Mental health in psoriatic disease

INTRODUCTION

Psoriatic disease is a chronic inflammatory condition that leads to typical erythematous, scaly skin plaques and affects 2-3% of adults in Western countries.^1,2
Current understanding views psoriatic disease as a chronic, systemic, immune-mediated inflammatory disorder comprising three major domains: the skin, the bones/joints, and the blood vessels, all characterised by a similar pattern of inflammation.³ Apart from these major domains, psoriatic disease is associated with a number of concomitant conditions referred to as comorbidity.⁴ Among these, cardiovascular and metabolic disorders need to be mentioned in particular. Meanwhile, different psychiatric diseases such as depression have also been recognised as comorbidity of psoriatic disease, which was insufficiently taken into account in the past.⁵
A growing body of data shows that the presence of psychiatric comorbidity is of high importance in the management of psoriatic disease for several reasons.

Prevalence of psychiatric comorbidity

Depression

Depression is a serious psychiatric illness that often presents with a combination of symptoms such as depressed mood, loss of interest or pleasure, decreased energy and fatigue, decreased concentration and attention, decreased self-esteem and confidence, feelings of guilt and unworthiness, pessimistic views of the future, thoughts or acts of self-harm or suicide, disturbed sleep, and decreased appetite⁶. Depression needs appropriate professional care.⁷
In epidemiological studies that enrolled ≥50 patients with psoriatic disease, depression prevalence ranged from 2.10% to 33.7% among patients compared with 0% to 22.7% among unaffected controls. This large spread in numbers can be in part explained by the use of different screening tools ⁸. Using International Classification of Diseases (ICD) codes, screenings of patients with psoriatic disease seeking help in dermatological clinics found prevalence rates for clinical depression of around 12-13%^9-11 while depressive symptoms have been reported to be present in up to 55% of patients with psoriatic disease.^11,12

Suicide and suicidal behaviour

Suicidal ideation refers to thinking about or making plans to commit suicide. Suicidal behaviour is any action a person takes to end their own life.¹³
Patients with psoriatic disease were shown to have a significantly higher likelihood of suicidal ideation and suicidal behaviour, including suicide attempts, and completed suicides.^9,14-17 Among several chronic skin diseases, only psoriasis was significantly related to thoughts of suicide in a cross-sectional study.¹⁸ Especially younger patients with psoriatic disease and those with more severe psoriasis were shown to be at risk.¹⁷ The risk is also higher with other pre-existing psychiatric conditions.^10,19

Anxiety

Anxiety is an emotion characterised by feelings of tension, worried thoughts, and physical changes such as increased blood pressure. There are several types of anxiety disorders, including generalised anxiety disorder, panic disorder, and social anxiety disorder.^20,21 Anxiety disorders are associated with a high burden of disease and require specialist treatment.²²
In epidemiologic studies, the prevalence of anxiety disorders is reported to be up to 48% in patients with psoriatic disease.^10,23 It is estimated that in the UK over 7100 diagnoses of anxiety are attributable to psoriasis annually.²⁴ Compared with patients with psoriasis alone, there is a higher prevalence of depression and anxiety in patients with psoriatic arthritis.^15,25,26

Addictive disorders

Addiction is a neuropsychiatric disorder characterised by a recurrent desire to continue taking a substance or perform certain activities despite harmful consequences.²⁷
The rates of addictive disorders, and in particular of alcoholism and smoking, are significantly higher in patients with psoriatic disease than in the general population.^28,29 Both smoking and alcohol use are considered potential risk factors for the onset or exacerbation of psoriatic disease and are associated with poorer adherence to treatment.^3,28,30-33 A German study also found gambling to be more prevalent in patients with psoriatic disease compared with the general population.³⁴

