Atopic dermatitis and psychosocial comorbidities – What’s new?

Atopic dermatitis (AD) is a chronic inflammatory disease. During the last years, researchers have focused on a variety of associated comorbidities, especially psychosocial disease. This article aims at giving an overview over recent data. A systematic literature research was performed in PubMed including data from the time period January 1, 2018 until March 1, 2020. Patients with AD frequently suffer from cocomitant depression, anxiety, and attention deficit hyperactivity disorder. There is less evidence about the relation between AD and schizophrenia, eating disorder, and obsessive compulsive disorder. There is still great need for research in the connection between AD and psychosocial disease, particularly about the pathogenesis and the influence of new therapies.


Introduction
Well-known comorbidities of atopic dermatitis (AD) are allergic bronchial asthma, allergic rhinoconjunctivitis, and food allergy [25]. This work aims to provide an overview of the current data on psychosocial comorbidities in AD.

Materials and methods
PubMed was searched for the terms atopic dermatitis/eczema, depression, anxiety, attention deficit hyperactivity disorder, anorexia, obsessive compulsive disorder, schizophrenia. Data from the period January 1, 2018 to March 1, 2020 were included. After a systematic literature search, 47 stud-Review ies were identified, including cross sectional studies (CS), case control studies (CC), and randomized, placebo-controlled studies. The number of patients examined ranged from 9 to 2.2 million patients ( Figure 1).
In Leipzig, it was shown that the risk of depression in AD patients is comparable to the risk of depression in cancer patients. In tumor therapy, due to the high incidence of psychosocial diseases, additional support from psycho-oncologists has long been established. The risk of anxiety was lower in AD patients than in cancer patients, but higher than in patients with diabetes mellitus or stroke [46]. AD patients with employments had significantly higher levels of depression, stress, and anxiety than those who were not working. The stress levels were increased in AD patients who smoke as opposed to nonsmoking ones [16].
In children with AD, the risk of depression and anxiety disorder was shown to be increased if they had a step-parent [29]. Mothers of children with AD had higher anxiety scores [10].
In three studies it could be shown that an adequate therapy of the skin symptoms leads to a reduction of the symptoms of anxiety and depression [7,15,48]. An exposurebased cognitive behavioral treatment showed a significant reduction in anxiety but no significant differences in depressive symptoms. Training the mothers of children with AD significantly reduced the anxiety levels of the mothers [50].
Little is known about the direct causal relationship between depression/anxiety and AD. In the period investigated, there were only two studies that dealt with the physical pathophysiology of the relationship. A significantly reduced serotonin level has been shown in patients with severe AD [24]. In men with extrinsic AD, blood cortisol levels were inversely correlated with anxiety scores [48].
In the study by Singh et al. [43] in medical consultations with both dermatologists and other specialists, only 1.2% of patients with AD were screened for depression. In men this was carried out even less than in women (0.8 vs. 2.4%). There was no significant difference in the frequencies of screening tests for depression in AD patients with regard to therapy intensity.
In summary, the connection between anxiety, depression, and AD has been strengthened over the past 2 years. Nevertheless, many questions regarding the influencing factors and the causes remain unanswered so that further research is necessary. Attention deficit hyperactivity disorder (Table 2) For patients with AD, especially children, an increased risk of attention deficit hyperactivity disorder (ADHD) could be shown. Only for children with AD, also an increased risk of hyperactivity, attention deficit, and impulsivity was seen [1,3,8,26,32,49].
It has been suggested that sleep deprivation due to neurocognitive disorders could be a trigger for attention deficit [3]. The use of antihistamines in children with AD, as well as the current severity of AD symptoms, showed a significant association with increased occurrence of ADHD symptoms [32]. Little is known about the direct causal relationship between ADHD and AD. Children with ADHD and children with AD and ADHD showed a reduced cortisol response to acute stress, but children with AD only did not [8]. Siblings of patients with ADHD were at increased risk of developing AD, asthma, allergic rhinoconjunctivitis, and other atopic diseases. It is believed that the same risk factors for developing atopic diseases exist as for ADHD [9].

Schizophrenia (Table 3)
Patients with AD had an increased risk of psychotic events (OR 1.20; p = 0.009) and hallucinations (OR 1.24; p = 0.002) compared to the general population [4]. Adult patients with AD had an increased risk of being hospitalized for mental illness (OR 1.78), but children did not (OR 0.68). Adults and children with AD showed an association with anxiety disorders and developmental disabilities. An association between AD and mood disorders, schizophrenia, addictions, personality disorders, adjustment disorders, ADHD, or behavioral disorders was only found in adults but not in children. Patients with AD who were hospitalized for mental illness were more likely to be younger, of Asian or African American descent, higher income, and multiple chronic illnesses [23].  In AD pat. an increased K-6 point value was found for low and middle income, but lower for pat. of African American origin and other/multiple descent. [15] Randomized, placebocontrolled, phase 3 Pat. with AD and asthma as well as pat. with AD, asthma, and allergic rhinitis showed an increased risk of mental illness (OR 1.723; p < 0.001) (OR 3.702; p = 0.027). The self-reported prevalence of depression (10.25%) and anxiety (3.31%) was higher in AD pat. compared to controls (p < 0.001).
The severity of AD did not have a significant impact on the prevalence. [50] Pro, interventional educational program for AD SCORAD, anxiety measurement by Spielberger 20 mothers of children with AD ≥18 y

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The scores for anxiety decreased significantly after the training. The mother's score for anxiety was independent of mother or child age, gender, family history of AD, and onset of symptoms.
[ In the presence of moderate to severe AD, significantly more intake of anxiolytics (OR 1.66) and antidepressants (OR 1.24). In mild AD, only a slight increase in the use of anxiolytics (OR 1.08).  These hospitalized pat. were more often younger, of Asian or African-American descent, had a higher income, and several chronic diseases. Adults and children with AD showed an association with anxiety and developmental disorder. An association between AD and mood disorder, schizophrenia, addiction, personality disorder, adaptation disorder, ADHD, or behavioral disorder was only found in adults. CS = cross sectional; pat. = patient; y = years; OR = odds ratio. Compared to the control group, significantly increased risk for behavioral problems and lower quality of life in patients with AD alone, ADHD alone, or both AD and ADHD.
Higher risk for symptoms of ADHD in children with AD compared to the control group.
Intake of antihistamines showed significant association with increased incidence of ADHD symptoms (OR1.88). Current severity of AD symptoms with influence on the severity of ADHD symptoms. [49] CS Medical history, DSM-4 2,772 thereof 411 with AD 3 -6 y TW Increased risk for ADHS (OR 4.5) in pats. with AD compared to controls.. CS = cross-sectional study; CC = case control study; pro = prospective; pat. = patient; y = years; D = Germany; TW = Taiwan; OR = odds ratio; RR = relative risk.

Anorexia and obsessivecompulsive disorder
No data on anorexia and obsessive-compulsive disorder in AD could be identified for the period investigated.

Conclusion
The research carried out in recent years more and more supports the connection between AD and psychosocial comorbidities. Due to the frequent presence of these disorders, screening for depression, anxiety, and other mental illnesses should be rigorous. This is necessary so that psychological support can be involved at an early stage if the illness occurs. The consequences of the presence and severity of AD on mental health should be taken into account when making therapy decisions, as adequate therapy can lead to the prevention and alleviation of mental symptoms. Despite the increasingly clear connection between AD and psychosocial comorbidities, many questions about the causal pathophysiology remain unanswered. Therefore, further research in this area is urgently needed.