Psoriasis is a chronic, immune-mediated skin condition with a high rate of psychiatric comorbidity, which often goes unrecognized. Beyond the negative consequences of mood disorders like depression and anxiety on patient quality of life, evidence suggests that these conditions can worsen the severity of psoriatic disease. The mechanisms behind this relationship are not entirely understood, but inflammation seems to be a key feature linking psoriasis with mood disorders, and physiologic modulators of this inflammation, including the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, demonstrate changes with psychopathology that may be contributory. Cyclical disruptions in the secretion of the sleep hormone, melatonin, are also observed in both depression and psoriasis, and with well-recognized anti-inflammatory and antioxidant activity, this aberration may represent a shared contributor to both conditions as well as common comorbidities like diabetes and cardiovascular disease. While understanding the complexities of the biological mechanisms at play will be key in optimizing the management of patients with comorbid psoriasis and depression/anxiety, one thing is certain: recognition of psychiatric comorbidity is an imperative first step in effectively treating these patients as a whole. Evidence that improvement in mood decreases psoriasis severity underscores how psychological awareness can be critical to clinicians in their practice.
Psoriasis vulgaris is a chronic, autoimmune, inflammatory skin disorder phenotypically characterized by clearly demarcated, salmon-colored plaques surfaced by micaceous, silvery scale. It is considered to be immune-mediated, arising with increase and activation of cutaneous T cells and dendritic cells [
Psychiatric comorbidity is estimated to affect over 30% of patients with dermatologic disease [
There is a growing body of literature supporting some link between major depressive disorder and inflammation [
Could depressive states induce elevations in the inflammatory cytokines previously mentioned? A randomized controlled trial revealed that antidepressant treatment with the selective serotonin reuptake inhibitor (SSRI), sertraline, significantly decreased not only depression scores, but also baseline measurements of CRP and IL-6 in depressed subjects [
One particularly plausible pathway involves abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. Various studies have identified chronically elevated baseline levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol in depressed individuals [
Decreases in the number or function of GRs may thus result in decreased negative feedback by cortisol, leading to the HPA hyperactivity demonstrated in depressed individuals. This mechanism is supported by reports of cortisol nonsuppression following administration of dexamethasone—which, recall, normally has strong GR affinity—in subjects with major depression: an effect that disappears with clinical recovery from depression [
HPA hyperactivity appears not only to influence mood, but also to effect changes in the skin. CRH has been shown to stimulate local cutaneous production of cytokines like IL-6 and IL-11 [
Evidence suggests that peripheral CRH is part of an HPA-like system that functions locally within the skin and hair follicles [
The way in which the HPA axis is affected appears to differ amongst psoriasis patients depending on whether they suffer from depression or anxiety. Those with depression have chronically elevated levels of CRH, ACTH, and cortisol, while those with stress-responsive psoriasis (psoriasis that worsens during periods of high stress) have been shown to have a blunted HPA-stress response, with less cortisol released into circulation following acute stress [
One study found that chronic psychological stress prolongs epidermal permeability barrier recovery following intentional disruption by repeated stripping with cellophane tape, and the extent of this prolongation was directly correlated with the patients’ measured stress levels [
Beyond HPA axis contributions, there may also be a role for autonomic modulation via the sympathetic nervous system (SNS). Anxiety, in particular, has been extensively correlated with sympathetic activation and vagal inhibition [
The SNS innervates both primary and secondary lymphoid organs and is known to promote inflammation [
Of the receptor subtypes involved in the sympathetic stress response, the alpha adrenergic receptors (
Given the opposing actions of these two AR subclasses, the particular immunologic stress reaction imparted in an individual is dependent upon the differential expression of
Presumably by further diminishing the anti-inflammatory effects of
Some have theorized that the adjuvant-like effect of acute stress on immunoreactivity is an evolutionary adaptation, the purpose of which is to prepare the body to fight off infection following injury [
This discussion is highly pertinent when considering the way that depression might influence psoriasis, as those with depression suffer from cognitive distortions that alter the ways in which they interpret their environment [
Beyond the effects of acute stress, chronic stress is likely to be a predominant issue for patients with depression/anxiety. How do the consequences of chronic stress differ, and how might they alternatively impact the course of inflammatory disease? There is ample evidence that chronic stress can result in immunosuppression or immune dysregulation [
With all considered, depression and anxiety likely contribute to the worsening of inflammatory disorders, like psoriasis, via both HPA axis and SNS hyperactivity. Those with mood disorders demonstrate baseline disruptions in these physiologic systems that contribute to ongoing immunopathology. Additionally, these populations show increased responsiveness to acute stressors, which further alters immune function and can acutely worsen chronic disorders of inflammation and autoimmunity.