Alexithymia

Alexithymia is a personality trait involving difficulty identifying and describing feelings as well as an externally oriented style of thinking.³⁵ Individuals with alexithymia have deficits in the ability to relate their emotional states to the factors that cause those emotions. As a result, alexithymic individuals are unable to effectively regulate and cope with negative emotions following stressful events.^35,36 Several studies have found a high prevalence of alexithymia in patients with psoriasis. Though it is no psychiatric comorbidity per se, it still causes an immense burden for these patients.^35,37-40 A meta-analysis showed that according to a random-effects model, the prevalence of alexithymia in psoriasis patients was 28% with significant heterogeneity between studies. Data suggest that females, patients with more severe disease, patients with psoriatic arthritis, and patients with visible skin lesions have a higher prevalence of alexithymia.⁴¹
For an overview of prevalence rates of psychiatric comorbidity compared with healthy controls, respectively the German general population, see Table 1.

Table 1. Prevalence of psychiatric comorbidities of psoriatic disease

Mental disease	Prevalence in psoriatic disease	Prevalence in controls / the German general population
Depression	Up to 33%8	8.1%97
Suicidal ideation	13.9%9 16	8.67%16
Suicidal behavior	3.34%16	1.33%16
Anxiety disorder	Up to 48%23	~9%98
Alcohol abuse	17-30%28	~3.8%99
Nicotine abuse	41-43.9%29	~26.2%100
Alexithymia	Ca. 28%41	~10%41

The pathophysiological link between psoriatic disease and psychiatric comorbidity, especially depression

The role of stigma

Several factors are thought to underlie the connection between psoriatic disease and psychiatric disorders. One possible explanation is the common stigmatizing attitude of society due to the highly visible skin manifestations in affected patients.⁴² A further complicating factor is that stigmatization in patients with psoriatic disease does not only occur in the context of their skin disease. About a quarter of patients with psoriatic disease also suffer from obesity which is another important cause of social stigma^{43 44}. In addition, depression itself often leads to further stigmatization⁴⁵. To make matters even worse, stigma is often accompanied by self-stigma which undermines self-confidence and contributes to exacerbation of depression.^46,47
Stigmatization, as well as the existence of mental and physical comorbidities, such as depression and obesity, are factors that promote a cumulative life course impairment in psoriatic disease. Remarkably, stigmatization does not instantly lead to psychiatric disease: The experienced burden is countered by the patient's resources, which are partly derived from the patient's personality and existing coping strategies. Irreversible "damage" to the patient's life course occurs when the impairing factors get out of control over time.⁴⁸

The role of inflammation

Stigma due to suffering from a chronic condition that is often visible to others is not the only reason why patients with psoriatic disease are affected by comorbid depression in so many cases. In recent years, our knowledge with regard to the close interactions between the skin, the psyche, the nervous system, and the immune system has increased.⁴⁹ The observation of peripheral inflammation both in psoriasis and in depression suggests that this may be one of the shared mechanisms of both diseases, underlying the high rates of psychological comorbidity and especially depression.^15,26,49

For years, depression has been attributed to reductions in monoaminergic neurotransmitters in the central nervous system (CNS) as monoamine agonists improve symptoms in a portion of patients.^50-52 However, it is now accepted that cytokine-mediated communication between the immune system and the brain plays a major role in the pathogenesis of depression.^53-56 Several theories attempt to explain how elevated proinflammatory cytokines might affect neurotransmitter metabolism within the CNS. One theory is that patients with major depression have a hyperpermeable blood-brain barrier that allows serum proinflammatory cytokines to enter the CNS.^57,58 Once proinflammatory cytokines are present in the CNS, they are capable of activating neuronal and non-neuronal cells, similar to their mode of action in the peripheral immune system.⁵⁹

