Hot Topics: Depression in Individuals With Psoriasis and Psoriatic Arthritis

Epidemiology

From the US National Health and Nutrition Examination Survey (NHANES) 2009-2012 database, people with PsO were twice as likely to have depression (odds ratio [OR] 2.09, 95% CI 1.41-3.11) compared to those without.¹⁰ In addition, people with PsO and PsA were nearly 3 times more likely to have depression independent of other comorbidities (OR 2.92, 95% CI 1.53-5.68) than those without PsA.¹¹ Among 73,447 individuals with PsO who were followed for up to 25 years in The Health Improvement Network (THIN), a primary care medical records database, those who developed major depressive disorder (MDD) were at significantly increased risk of developing PsA compared with those who did not develop MDD (hazard ratio [HR] 1.37, 95% CI 1.05-1.80).¹² Individuals with PsA also have been found to have an increased risk of depression (OR 1.68, 95% CI 1.37-2.08) compared to those without PsA.¹³ In a cross-sectional study, the prevalence of depression was shown to be higher in those with PsA (22.2%) than with PsO (9.6%).⁵

With respect to suicide, a metaanalysis of 18 studies comprising 1,767,583 participants revealed that among the 330,207 who had PsO, there was a greater likelihood to attempt and to complete suicide (OR 1.32, 95% CI 1.14-1.54 and OR 1.20, 95% CI 1.04-1.39, respectively) compared to those without PsO.⁸ Further, more severe PsO and younger age were associated with a greater likelihood of suicidality.⁸ Though studies have not conclusively shown an increased risk of suicidal ideation or behavior (SIB) in those with PsA,^14,15 increased deaths by suicide in those with PsA compared to the general population were reported in a large cohort in the United Kingdom (HR 3.03, 95% CI 1.56-5.90).⁹

Although not examined in depth in the literature, available studies have shown a higher PsD burden and worse quality of life in those with depression and anxiety as well as poorer adherence to treatment.⁵ In a cohort study of 306 individuals with PsA and 135 with PsO, McDonough et al showed an association of worse scores on patient-reported outcome measures evaluating function, general health, skin, and fatigue with depression and anxiety in PsA and PsO.⁵ Interestingly, whereas increased inflammatory joint count was associated with depression and anxiety in PsA, worse skin disease as measured by the Psoriasis Area and Severity Index (PASI) was not associated with depression and anxiety in PsA or PsO.⁵ In addition, 1 study showed that concomitant depression or anxiety can result in discrepancies between patient and physician global assessments of PsO severity, with the former more likely to rate it worse.¹⁶ Poorer quality of life in PsO was also noted in another small cross-sectional study comprising 90 individuals with PsO in association with the presence of depression or anxiety.³ In a longitudinal study, Kulkarni et al showed that adherence was worse in elderly adults with PsO,⁶ and in a cross-sectional study, Vestergaard et al showed that adherence was worse in individuals with PsA.⁷

Proposed pathogenetic contributors

Pathophysiologic links between PsD and mental health conditions have not been fully elucidated. Depression and PsD have many pathophysiologic processes in common, including elevated proinflammatory cytokine production and a dysfunctional hypothalamic-pituitary-adrenal [HPA] axis.^17-26 Moreover, individuals with PsD experience many environmental and physical stressors, such as less social support, the economic impact of reduced productivity, and stigmatization due to visible plaques.^{21,22,24,25,27,28} Stress may cause PsD to flare and influence immunomodulatory responses, including neuroendocrine responses,^26,29 and the development of neuropsychological disturbances.^20,22,29

Gut dysbiosis including less richness and diversity of the microbiome may contribute to both depression and PsD.^23,30 As a result, it is postulated that local inflammation results in disruption of the gut epithelial barrier and subsequent translocation of bacteria.^23,30 These bacteria, metabolites, or endotoxins (such as lipopolysaccharide) in turn stimulate toll-like receptors, resulting in the production of many proinflammatory cytokines.^23,30

