Major Depression and Psoriasis: A Psychodermatological Phenomenon

Psychosomatic medicine is an interdisciplinary branch of medicine which studies the effects of social, psychological, and behavioral factors on bodily processes, their relationship with one another, and quality of life [1]. This article addresses the topic of psychodermatology, which is a subbranch of psychosomatics [2].

A psychodermatological disorder is a condition that involves an interaction between the nervous and the integumentary system. Psychodermatological disorders fall into three categories: psychophysiological disorders, primary psychiatric disorders, and secondary psychiatric disorders [3].

In this paper we attempt to further explore a psychodermatology topic: ‘the relationship of major depression with psoriasis'. Currently, not much is known about this association other than specific research which emphasizes that psoriasis leads to depression. However, in this article we attempt to explore a different aspect of this association, i.e. ‘whether major depression causes enough skin damage which ultimately leads to psoriasis? Or are there any inflammatory markers or cytokines released during depression that can trigger the onset of psoriasis?' Significant research has been done on depression and psoriasis in the past, and on many of their respective comorbidities related to the field of psychodermatology. However, little has been done regarding their bidirectional nature, and this paper aims to change that.

Psoriasis, or psoriasis vulgaris, is a long-lasting, and often chronic, immune-mediated inflammatory disease that is typically characterized by the appearance of patches of abnormal skin [4]. These patches are well-defined red, itchy, scaly plaques of a silver/white fashion and range in severity from a minute localization to full body coverage [5]. Psoriasis disease phenotypes can potentially weaken with age or increase in severity, depending on external factors [6]. However, psoriasis is currently not completely understood as considerable variance exists amongst disease phenotype and genotype amongst individuals. Generally speaking, psoriasis is defined as a genetic disease whose onset is due to certain environmental factors, including family history, physical or emotional stress, poor standards of living, and withdrawal of systemic corticosteroids [7,8]. It is believed to be associated with 2-4% of the population in western countries, with a higher prevalence amongst Caucasians [9].

Contrary to popular belief, psoriasis is not just a physical skin problem which leads to depression; it could actually be caused by major depression due to an immunological and a neurochemical phenomenon [10]. The pathophysiology of depression has long been in debate, and its association with various neurochemicals has been found. It is a common belief that depression causes behavioral problems. However, depression can also lead to physical pathology on the skin and other organs such as the heart [11,12,13,14,15]. This subject is widely studied in psychosomatics. This comprehensive review highlights the pathophysiological association between major depression and psoriasis.

Psoriasis, which is a long-lasting immune-mediated skin disease characterized by the emergence of red, silver scaly patches of abnormal skin that range in severity from a minute localization to full body coverage, is found to be associated with clinical depression commonly known as major depression through an immunological phenomenon [10].

Many studies have shown the possibility of a relationship between common forms of psoriasis and major depressive disorder. In a study by Akay et al. [16], patients with psoriasis were found to have extremely high Beck Depression scores, which correlated with Psoriasis Area and Severity Index scores, and were considered to be at a higher depression score than the non-psoriasis-afflicted controls, similar to an experiment done by Esposito et al. [17] where depressive symptomology was observed in 62% of psoriasis patients involved in the study of 2,391 patients. In fact in two studies done by Gupta et al. [18,19], an increase in stress and depressive symptoms were found to have a significant statistical correlation with an increase in psoriasis flare-ups and pruritus severity along with a more clinically disfiguring disease. In addition, studies have shown that a decrease in depression/depressive symptoms due to medication or therapy is associated with a decrease in psoriasis severity and vice versa [20,21,22,23,24,25,26]. The question now remains: is this correlation merely due to the negative psychological effects inherent in any clearly discernible skin disorder, or any disorder in general, such as social anxiety, low self-esteem, shame/embarrassment etc., or is there an underlying pathophysiological mechanism involved? This study explores the different mechanisms that have been shown in relation to the aforementioned conditions.

