Psoriasis is a chronic inflammatory disease that affects between 2% and 3% of the population. The physical and psychosocial impact of the disease is considerable and negatively affects the patient's quality of life.1 While psoriasis has traditionally been considered to be a disease of the skin, there is now ample evidence of its systemic nature and concomitant involvement of other organs and systems. The prevalence of comorbidities is high. These include psoriatic arthritis, metabolic syndrome, cardiovascular disease, non-alcoholic fatty liver, inflammatory bowel disease, smoking, alcohol abuse, as well as psychiatric disorders, in particular anxiety and depression. When suspected, these conditions should be diagnosed promptly and treated because in combination they can produce a complex negative interrelation.2 The role of the dermatologist is, therefore, critical in the comprehensive and interdisciplinary management of psoriasis.3,4

Psoriasis is associated with various affective disorders, in particular anxiety and depression.5 Anxiety has been observed in 43% of patients with this disease.6

The prevalence of comorbid depression in patients with psoriasis is estimated at between 20% and 30%, and rates as high as 62% have been reported.7,8 These rates are higher1,5 than those observed in the general population and in patients with other skin diseases.9 The prevalence of depression in cases of more severe psoriasis is even higher.8,10,11 Kurd et al. confirmed these findings in a large case series of patients with psoriasis: they found a high prevalence of depression, anxiety, and suicidal ideation (39%, 31%, and 44%, respectively), which increased in the most severe cases.12

Moreover, depression in patients with psoriasis tends to be more severe than in the general population and more often associated with anxiety and suicidal ideation (between 2.5% and 9.7%, respectively).13

The connection between the skin and the mind is complex. The skin and the nervous system share a common embryonic origin. The skin is the body's envelope, the outer layer that establishes our identity. It contains us and protects us. It plays an essential role in our interaction with the environment that surrounds us. Through the skin we perceive the world and are perceived by it. It helps us to communicate with others and to express our feelings and emotions.

Although the association between psychiatric and dermatological disorders is well known, not all the links between them have been identified.

The onset and course of depression in patients with psoriasis appears to be influenced by multiple factors (see Fig. 1).

Figure 1.

Etiological factors related to the interaction between depression and psoriasis.

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Inflammation

Although it is unclear whether depression is a primary inflammatory disease, a growing body of evidence indicates that inflammation plays a role in the pathophysiology of mental illness, including major depression.

The negative bidirectional relationship linking depression and inflammation has been demonstrated. Depression, early adverse experiences, and difficulties in relating to others all favor stress responses and increase inflammation, which, in turn, can exacerbate the depression.27 In response to stress, the sympathetic nervous system promotes the release of amines (norepinephrine and others), thereby stimulating the proliferation of myeloid cells (monocytes, for example). These cells interact with other stress-induced substances, some of which, such as lipopolysaccharides and flagellin, are derived from bacteria (the intestinal microbiome, for example), but more often stress-induced damage-associated molecular patterns. In addition, corticosteroid resistance is produced by the inhibitory effect on the receptors that activate the hypothalamic-pituitary-adrenal axis, further increasing the inflammatory response.28

In a similar way to what occurs in the microenvironment of the skin, in the nervous system the inflammatory response is maintained by the interaction between cytokine-receptor and cytokine-producing elements, such as astrocytes, microglia and oligodendrocytes.29

The cytokine hypothesis explains the connection between the immune system and the neuroendocrinal and behavioral alterations that occur in certain forms of depression. It is supported by numerous studies that demonstrate a 30% elevation of proinflammatory cytokines in patients with depression compared to the healthy population. These cytokines include interleukin (IL) 1ß, IL-6, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), adhesion molecules, and prostaglandins.19,30,31 These inflammatory biomarkers cross the blood brain barrier and interact with virtually all the known pathophysiological spheres involved in depression. They affect the metabolism of neurotransmitters (such as dopamine, serotonin, and glutamate), neuroendocrine function, and even neuroplasticity through the confluence of decreased neurotrophic support, neuroprotective function and neurogenesis in conjunction with an increase in neurotoxicity and neuronal apoptosis.32–34 This hypothesis is in line with the neuropathological findings that characterize depressive disorders, including the reduction of hippocampal volume (Fig. 2).35 It would explain the high incidence of major depression in patients with inflammatory diseases and patients receiving immunotherapy with interferon α (IFN-α), IL-2 and IL-12 for infectious diseases (such as hepatitis C) and cancer.36 It is also supported by the fact that the administration of inflammatory cytokines produces a symptomatic picture called sick behavior, a condition that includes many symptoms that fall within the scope of depressive disorder.37–40

Figure 2.

Inflammation in the etiology and pathogenesis of depression.

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All these facts support the concept of depression as a heterogeneous disease in which inflammation can, at least in some cases, play an important role. A novel change in our approach to this disease would be to identify a subgroup of patients who respond to anti-inflammatory treatment by detecting possible biomarkers or endophenotypes (Table 1).41 Such a group might include the 30% of patients with depression who are resistant to current treatments.42

Table 1.