Although there are inconsistent results between various studies, generally, elevated levels of proinflammatory cytokines such as interleukin (IL)-6, IL-17, IL-23, and tumor necrosis factor (TNF) have been measured in the blood of individuals with depression, and the latter 3 are known therapeutic targets for the treatment of PsD.^18,25,31,32 Increased cytokine levels can contribute to both peripheral and central neuroinflammation by crossing a permeable blood-brain barrier (BBB) induced by activated mast cells and central cytokine production by astrocytes, neurons, and microglia.³¹ Peripherally activated T helper 17 cells also contribute to disrupted BBB integrity and activation of astrocytes and microglia via the IL-17A receptor; downstream events include synaptic dysfunction and neuronal cell death.³¹ Inflammatory cytokines can also activate a key enzyme, indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine, resulting in a partial depletion of serotonin in the brain, a known factor in depression pathogenesis. IDO also shifts kynurenine metabolism toward microglial byproducts such as 3-hydroxykynurenine and quinolinic acid, resulting in elevated oxidative stress and glutamate, all which can contribute to neurotoxicity.³¹

Elevated proinflammatory cytokines (eg, TNF) also activate the HPA axis, increasing levels of corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol, as well as decreasing the effects of glucocorticoid receptors.¹⁷ However, the effect of cortisol to reduce inflammation is likely blunted as a result of the decreased activity of the glucocorticoid receptors.¹⁷ Cortisol also increases hepatic tryptophan 2,3-dioxygenase activity and like IDO, results in tryptophan depletion, decreased serotonin synthesis, and shifts to kynurenine and quinolonic acid production.¹⁷ Cortisol and increased proinflammatory cytokines can also contribute to amygdala dysfunction and decreased release of neurotropic growth factors, resulting in decreased neurogenesis and hippocampal volume loss.²⁹ Hippocampal loss, a well-documented feature of the brain associated with depression, may also occur in part due to the production of neurotoxins.²⁹

Considerations for clinical practice

Patient voice. At the annual meeting, a patient research partner (PRP) provided a patient perspective on the topic recognizing that depression, anxiety, and mood disorders are complicated, especially in the setting of PsD. She acknowledged that inflammation could drive depression and vice versa. More importantly, she stated that the overall effect of mood disorders on PsD is multidimensional and that we do not yet fully understand the interplay between inflammatory disease and mood. However, because these disorders affect people with PsD in many ways (eg, effectiveness of care, adherence, response to treatment, remission rates, and quality of life^{2,4,5,16,33-36}), they should be assessed and treated effectively. The PRP indicated that their PsD specialist need not be a therapist or prescribe medications for mood disorders. However, she requested that this topic be discussed with the patients at their visits related to PsD and that healthcare providers (HCPs) understand that anxiety and depression may be a result of still-active disease and/or affect PsD outcomes. Referrals to a care team partner or other HCPs who understand how to screen/diagnose and treat anxiety and depression should be offered.³⁷ She requested that HCPs treating PsD build a plan within their institution or office setting to address mood disorders, allowing affected individuals to get the care they need for these issues. Ultimately, it was felt that instituting such measures would help people with PsD achieve better outcomes and potentially positively change the trajectory of treatment responses.

Education and screening. Dermatologists and rheumatologists play a critical role in educating individuals with PsD about associated mental health conditions. When sharing with patients that people with PsD are more likely to be depressed, anxious, and have higher rates of suicide, it can be helpful for HCPs to provide supporting data and rationale for why identification of these mood disorders plays a role in PsD management and treatment outcomes to assist in shared decision making.

