Cody J. Connor, Jess G. Fiedorowicz, M.D., Ph.D.

Psoriasis vulgaris is a chronic, immune-mediated skin disorder characterized by well-defined, salmon-colored patches with a silvery scale. It’s believed to occur when T cells and dendritic cells migrate from the dermis to the epidermis and aberrantly release inflammatory cytokines, such as tumor necrosis factor a (TNF-a), interleukin 1 (IL-1), and IL-6, that cause inflammation and keratinocyte proliferation. These skin cells then accumulate without shedding, resulting in the characteristic, thickened, scaly appearance. Although often overlooked, this condition causes much disability to affected patients, and some contend that the burden imparted is comparable to that of other chronic conditions like chronic obstructive pulmonary disease and heart failure [1].

Psoriasis is associated with a higher prevalence of depression and anxiety than other dermatologic conditions, and up to 40-70% of cases seen in dermatology clinics have a co-occurring psychological disorder [2]. The dramatic association between psoriasis and depression might be explained as simply the psychological effect of the related embarrassment, shame, and social anxiety, but could there be more to it than this? Might there be a common etiologic mechanism linking both disorders? Inflammation could be the key.

Inflammation manifests in a variety of conditions, both systemic and localized. Such disorders include rheumatoid arthritis, Crohn’s disease, giant cell arteritis, acne, and psoriasis vulgaris. One condition, despite its prevalence and dramatic effect on quality of life and function [3], might find itself excluded from most physicians’ lists, but over the past decade, chronic inflammation has become a well-supported component of mood disorders like major depression [4].  Several studies have linked major depression to elevations in pro-inflammatory cytokines like prostaglandin E2 (PGE2), C-reactive protein (CRP), TNF-a, IL-1ß, IL-2 and IL-6, and there is some evidence of a dose response with higher levels of inflammatory markers associated with more severe depression [4]. But while this association has been widely demonstrated, it does not distinguish whether the depression is causing the inflammation or vice versa. In exploring this question of temporality, there is evidence and biological plausibility for both directions.

Could depressive states induce elevations in the inflammatory cytokines previously mentioned? A large meta-analysis demonstrated that psychological stress elevates inflammatory markers like CRP, TNF-a, IL-1ß, and IL-6 [5]. In accordance, a case study from 1990 described a 28 year-old woman with psoriasis and schizoaffective disorder whose psoriasis consistently worsened during periods of increased depression and suicidality and significantly improved during euthymic periods [6]. Conversely, induction of an inflammatory state can precipitate depressive symptoms, as observed when healthy volunteers were vaccinated for Salmonella typhi and subsequently displayed increases in inflammatory markers like TNF-a, IL-1Ra, and IL-6 as well as depressive symptoms without signs of physical sickness [7]. Other researchers have observed the induction of “sickness behavior” in rats after injection of lipopolysaccharide (LPS) and IL-1. This “sickness behavior” includes decreases in sleep, sexual activity, energy, appetite, and interest exploring: a presentation reminiscent of major depression [8].

Inflammatory cytokines are not the only biomarkers linking depression and psoriasis. Depression is associated with disruptions in the secretion of the hormone, melatonin, which follows a circadian rhythm with higher levels at night, usually peaking around the early morning hours between 2 and 4 a.m. [9]. Melatonin is widely known for controlling the daily sleep cycle, but it also modulates immune function. By decreasing levels of TNF-a, IL-6, and IL-8, melatonin can theoretically attenuate the severity of inflammatory disorders [10, 11]. Dysregulation of melatonin has also been observed in other inflammatory conditions including sarcoidosis and, go figure, psoriasis vulgaris [12, 13]. Cyclic disruptions in melatonin levels could contribute to the inflammation seen in these disease states.  Nighttime melatonin levels have been observed to be significantly lower in patients with psoriasis relative to healthy controls, although levels were not correlated with cross-sectional severity of psoriasis and depression [9]. Further study is certainly needed to better characterize the relationship between cyclic changes in melatonin and these disease entities.