The pathophysiology of psoriasis has been studied in depth, and inflammatory and immunological associations have been found. Psoriasis has been found to be due to the occurrence of macrophages, T cells, and dendritic cells migrating away from the dermis and towards the epidermis [27,28] and subsequently releasing inflammatory cytokines such as tumor necrosis factor-α, (TNF-α), interleukin 1β (IL-1β), and IL-6, IL-22, or a type-1 cytokine profile (IL-2, interferon-γ, IFN-γ, and TNF-α). According to another notion, psoriasis involves a defect in regulatory T cells and in the regulatory cytokine IL-10. These chemical messages from dendritic cells and T cells trigger keratinocytes to release cytokines (IL-1, IL-6, and TNF-α), which signal downstream inflammatory cells to cause more inflammation [29].

Dendritic cells bring the use of the innate immune system and adaptive immune system together. These systems are activated in psoriatic lesions [30], consequently resulting in inflammation, psoriatic lesions, and increased keratinocyte production [31]. Skin in psoriatic patients goes through excessive cell growth and production, which is probably more than that observed in wound healing [32], and is replaced rapidly in 3-5 days in psoriatic patients compared to the standard 28-30 days, without release through shedding [33]. Theoretically speaking, this is all assumed to be due to a mutation in the regulatory cytokine IL-10 or defects in surrounding regulatory T cells; however, the inflammatory pathway itself is not unique [29]. A neurotrophin known as brain-derived neurotrophic factor (BDNF), which plays an integral role in neuroplasticity and mental disorders, was found to be associated with psoriasis by Brunoni et al. [34]. The authors calculated the blood BDNF levels instead of brain BDNF levels and found that these BDNF levels are reduced in depression and psoriasis. Abnormal IL-17 expression has also been observed in psoriatic patients with therapeutic inhibition showing success in reducing disease severity [35,36]. Furthermore, as has been discussed above, inflammatory cytokines like TNF-α, IFN-γ, and other type-1 cytokines play a crucial part in the pathophysiology of psoriasis [26].

On the other hand, major depression along with inflammatory markers have been studied in depth by many authors. A study by Wong et al. [37] also highlighted that immune system dysregulation occurs in major depressive disorder along with increased levels of CXCL10/IP-10, which decreased in response to antidepressants, suggesting type-1 T-cell activity. Another study by Miller et al. [38] found that patients with major depression had augmented levels of peripheral blood inflammatory biomarkers, including inflammatory cytokines, which interacted with the pathophysiological domains involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. They further activated inflammatory pathways which increased oxidative and nitrosative stress which, in turn, stimulated inflammatory signaling molecules such as nuclear factor kappa B through sympathetic nervous system outflow pathways [38,39]. Moreover, evidence exists that antidepressant therapy is associated with reduced inflammatory responses [40]. It has also been observed that in certain cases chronic inflammation is a prevalent component of mood disorders, including depression [41]. Elevation in the concentration of proinflammatory cytokines, including prostaglandin E2, C-reactive protein (CRP), TNF-α, IL-1β, IL-2, and IL-6, has also been connected with major depressive disorder, and there may potentially exist a dose response with a higher concentration of inflammatory markers linked to more severe depressive morbidity [41,42]. Additionally, proinflammatory cytokines have been shown to induce sickness behavior and depressive symptoms in dogs, and this may also occur in humans [43]. Serotonin transporter availability and function is increased by proinflammatory cytokines, thus triggering depression in rodent models. Krishnadas et al. [10] proposed that increased circulating inflammatory cytokine concentrations, especially of TNF-α, could be linked with greater 5-HTT availability, and that TNF-α inhibition with etanercept (soluble TNF receptor:Fc) would possibly decrease the 5-HTT availability.

According to a study, high levels of proinflammatory cytokines (TNF-α and IL-6) have been found in depressed patients [44]. This is usually independent of any preexisting chronic inflammatory disorders. Inflammation in depression has been studied in depth by various other authors. They discussed increased proinflammatory cytokines, increased acute-phase proteins, and increased expression of chemokines and adhesion molecules in depressive patients [45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. In relation to depressed patients, increased levels of IL-1-β and TNF-α have also been found in the peripheral blood circulation and in the cerebrospinal fluid [62,63,64,65]. In addition, it has also been observed that the therapeutic administration of the cytokine IFN-α causes depression in up to half of depressive patients, which provides further evidence about the role of inflammation in depression [66].