Dermatologists and rheumatologists are encouraged to routinely screen their patients with PsD for depression and anxiety, which can be accomplished through self-reported questionnaires.^2,35,38 In 1 study, screening for depression led to better outcomes for people with PsO at 1 year.³⁹ However, screening rates are reportedly low. In 1 cross-sectional survey study of 74 dermatologists, although almost 60% of participants agreed or strongly agreed that people with PsO require regular monitoring for depression and SIB, only about a quarter said they asked about mood in the majority of visits with individuals with PsD.⁴⁰ Further, only 7% reported using a depression screening tool, and only 30% were familiar with the 2-item Patient Health Questionnaire (PHQ-2; see below). On a scale of 1 (not at all comfortable) to 10 (very comfortable), dermatologists scored approximately 7-8 for asking their patients about mood, discussing depression, and referring for mental health services, but only 6.3 for asking about SIB. Use of a screening tool, frequency of screening, and belief that regular monitoring is required were associated with more comfort in talking about depression and SIB. Regular monitoring was also associated with more comfort in talking about depression, whereas awareness of the PHQ-2 was associated with more comfort in asking about SIB. Therefore, normalizing conversations between HCPs and patients around mental health is crucial.⁴⁰

The PHQ2 is suitable for busy dermatology and rheumatology clinics as it takes less than 2 minutes to complete. It was developed and validated to screen for depression with follow-up using the PHQ-9 (a 9-item questionnaire with a score range of 0-27, taking up to 5 minutes to complete) if the PHQ-2 score is suggestive of depression.⁴¹ The 2 questions in the PHQ-2 tool ask about the frequency of depressed mood and lack of enjoyment of daily activities, scoring each as 0 (not at all) to 3 (nearly every day) with a total possible score ranging from 0 to 6. A PHQ-2 score ≥ 3 was shown to have a sensitivity of 83% and a specificity of 92% for detecting major depression; a PHQ-9 score ≥ 10 had a sensitivity of 88% and a specificity of 88% for major depression with scores of 5, 10, 15, and 20 representing mild, moderate, moderately severe, and severe depression, respectively.^41,42 Other potential screening tools include the Hospital Anxiety and Depression Scale, a 14-item self-report questionnaire (questions scored 0-3), with 7 questions assessing depression and 7 assessing anxiety. A score ≥ 8 for anxiety has a specificity of 0.78 and a sensitivity of 0.9, and for depression, it has a specificity of 0.79 and a sensitivity of 0.83. It also takes 2 to 5 minutes to complete.⁴³ Other scales exist, such as the Goldberg Anxiety and Depression Scale comprising 18-items, which may also be used.

Individuals with a positive screening result using any tool should be referred to a mental health professional for further evaluation. Since these screening tools were developed for the general population and have not been fully validated in PsD, they may not capture all those with PsD who are affected with anxiety or depression. These individuals may require the application of different cut-offs to optimize sensitivity and specificity in PsD.⁴⁴ Mathew and Chandran also caution that these screening tools do not delve into the multifaceted nature of depression; for example, they are missing constructs of cognitive dysfunction.²⁰ Therefore, even if the screening results are negative, referral should still be considered if mental health concerns are suspected.

Optimize PsD treatment. Successful treatment of PsD can reduce depression³⁵ and vice versa.⁴⁵ There has been a call to use PsD treatments to improve associated anxiety and depression.³⁸ Data support that this is best accomplished with targeted therapies.⁴⁶ Though most randomized placebo-controlled trials leading to the approval of targeted therapeutics for PsD tend to exclude individuals with severe psychiatric disorders, depression in PsO was shown to statistically significantly improve on treatment with multiple targeted therapies as assessed by various mental health measures (Table). In randomized placebo-controlled studies of PsA, the most reported measure of mental health appears to be the 36-item Short Form Health Survey (SF-36) mental component summary (MCS). Baseline SF-36 MCS scores were similar for enrolled participants with PsO and PsA, and were slightly below the US norm. Treatment of PsA improved symptoms of depression compared to placebo, similar to treatment of PsO, but the results were only statistically significantly different in some studies^47-52 and not others.^48,53-58 Reasons for the variance in these results and results compared to PsO are largely unknown, but they might reflect drug dosage differences used for PsO compared to PsA, different pathophysiological mechanisms of depression in PsA, and/or the relative insensitivity of the SF-36 MCS (or the SF-36 domains evaluating emotional or mental health) to detect improvement of depressive symptoms in PsA.