One specific mechanism involved might be the upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan to the neuroactive metabolite intermediary kynurenine by inflammatory signalling pathways. IDO activation competes with the tryptophan hydroxylase metabolism of serotonin. This is thought to deplete brain tryptophan and thereby reduce serotonin levels.⁶⁰ Recent data show that next to e.g. interleukin (IL)-6, IL-1ß, tumour necrosis factor (TNF)-α, and also IL-17 play a role in mediating the interactions between psoriatic disease and depression.⁶¹ Results from animal experiments demonstrated that the IL-17A expression in mice with experimentally induced psoriatic inflammation is associated with depressive symptoms while antibodies targeting IL-17A were capable of reducing depressive behaviour in this mouse model.⁶²
Another pathway potentially playing a role in shaping the pathophysiological link between inflammation and depression is the activation of cerebral vasculature endothelial cells leading to the secretion of cytokines inside the blood-brain barrier.^63,64
Further, peripheral inflammatory signals might be transmitted to the CNS via the vagus nerve, as vagus nerve fibres possess receptors that can bind serum proinflammatory cytokines.⁶⁵

Another mechanism that is thought to play a role is a reduced glucocorticoid receptor function.⁶⁶ In the context of systemic inflammation, but also depression, cortisol together with its receptor can no longer bind properly to the promoter regions of the corresponding genes inside the cell nucleus, which reduces the negative cortisol feedback.⁶⁰ This leads to activation of the stress axis (hypothalamic pituitary adrenal (HPA) axis). As a first step, corticotropin-releasing hormone (CRH) is released from the hypothalamus. In addition to stimulating the stress axis, CRH has direct proinflammatory effects on keratinocytes, which contributes to the worsening of psoriasis. Another mechanism that has been described to potentially underlie the close connection between psoriatic disease and depression is that of sympathetic tone. Both depression and anxiety disorder, which often occur comorbidly, lead to an increased sympathetic tone. Mainly via noradrenaline signalling, the release of pro-inflammatory cytokines such as IL-6 and IL-1ß is increased, which contributes to the exacerbation of psoriasis.⁶⁶ Overall, stress is a major trigger for psoriatic disease. Chronic stress in affected patients might result from stigma, everyday demands, but also from chronic itch and pain. Via activation of the stress axes, chronic stress leads to an upregulation of immune cells, especially with a Th1 and Th17 profile and their pro-inflammatory mediators, which drives the psoriatic inflammatory response and thus plays an important role in the exacerbation and maintenance of psoriatic disease.^67,68 In addition, stress and local and systemic inflammation can disrupt the blood-brain barrier, allowing peripheral inflammatory cytokines, such as IL-6, to enter the brain, increasing neural inflammation and leading to various adverse effects, such as an increased risk of depression.^58,69 Also from a clinical point of view, stress has been shown to be of great importance. Already years ago, stressful life events were identified to play a role in the induction and exacerbation of psoriasis.⁷⁰ A recent study by Mrowietz et al. impressively showed that patients themselves described stress as their number one trigger for psoriatic disease. Infections came second, and drugs, which were previously considered to be of great importance, only played a minor role.⁷¹

An interesting recent brain imaging study using magnetic resonance imaging (MRI) data from 1,048 UK Biobank participants: 131 patients with comorbid psoriasis and depression and, 131 non-depressed psoriasis patients matched for age and sex; as well as 393 depressed and 393 non-depressed controls. They investigated brain structure and connectivity in psoriasis in relation to depression comorbidity. Thickness of the right precuneus was increased in patients with psoriasis compared with controls only when depression was present. The finding was not directly linked to systemic inflammation and may relate to suicidality or altered somatosensory processing.⁷²

The current understanding of the connections between psoriatic disease, the psyche, the nervous system, and the immune system is shown schematically in Figure 1.

Figure 1. Schematic representation of the interrelationships between psoriatic disease, the psyche, the nervous system, and the immune systemFigure adapted and modified from Hölsken S, Krefting F, Schedlowski M, Sondermann W. Common Fundamentals of Psoriasis and Depression. Acta Derm Venereol. 2021 Nov 30;101(11):adv00609.