The above-mentioned paragraphs denote that many inflammatory markers and cytokines which are released during depression are also released during psoriasis. Therefore, we believe a possible connection between the two conditions exists. This notion is also supported by many other authors in various research articles [67]. Furthermore, genetic variations of the serotonergic system have been described, including a variable number of tandem repeat polymorphisms in intron 2 of the 5-HTT gene and polymorphism of serotonin receptors, which could play a role in the pathogenesis of psoriasis and depressive symptoms in psoriasis patients [67].

Proof of any sort of direct positive or negative relationship between psoriasis and depression and its directionality in it is extremely difficult to attain, yet despite that evidence does exist supporting the theory that the relationship is bidirectional. Psoriasis is known to have a number of different comorbidities, as shown in a study by Ni and Chiu [68], such as cardiovascular disease, obesity, diabetes, hypertension, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver disease, cancer, anxiety and depression, and inflammatory bowel disease. Inflammatory bowel disease was found to be at a higher prevalence in psoriasis patients compared to the general population. Additionally, the administration of proinflammatory cytokines in certain of the above therapies was linked to psoriasis morbidity. A similar study by Schiepers et al. [69] found that the administration of proinflammatory cytokines in animals induced ‘sickness behavior' or a pattern of behavioral abnormalities closely associated with the behavioral symptoms of depressive disorder in humans. In theory, an increase in proinflammatory cytokines such as those previously mentioned to be associated with psoriasis - that lead to inflammation and psoriatic lesions observed in psoriasis patients - can cause hypothalamic-pituitary-adrenal (HPA) axis hyperactivity observed in major depressive disorder and disturb the negative feedback inhibition of circulating corticosteroids on the said axis as well as lower serotonergic (5-HT) neurotransmitter levels. This can activate signal cascades that lead to what is considered depressive symptomology, including peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress pathways, central microglial activation, decreased neurogenesis, increased apoptosis, and melancholy, anxiety, and fatigue and somatic symptoms [69,70]. On the flip side, major depressive disorder can increase the concentration of inflammatory cytokines present systemically, which can lead to or increase psoriasis severity, and studies have also shown that depressive events generally predate psoriasis onset [71,72,73]. In addition, some other research studies also described that the risk for having psoriasis increases significantly in patients who have moderate to severe depression [74,75,76]. Psychological stress has also been found to cause phenotypic changes in patients, potentially triggering psoriasis, and to have an association with CRP levels in women with psoriasis [77,78].

In addition to Inflammation, melatonin levels can also relate depression with psoriasis. Depression has been found to lead to diminished melatonin secretion in patients compared to unafflicted patients following a normal circadian rhythm. Although primarily involved in regulating sleep cycles, melatonin has been found to have an additional influence on the immune system, specifically on levels of TNF-α, IL-6, and IL-8 along with other products of the inflammation cascade [79,80,81,82]. Similarly, melatonin levels were found to be abnormally low in patients with skin disorders, including psoriasis [83]. Furthermore, a reduction in depressive state was found to normalize melatonin levels and cause a regression of psoriatic lesions [80]. Phototherapy may be an effective strategy in regulating melatonin levels, decreasing psoriatic inflammation, and lessening depressive symptoms that further aggravate psoriasis [84].