One consideration in individualizing treatment for PsD is that 2 systemic treatments, which include (1) apremilast, a phosphodiesterase-4 inhibitor (approved for both the treatment of plaque PsO and PsA in the US and European Union [EU]), and (2) brodalumab, an IL-17A receptor antagonist (approved for the treatment of moderate-to-severe plaque PsO in the US), contain warnings in their prescribing/product information related to depression and/or suicidality.^59-62 Specifically, brodalumab has a black box warning in the US for SIB, including completed suicides. Prescribers are required to undergo certification through the company’s Risk Evaluation and Mitigation Strategy to prescribe brodalumab, and patients must register to be able to receive brodalumab when prescribed.⁶¹ Follow-up studies are indicated in the EU to evaluate SIB as part of the risk management plan for brodalumab.⁶³

For apremilast specifically, across 3 16-week randomized placebo-controlled trials in moderate-to-severe plaque PsO, there were more reports of depression and depressed mood for those treated with apremilast (1.3% [12/920]) compared to placebo (0.4% [2/506]), but there was no apparent imbalance in SIB.^60,64-66 Similarly, across 3 16-week randomized placebo-controlled PsA trials, slightly more participants on apremilast (1% [10/998]) reported depression or depressed mood than those receiving placebo (0.8% [4/495]). Slightly higher rates of SIB were also seen in individuals with PsA on apremilast (0.2%, 3/1441) compared to placebo (0/495), though no individuals on apremilast attempted suicide and 2 on placebo committed suicide.^60,67

In the pooled trials with brodalumab during the 12-week randomized treatment period,^68-70 1 of 3066 individuals on brodalumab attempted suicide and none attempted suicide in the placebo (n = 879) or ustekinumab (n = 613) groups. From initiation through week 52 of the trials, SIB occurred in 7 of 4019 individuals (0.2/100 patient-years [PY]) treated with brodalumab and in 2 of 613 individuals (0.4/100 PY) treated with ustekinumab. During the course of the PsO clinical trials, SIB occurred in 34 of 4464 participants treated with brodalumab (0.37/100 PY). Overall, there were 4 completed suicides on brodalumab in the PsO development program.⁶¹ Subsequent analyses demonstrated that brodalumab users with a history of depression or suicidality had an approximately 7-fold and 12- to 18-fold increased SIB incidence, respectively, compared to users without this history. Additional analyses demonstrated that the rate of SIB observed in the brodalumab development program was 3 to 4 times higher than in pooled trials of other biologics for PsO based on publicly available data. The proportion of all deaths due to suicide in brodalumab clinical trials (19%) was roughly twice the proportion in PsO trials of other biologics (9%). In the same comparison, brodalumab was associated with a 3-fold higher than expected suicide rate (58 suicides/100,000 PY vs 19 suicides/100,000 PY).⁷¹

It is important to understand that no formal link has been established between these medications and depression or suicide. Further, mechanistically, the reason for these imbalances in depression and SIB incidence are not well understood, especially as both therapies in PsO have shown a benefit in depressive symptoms with treatment vs placebo (Table). However, due to the warnings on these drugs and the increased risk of depression and SIB in individuals with PsD, it is imperative that companies with drugs in development or approved for PsD treatment (Table) evaluate depression in their phase III clinical trials using various measures aside from reporting adverse events of depression and SIB. Ultimately, these data need to be reported in the literature, since not having these data diminishes the ability of treating clinicians to offer information about risks and benefits of various PsD treatments to their patients.

Clinicians must be aware of these warnings and supporting data when considering prescribing one of these systemic therapies to individuals with PsD. A discussion of the risk-benefit analysis regarding the use of these therapies is necessary to have with individuals with PsD. Alternative therapies for individuals with PsD should be considered for those either with a suggestive screening evaluation for depression or with PsD and a history of depression (eg, through PHQ-2 with follow-up using PHQ-9) and/or SIB. HCPs must conduct a careful reevaluation of need for continued treatment with these systemic therapies should depressive or SIB events occur. Regardless of therapeutic options used, patients should be thoroughly counseled on what steps to take if depressive or SIB events occur during treatment, including contacting their HCP.