Factors Associated with Increased Risk of Inflammation That Could Indirectly Facilitate the Detection of the Inflammatory Phenotype.

Female sex

Older age

Stressful event in early life

Comorbidity

Recurrent chronic depression

Obesity

Insomnia

Poor diet

Sedentary lifestyle

Pain

Fatigue

Tobacco or alcohol addiction

Source: Kiecolt-Glaser et al., 201541

The endophenotypes correspond to the biochemical, neurophysiological, neuroanatomical, and cognitive alterations determined by genetic and environmental factors, which together show the underlying pathophysiology of the disease and vulnerability. Thus, their presence indicates an increased risk for the disease.43

Effective management of psoriasis must be multidimensional and take into account the patient's psychological, social, and physical well-being. Prevention and prompt treatment of depression in these patients is important, not only to improve their quality of life but also because this treatment can help to improve the skin symptoms as well. Psychosocial support that helps to reduce distress or improve personal and interpersonal resources and work with families may also be beneficial for these patients.44 Anti-stigma interventions help to change attitudes in the population towards diseases that affect the patient's appearance and image.

If we start from the premise that chronic systemic immune-inflammatory disorder is the critical point of connection between psoriasis and its comorbidities, the study of treatments designed to diminish the inflammatory immune response is justified. These include pharmacological treatments (such as cytokine antagonists [TNF inhibitors and IL-12 and 23 inhibitors] and celecoxib) as well as lifestyle changes that favor a healthier diet or reduce stress, obesity, sedentary lifestyle, and substance abuse (Table 2).27,45–48

Neuroimmunology studies are giving rise to new pharmacological discoveries in psychiatric treatments. The use of anti-inflammatory agents alone or in combination with antidepressants is being investigated. While the results appear promising, most of these substances are still in preclinical studies.49

It would appear that biologic agents play an important role in the treatment of moderate to severe psoriasis and have a highly beneficial effect on quality of life in this setting (Table 3).

Many studies have provided evidence of a significant improvement in affective symptoms following treatment with biologic agents. Ustekinumab improves the symptoms of depression and anxiety in patients with moderate to severe psoriasis.57

TNF-α inhibitors appear to have positive effects on mood and cognitive function, especially when inflammation levels are high.68,69 Although they do not cross the blood-brain barrier, these molecules appear to produce changes in cytokine expression by acting on the hypothalamic-pituitary-adrenal axis.70 The results of several studies have confirmed that TNF inhibitors decrease the severity of depressive symptoms independently of the severity of psoriasis.71 For example, in a large-scale, placebo-controlled study of etanercept in the treatment of psoriasis, patients who received the active drug showed a significant improvement in depressive symptoms compared to the control group independently of improvement in disease activity.72

Studies with infliximab have reported similar results, such as enhanced quality of life and improvements in other aspects of psoriasis and in the symptoms of depression in patients with Crohn disease.50,73,74

In the case of adalimumab, authors report improvements in physical functioning and the social and psychological aspects of psoriasis, with patients in some cases achieving quality-of-life scores higher than those of the general public.51 Several studies have provided evidence that adalimumab improves functioning, quality of life, and affective symptoms in these patients.74–77

These drugs may represent an objective that can extend the boundaries of our approach to mental disorders. They appear to improve depressive symptoms in patients with chronic inflammatory diseases, but the studies on this topic have limitations that must be overcome to confirm the evidence. The study populations were heterogeneous in terms of etiology, pathogenic mechanism, diagnosis, and comorbidities. Moreover, the use of several different diagnostic tools limits comparison between studies. Further studies are needed to determine what proportion of the improvement in depressive symptoms is due to improvement in the symptoms of psoriasis and how much can be attributed primarily to the drug itself (Table 4).

Comorbid depression and psoriasis interrelate negatively, giving rise to a dangerous vicious circle. We can reduce the impact of depression by prompt diagnosis and treatment of the depression while alleviating the biopsychosocial impact of the skin disease.

The treatment of psoriasis with negative immune regulators is promising and offers an additional beneficial effect on psychiatric comorbidity, which is directly or indirectly associated with improvement in the skin disease. Most biologic drugs for psoriasis are only approved for use in moderate to severe disease. This indication gives rise to a new discussion about the definition of severity in psoriasis. Traditionally, severity was defined in terms of the intensity and extent of the psoriatic skin lesions. Today, however, other aspects, such as socioeconomic factors and the impact of psoriasis on the patient's physical and social activity and psychological and emotional state (which from the patient's perspective are the most important aspects) are becoming increasingly important.81 The inclusion of these factors in decision trees represents an advance in the comprehensive treatment of the disease.

Although we have considerable data on psychological comorbidity in psoriasis, much remains to be done. More multicenter studies are needed to clearly determine the pathophysiological mechanisms and would allow us to improve the detection and clinical management of comorbid psychiatric disease and the quality of life and prognosis of these patients.

The authors declare that they have no conflicts of interest.