Increased vascular comorbidities are associated with reduced performance in verbal fluency, information processing speed, verbal learning, and visual memory cognitive domains in people with inflammatory bowel disease [119]. A potential mechanism behind vascular damage‐induced cognitive impairment is reduced cerebral blood flow due to vascular stenosis, with chronic reduction in cerebral blood flow inducing deficits in spatial working memory in a mouse model of chronic cerebral hypoperfusion [120]. Hypoxia resulting from hypoperfusion and/or ischaemia, leading to increased HIF‐1α has also been implicated as one of the molecular mechanisms underlying the role of chronic hypoxia in cognitive impairment. HIF‐1α can induce neuroinflammation and reduce brain derived neurotrophic factor (BDNF) levels by facilitating the downstream activation of the pro‐inflammatory nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) [121]. The contribution of vascular damage to cognitive impairment in people with chronic wounds is not clear, but as vascular conditions such as hypertension and hypercholesterolaemia are risk factors underlying the development of chronic wounds, it is likely that these risk factors themselves contribute to both chronic wound development and cognitive impairment.

8. Therapies for Treating Comorbid Anxiety and Depression in People With Chronic Wounds

There has been little emphasis on the treatment of comorbid anxiety and depression despite the high incidence of mood and anxiety disorders in people with chronic wounds and their negative impact on quality of life. The majority of healthcare professionals treating chronic wounds believe that more than half of their patients display symptoms of a mood disorder [122]. Despite this, less than a quarter of their patients were receiving treatment for their concurrent mood disorder. In a study of depression in people with DFUs, 28.3% of patients with moderate to severe depressive symptoms were not receiving treatment for their depressive symptoms, while 70.6% of patients who were taking antidepressants still reported moderate to severe depressive symptoms [46]. Even in patients that were receiving treatment for mood disorders, the class and type of antidepressant prescribed are not clear. This highlights an unmet clinical need to diagnose and actively treat anxiety and depression in patients with chronic wounds who present with these comorbid conditions.

Anxiety and depression are often treated using the same pharmacological therapies, indicating that there are pathophysiological pathways and mechanisms common to both disorders. First‐line pharmacological treatment for anxiety and depression includes selective serotonin reuptake inhibitors (SSRIs) and serotonin‐noradrenaline reuptake inhibitors (SNRIs), while tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and benzodiazepines are second‐line therapeutics [123]. Anticonvulsant drugs and second‐generation antipsychotics have shown mixed efficacy in certain anxiety disorders. Non‐pharmacological therapies such as psychotherapy and exercise can also be used in the treatment of depression and anxiety disorders; however, these treatments may not be suitable for all people with chronic wounds, for example, those who suffer from impaired mobility [124].

Many molecular pathways and neurotransmitters have been studied as targets for the treatment of anxiety and depression, including the serotonergic, dopaminergic, noradrenergic, glutamatergic, GABAergic and endocannabinoid systems, with drugs targeting some of these pathways approved for clinical use (for reviews see [123, 125]). There is limited evidence that targeting the endocannabinoid system may have efficacy for the management of wound‐related pain, which could aid in the management of comorbid anxiety and depression [98]. It is clear that there is an unmet clinical need to manage these symptoms in people with chronic wounds through greater consideration of comorbid mood and anxiety disorders and the development of effective therapies.

9. Therapies for Treating Comorbid Cognitive Impairment in People With Chronic Wounds

Pharmacotherapies to manage cognitive impairment are limited but include cognitive enhancers such as cholinesterase inhibitors and N‐methyl‐D‐aspartate (NDMA) antagonists that are commonly used to manage dementia [126]. Non‐pharmacological treatments for cognitive impairment include participating in cognitive training, physical exercise, and socialisation, which have been shown to be beneficial as an intervention for cognitive impairment [127]. While these therapies may improve cognitive impairment, they do not prevent the progression of cognitive decline. A greater understanding of the causal mechanisms underlying cognitive impairment in people with chronic wounds is required to identify potential therapeutic targets for the management of chronic wound‐related cognitive impairment.

10. Conclusions

Current research supports the hypothesis that chronic wounds are associated with comorbid anxiety, depression, and cognitive impairment, and negatively affect quality of life, with a high burden on both individuals with chronic wounds and the health system. Preclinical studies examining anxiety in animal models have indicated that wounding is associated with anxiety‐related behaviour. However, the development of preclinical chronic wound models in both sexes that can replicate these comorbidities will be important in ascertaining the pathways underlying the link between chronic wounds and their comorbidities and aid in the identification of potential therapies.

There are numerous clinical studies examining anxiety, depression, and quality of life in people with chronic wounds, but there is variability in published results, and the mechanisms underpinning these comorbidities are under‐studied. The variability in reported findings may be due to heterogeneity in study designs, patient cohorts, or assessment tools, as well as accounting for comorbidities that may impact anxiety and depression independently. Future studies should investigate the molecular mechanisms underlying the link between negative affect and chronic wounds both preclinically and clinically, with the aim of identifying novel targets for the therapeutic treatment of these comorbidities. The efficacy of current pharmacological therapies for anxiety and depression should also be assessed, with a focus on their safety (e.g., potential drug–drug interactions) due to the high degree of polypharmacy and comorbidity in people with chronic wounds. Few studies investigate the impact of chronic wounds on cognition, with conflicting results, suggesting that more studies are required in this area to understand the contribution of chronic wounds to cognitive impairment and decline.

There appears to be deficiencies in the management of comorbid psychological symptoms in people with chronic wounds, despite their profound impact on quality of life. This may be due to the belief that healing the chronic wound will also treat comorbid conditions, but with evidence suggesting the bidirectional relationship between chronic wound healing and negative affect, there should be an increased focus on understanding and treating comorbid psychiatric conditions to effectively manage chronic wounds and improve quality of life. People with chronic wounds should undergo a clinical assessment and monitoring of negative affect and cognition through the use of validated screening tools, such as HADS, BDI, or MMSE administered at wound care consultations, follow‐up appointments, or dressing changes. These assessments can help to identify and refer individuals that potentially require treatment for psychological conditions, enabling them to receive treatment. Identifying cognitive impairment would also allow for the adaptation of wound care plans as cognitive decline may impact adherence to treatment plans and wound care. The implementation of this screening would provide both economic and clinical benefits. A reduction in wound care duration has the potential to reduce direct healthcare costs and costs associated with chronic wound complications, providing economic benefit. Clinically, it could promote wound healing, improve patient adherence to wound care plans, and ameliorate quality of life for individuals with chronic wounds.

Conflicts of Interest

The authors declare no conflicts of interest.

Redmond M. C., Gethin G., and Finn D. P., “A Review of Chronic Wounds and Their Impact on Negative Affect, Cognition, and Quality of Life,” International Wound Journal 22, no. 8 (2025): e70748, 10.1111/iwj.70748.

Data Availability Statement

Data sharing is not applicable to this article as no new data were generated or analysed in this review article.