Changes in psychological symptoms under anti-psoriatic therapy

In light of the relationship between psoriatic disease and depression and the systemic inflammation that underlies both, it is very interesting to look at the influence of systemic anti-psoriatic therapies on depressive symptoms. Up to now, the total number of trials that have systematically addressed this question is still small. On the one hand, previous studies of modern systemic therapies were not primarily designed to measure improvement in patients' depressive symptoms, and therefore psychological measures beyond the DLQI (Dermatology Life Quality Index) were often not included. On the other hand, the different depression screening and assessment tools, when used, have been inconsistently applied in previous studies of the newer systemic agents.⁴⁹ The exclusion of patients with depression and suicidal behaviour from most pivotal trials testing new agents is another limiting factor.
However, several clinical trials investigating the efficacy and safety of modern systemic anti-psoriatic agents showed improved symptoms of depression under anti-inflammatory therapies.⁴⁹ So far, to the best of our knowledge, no meta-analysis has focussed on the question of an improvement of depressive symptoms under anti-inflammatory treatment exclusively in psoriasis patients.⁴⁹ However, meta-analyses analysing data from patients with various inflammatory conditions including psoriatic disease demonstrated an anti-depressant effect of anti-cytokine treatments.^73,74 Real-world, longitudinal observational studies investigating the improvement of psychological symptoms with anti-psoriatic treatment may be better suited to make a statement about patients with clinically significant depression, but the database is also meagre. The question of whether conventional or biological agents have a better effect on depression was investigated in an evaluation of the United States PSOLAR registry. In this analysis, biologics were shown to reduce depressive symptoms as measured with the Hospital Anxiety and Depression Scale significantly better than conventional systemic agents in psoriatic disease.⁷⁵

A question that is difficult to answer in the overall context is in how far improved depression is a direct effect of the anti-inflammatory treatment or rather an indirect effect of the improved skin condition that leads to a better psychological status.^26,49 Data from a meta-analysis demonstrated an anti-depressant effect of anti-cytokine treatments even if the somatic disease did not respond to treatment, which suggests at least a partial direct effect.⁷⁴

Psychological therapies in the management of psoriatic disease

An increasing number of studies have attempted to investigate the efficacy of various psychological interventions in the management of psoriatic disease. However, the interpretation is limited by the heterogeneity of the approaches. Based on assigned levels of evidence, the most promising methods of psychological intervention in psoriatic disease include cognitive behavioural therapy, mindfulness-based therapies, motivational interviewing as well as educational and interdisciplinary interventions.⁷⁶ Unfortunately, access to psychotherapeutic treatment is limited by long waiting lists in many countries. This is why a large number of patients currently have no chance to benefit from psychotherapeutic interventions. However, there is a growing awareness of the need to expand psychodermatology services.⁷⁷ A diagnosis of a serious psychiatric disorder, such as major depression and/or acute suicidality, may require urgent referral to a psychiatrist.^{78 79}

Practical implications

Screening for psychiatric comorbidities

Given the high rates of depression and other psychological disorders such as anxiety in psoriasis patients, routine screening for psychological comorbidities in dermatology practice is essential to ensure multidisciplinary management of these patients, involving mental health professionals as needed.^29,80-82 As mentioned above, this is important in general, but also with regard to the selection of treatment. When making a therapy decision, the dermatologist has to take into account that caution is required prior to prescribing the IL17-receptor blocker brodalumab, the small-molecule apremilast, and retinoids such as acitretin in patients with depression and/or (history of) suicidal ideation.^83-85 However, up to now broad screening of patients with psoriatic disease for psychological disorders and mental health problems is not yet well established in the dermatological practice.¹⁸ One reason for the lack of screening may be the abovementioned difficult referral to mental health care professionals, putting the dermatologist in a difficult position if they find out that their patients need psychological care. Another factor explaining the insufficient screening in clinical routine may be that there is no consistently recommended screening tool for the assessment of psychological comorbidity.⁴⁹ The German National Conference on Healthcare in Psoriasis e.g. recommends to use Whooley's 'Two-Questions Test' (TQT).^82,86-88 If patients answer 'yes' to both questions, referral to a general practitioner or preferably to a psychiatrist or psychotherapist is indicated in order to clinically establish formal diagnostic criteria.⁸² Beck’s Depression Inventory (BDI) can serve as a further and, compared with the TQT, more comprehensive screening tool.⁸⁹ Another common instrument to assess symptoms of anxiety and depression in clinical contexts is the Hospital Anxiety and Depression Scale (HADS).⁹⁰ Two well-established methods to screen for alcohol consumption and misuse are the AUDIT^82,91 and the even shorter the CAGE questionnaire.⁹² Screening for nicotine abuse should be performed in the context of the anamnesis.⁸²