While the discussion thus far has centered on the ways in which depressive or anxious states appear to increase inflammation, induction of an inflammatory state, as in psoriasis, can also precipitate changes in mood, including depressive symptoms. One study found that healthy volunteers vaccinated for
Cytokines, more specifically IL-2 and IFN-
Inflammatory cytokines are not the only biomarkers linking depression and psoriasis. Depression is associated with disruptions in the secretion of melatonin [
In those with depression, decreased melatonin levels and a dysfunctional circadian rhythm may disinhibit the release of melanocyte stimulating hormone (MSH), which has been linked to seborrhea in rats and may play a role in psoriasis [
Thus, MSH may be elevated in depression due to both low melatonin levels and hypersecretion of CRH, and this could contribute to the presentation of patients with psoriasis. Interestingly, studies have implicated MSH as a contributor to depressive symptoms [
Low melatonin may also play a role in the morbidity of psoriasis. A prospective cohort study with 14,128 subjects demonstrated a significantly increased risk for developing diabetes mellitus type II (DMII) in psoriasis patients versus the comparison group, and this risk was directly related to the severity of the psoriasis [
The mechanism behind the apparent protective effects of melatonin is not established, but available evidence offers some clues. Some studies have found that melatonin might sensitize pancreatic beta cells [
Insulin resistance has also been associated with major depression, a condition which, as discussed, also demonstrates abnormalities in melatonin secretion and is a common comorbidity of psoriasis. Might abnormalities in melatonin be the link between psoriasis, depression, and diabetes? This conclusion cannot be drawn by the simple associations observed, but melatonin levels naturally decline with age, and this may contribute to the incidence of diabetes as well as the other inflammatory conditions mentioned, including psoriasis. Both later-onset (type II) psoriasis [
In addition to depression and diabetes, psoriasis is associated with a variety of conditions in which chronic inflammation plays a pathophysiological role, including myocardial infarction, hypertension, stroke, metabolic syndrome, and cardiovascular mortality [
Clinical practice may already hint at the significance of melatonin in both depression and psoriasis. Phototherapy is a common, and effective, treatment for depression, and it is also a current treatment for psoriatic lesions. The mechanism underlying its usefulness in psoriasis is not entirely known, but the current conceptual model implicates inhibition of keratinocyte proliferation, and more importantly, immunomodulation via altered cytokine composition and cytokine receptor expression decreased adhesion molecules necessary for immune cell trafficking, altered types and functions of antigen presenting cells, and induction of lymphocyte apoptosis [
Not only is managing depression important for enhancing the patient’s quality of life, but it may also be helpful in improving his/her psoriasis. According to one study, three negative schemas—vulnerability to harm, defectiveness, and social isolation—predict anxiety and depression in psoriasis patients [
While SSRIs are often the first-line treatment for depression, fluoxetine has been observed to exacerbate psoriasis in some patients [
Overall, psoriasis vulgaris and mood disorders are highly associated, and despite frequent underdiagnosis, this combination of comorbidities causes patients much disability. Interestingly, fluctuations in mood appear to affect the severity of psoriasis (Figure
Overview: psoriasis and mood disorders. Depression and anxiety interact with psoriasis through associations with HPA axis hyperactivity, sympathetic hyperactivity, chronic inflammation, and delayed wound healing.
The authors have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the paper. The authors declare that there is no conflict of interests regarding the publication of this paper.
Jess G. Fiedorowicz is supported by the National Institute of Mental Health (K23MH083695) and the National Heart, Lung, and Blood Institute (P01HL014388).