Clinical practice may already hint at the relevance of melatonin in both psoriasis and depression. Phototherapy is commonly, and effectively, used in the treatment of depression, and it is also a popular treatment for psoriatic skin lesions. In psoriasis, the current understanding of the mechanism involves inhibition of keratinocyte proliferation and, more importantly, immunomodulation by decreasing adhesion molecules necessary for immune cell trafficking, inducing lymphocyte apoptosis, changing the types and function of antigen presenting cells, and altering cytokines and cytokine receptor expression [14-17]. Given the fact that sunlight serves as the main zeitgeber in setting the circadian rhythm of melatonin secretion, it’s possible that normalizing melatonin derangement may be another benefit of phototherapy, as long as light exposure includes the retina. Melatonin may be a candidate for study as a treatment option for co-morbid depression and psoriasis, given its potential to address aberrations in cyclical melatonin secretion observed in both conditions.

Overall, psoriasis vulgaris is strongly associated with major depression, and this combination appears to cause much disability in patients, yet is often undiagnosed. Interestingly, changes in mood appear to affect the severity of psoriasis and, thus, may represent a target of possible intervention [1, 6]. By ensuring that patients are properly referred and diagnosed when depression is suspected, treatment can begin, morbidity can be prevented, and the psoriasis itself may improve in kind. The overlapping inflammatory cascades in both conditions could also serve as a potential target for intervention, which could theoretically have a synergistic effect on improving psoriasis by mitigating both the basal inflammatory state and the depression and anxiety that cause exacerbations.

References

1.    Moon, H.S., A. Mizara, and S.R. McBride, Psoriasis and psycho-dermatology. Dermatol Ther (Heidelb), 2013. 3(2): p. 117-30.
2.    Gupta, M.A. and A.K. Gupta, Psychiatric and psychological co-morbidity in patients with dermatologic disorders: epidemiology and management. Am J Clin Dermatol, 2003. 4(12): p. 833-42.
3.    Murray, C.J. and A.D. Lopez, Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet, 1997. 349(9064): p. 1498-504.
4.    Rosenblat, J.D., et al., Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry, 2014.
5.    Steptoe, A., M. Hamer, and Y. Chida, The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun, 2007. 21(7): p. 901-12.
6.    Sandyk, R. and R. Pardeshi, Mood-dependent fluctuations in the severity of tardive dyskinesia and psoriasis vulgaris in a patient with schizoaffective disorder: possible role of melatonin. Int J Neurosci, 1990. 50(3-4): p. 215-21.
7.    Wright, C.E., et al., Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun, 2005. 19(4): p. 345-50.
8.    Dunn, A.J., A.H. Swiergiel, and R. de Beaurepaire, Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev, 2005. 29(4-5): p. 891-909.
9.    Kartha, L.B., et al., Serum melatonin levels in psoriasis and associated depressive symptoms. Clin Chem Lab Med, 2014: p. 1-3.
10.    Carrillo-Vico, A., et al., Melatonin: buffering the immune system. Int J Mol Sci, 2013. 14(4): p. 8638-83.
11.    Esposito, E. and S. Cuzzocrea, Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol, 2010. 8(3): p. 228-42.
12.    Miles, A. and D. Philbrick, Melatonin: perspectives in laboratory medicine and clinical research. Crit Rev Clin Lab Sci, 1987. 25(3): p. 231-53.
13.    Mozzanica, N., et al., Plasma melatonin levels in psoriasis. Acta Derm Venereol, 1988. 68(4): p. 312-6.
14.    Johnson, R., et al., PUVA treatment selectively induces a cell cycle block and subsequent apoptosis in human T-lymphocytes. Photochem Photobiol, 1996. 63(5): p. 566-71.
15.    Laing, T.J., et al., Ultraviolet light and 8-methoxypsoralen inhibit expression of endothelial adhesion molecules. J Rheumatol, 1995. 22(11): p. 2126-31.
16.    Sethi, G. and A. Sodhi, Role of p38 mitogen-activated protein kinase and caspases in UV-B-induced apoptosis of murine peritoneal macrophages. Photochem Photobiol, 2004. 79(1): p. 48-54.
17.    Singh, T.P., et al., 8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder. J Immunol, 2010. 184(12): p. 7257-67.