Increased levels of proinflammatory cytokines, especially TNF-α and IL-6, are seen in depressed patients. In a study by Golpour et al. [85], 60% of psoriatic patients believed stress was a causal factor for their psoriasis, and a significant association has been found for patients with psoriasis with clinical depression, clinical anxiety, and suicidal ideation [85,86]. Research evidence suggests that TNF-α blockers, used in the treatment of psoriasis, could be helpful in reducing depressive symptoms for patients with psoriasis and other chronic inflammatory conditions [44]. Furthermore, an interesting study involving genes was conducted between depression and psoriasis by Demirhan et al. [87]. The authors used cell cultivation and conventional G-banding. They observed mostly numerical changes; chromosomes 8, 22, 21, 15, X, and Y were affected mostly, with 8 being the most commonly involved chromosome. Structural changes comprised of duplications, deletions, translocations, and breaks, with a focus on loci on del(1)(q12-q23), del(1)(q21.1-q24), del(1)(q21.1-q23), del(10)(p11.2-pter), der(2)t(2;4)(p25;p12), t(2;22)(p14;p13), t(19;Y)?, and dup(10)(q26). They thought that the susceptibility genes of major depression or psoriasis could be located on these loci. Numerical sex chromosomal analysis included 4 with 45,X (5.8%), 3 with 47,XXY (4.3%), and 4 with structural chromosome X (5.8%): del(X)(q13), del(X)(p11-pter), del(X)(q21.3), and inv(Y)(q11.2). They also performed an immunological study. The results of the immunological study demonstrated that the percentage of CD2+, CD4+, and CD8+ lymphocytes of the father were remarkably raised, while on the other hand CD4+ lymphocytes were reduced in the mother, in comparison to the controls. In the son, the percentage of CD8+ lymphocytes was higher, whereas the CD4 level was reduced. The CD4/CD8 ratio of the father and the son was found to be remarkably high. The results may suggest that major depression and psoriasis have a high impact on both genetic and immunological parameters (tables 1, 2).

Although extensive research has not been conducted on the subject, there is substantial evidence that a relationship between depression and psoriasis exists and that this relationship is bidirectional. Depression and psoriasis are more than coincidental comorbidities of each other, and in many cases psoriasis severity is strongly associated with an increase in depressive symptoms and vice versa. Major depression itself is a disorder that is often poorly characterized and not well defined in a majority of psoriasis and depression studies, and therefore there is an incredible amount of missing data as to what proportion of psoriasis patients may actually be suffering from major depressive disorder, potentially leading to smaller observed numbers. Depression and psoriasis have been hypothesized to be linked through inflammatory mechanisms, and this paper supports that hypothesis. Depression has been found to increase the concentration of proinflammatory cytokines systemically in patients afflicted with the disease, and these same proinflammatory cytokines migrate towards the epidermis and cause psoriatic lesions in susceptible patients, either increasing psoriasis severity or potentially leading to its outbreak. On the other hand, mutations in genes related to psoriasis cause an increase in the same proinflammatory cytokines. These cytokines can cause HPA axis hyperactivity observed in major depressive disorder and disturb the negative feedback inhibition of circulating corticosteroids on the said axis and lead to lower serotonergic (5-HT) neurotransmitter levels, thus leading to depressive disorder. In addition, circulating melatonin levels are known to be increasingly low in both psoriasis and depression patients, more so in patients with both conditions, and regulating melatonin levels have shown an effect on reducing the clinical severity of both conditions simultaneously. Thus, we believe that in the near future this melatonin level could also be used globally as a marker for depression-induced psoriasis until the mystery of the psoriasis caused by the depression neurochemicals is totally resolved. As of now, we believe that depression leads to psoriasis by a pathophysiological phenomenon which needs more understanding in the near future, especially due to the fact that certain biomarkers present after inflammation in depression are not present in psoriasis and vice versa. As such, antidepressant therapy may be effective in reducing psoriasis severity, psoriasis treatment may also have an effect on a patient's depressive symptoms, and phototherapy may be a potent treatment for both. However, we believe that the above evidence is still inconclusive about why not all depressed patients acquire psoriasis and why not all psoriasis patients acquire depression. We believe future studies dealing with the neuroimmunology of major depression will be able to unearth this association in detail and help future scientists in exploring the detailed mechanism of how major depression induces psoriasis through a neurochemical phenomenon.

The authors are grateful for the help, guidance, and support of Nobel Prize-nominated professor Dr. Howard I. Maibach (University of California, San Francisco).

All ethical standards were followed and maintained by the authors.

The authors declare no conflicts of interest. There was no financial support for this work.