Early initiation of an effective anti-psoriatic therapy

Based on data showing that depressive symptoms can be reduced by systemic anti-inflammatory therapy, modern anti-psoriatic systemic therapy should be initiated as soon as possible in patients with evidence of high psychological burden. A high level of psychological distress is often also reflected in a high score on the DLQI.⁸¹ Thus, it is of great importance to keep in mind that a significantly impaired quality of life (DLQI >10) and/or the presence of disease manifestations in sensitive areas (for a summary see⁹³) may alter the classification from mild disease to moderate to severe disease which warrants systemic treatment even if PASI (Psoriasis Area and Severity Index) and BSA (Body Surface Area) are below 10.⁹³ Since biologics were shown to have a more pronounced effect on depressive symptoms than conventional agents⁷⁵, an early initiation of a modern biologic therapy is desirable. According to the European and German guidelines, the initiation of a biologic or deucravactinib as a small molecule approved for first-line therapy is recommended if treatment success cannot be expected with conventional systemic agents.^84,85 The criteria for first-line biologic use are specified in the current version of the German guideline.⁸⁵ The criteria include severe psoriasis with a PASI equal to or greater than 20, rapid deterioration of the disease and severe involvement of sensitive areas that are particularly difficult to treat. In addition, the guideline also lists a particularly high impairment of quality of life (DLQI ≥15) as a criterion, which is often the case with psychologically stressed, stigmatised patients.⁸¹ Studies could impressively show that it can be difficult for patients to let go of habits such as social isolation that have developed over a lifetime of living with psoriatic disease.^94,95 Thus, to counteract cumulative life course impairment, early initiation of an effective anti-psoriatic therapy, which helps to reduce stigma and the burden of comorbidities such as depression, is crucial.^48,96

Conclusion

Psoriatic disease is frequently associated with psychiatric comorbidities such as depression. In the past, stigmatization was thought to be the primary cause of this association. Today, however, there is increasing evidence that overlapping biological mechanisms contribute to the close relationship between psoriasis and depression. Elevated levels of proinflammatory cytokines are present in psoriatic disease and depression indicating that inflammation may represent a pathophysiologic link between both diseases. Stress has been identified as an important triggering factor at both the clinical and biological levels. Through activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, chronic stress can cause a constant upregulation of proinflammatory cytokines. Several studies that assessed the efficacy of systemic treatments for psoriatic disease could show an improvement in psychological symptoms over the course of treatment. Thus, it is of high importance to initiate a modern anti-psoriatic systemic therapy as soon as possible. Screening for comorbid mental health diseases should be standardised and implemented on a regular basis in dermatological practice. Appropriate interprofessional care, including mental health professionals, should be provided to every patient with psychiatric comorbidities.

Conflict of interest

Wiebke Sondermann reports grants and/or travel support and/or personal fees and/or speaker honoraria from medi GmbH Bayreuth, Abbvie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme and UCB outside the submitted work. Frederik Krefting has received travel support and/or consulting fees from Almirall, Boehringer Ingelheim and Novartis outside the submitted work. Stefanie Hölsken has no conflicts of interest to declare.

FUNDING

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 422744262 – TRR 289. Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) – Projektnummer 422744262 – TRR 289.

Acknowledgements

Wiebke Sondermann: Conceptualization, Methodology, Writing- Original draft preparation, Visualization; Stefanie Hölsken: Conceptualization, Methodology, Writing- Reviewing and Editing. Frederik Krefting: Writing- Reviewing and Editing. Guarantor's name: Wiebke Sondermann

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