In another large-scale study, 4,994 participants were surveyed regarding skin disease and psychological disorders.6 Depression was present in 13.8% of patients with psoriasis compared with 4.3% of healthy controls (OR 3.02; 95% CI 1.86–4.90). Among all reported skin disorders –including non-melanoma skin cancer, eczema, and acne—only psoriasis showed a significant association with suicidal ideation (OR 1.94, 95% CI 1.33–2.82).A meta-analysis of 98 studies has supported the connection between psoriasis and depression.13 Patients with psoriasis were found to be one and a half times more likely to demonstrate signs of depression relative to non-affected controls (OR 1.57; 95% CI 1.40–1.76) and were also more likely to use anti-depressant medications (OR 4.24, 95% CI 1.53–11.76). Overall, 28% (95% CI 22–34%) of the psoriasis patients showed symptoms of depression; 19% (95% CI 12-29%) and 12% (95% CI 8-18%) demonstrated signs of clinical depression based on criteria from the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) and the International Classification of Disease (ICD), respectively.Patients with concomitant psoriatic arthritis may represent an especially vulnerable population. In a prospective cohort study of 50,750 US female nurses, the risk of depression was found to be higher in individuals with psoriasis relative to non-affected controls (RR 1.29, 95% CI 1.10-1.52), after controlling for BMI, physical activity, smoking, and the presence of major chronic conditions.14 When individuals with psoriasis were further examined for the presence of psoriatic arthritis, those with concomitant psoriatic arthritis had a higher risk of clinical depression (RR 1.52, 95% CI 1.06–2.19) than those without (RR 1.25, 95% CI 1.05–1.49). Similarly, a smaller study of 607 individuals with psoriasis found that patients who also carried a diagnosis of psoriatic arthritis were at an increased risk for depression (OR 2.1, 95% CI 1.29-3.45) as well as anxiety (OR 1.92, 95% CI 1.24-2.98).15Brodalumab and Observations of SIBBrodalumab is a human monoclonal IgG2 antibody that selectively binds to the IL-17 receptor A, thereby inhibiting its interactions with cytokines IL-17A, IL-17C, IL-17F, IL17A/F heterodimer, and IL-25. It was approved in 2017 for the treatment of adult patients with moderate-to-severe plaque psoriasis. Due to the perceived heightened level of psychiatric risk associated with brodalumab, the drug was recommended by FDA reviewers for use as a second-line therapy, with the need to reassess treatment in patients who do not achieve adequate response within 12 weeks, as well as the incorporation of a risk evaluation and mitigation strategy program that requires certification from both prescribers and pharmacies.16During the clinical development program for plaque psoriasis, there were 4 completed suicides and 10 suicide attempts in brodalumab-treated subjects, the majority of which occurred during the long-term, open-label phase of the study.17 One case of completed suicide was later adjudicated as indeterminate according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA).17 In each case of completed suicide, confounding risk factors were present, including a history of depression, substance abuse, significant financial and legal stressors, and psychosocial stressors.17 While there is not a compelling reason to attribute these deaths to brodalumab, as opposed to comorbid psychiatric disorders or life circumstances, the number of events was of concern. The details of these events are summarized in Table 1.With the goal of improved SIB evaluation, the electronic Columbia Suicide Severity Rating Scale (eC-SSRS) and Patient Health Questionnaire-8 (PHQ-8) were implanted for prospective evaluation during the studies. Importantly, at this point, most patients had already entered the long-term extension phase, which resulted in the lack of an adequate randomized comparison group (the double-blind phase had been completed for most patients).There are several factors that may have created an exaggerated suicidality signal in the brodalumab trials. Unlike the clinical trials for other recently approved biologics, there was not a specific exclusion of subjection with a history of psychiatric events or prior suicide attempts.17 Subjects in the brodalumab trials were also predominantly middle-aged white males, who represent the demographic at greatest risk for suicide.18,19 The rate of suicides in this group has increased in recent years, from 20.7 suicides per 100,000 in 2007 to 23.4 per 100,000 in 2013.19 During the pre-recession time period of 1999-2007, suicide mortality increased by 0.12 per 100,000 per year; however, the recession period from 2008-2010 saw an additional 0.51 deaths per 100,000 per year (which translates to an additional 1580 suicides annually).18In an analysis by Lebwohl et al.,20 the psychiatric data from five brodalumab clinical trials (one phase II trial, one phase II long-term extension, and three phase III trials) was collectively examined. The set included 4464 patients with 9161.8 patient-years of brodalumab exposure, and the analysis focused on controlled periods of the studies where comparator data was available. There was no observed increase in brodalumab SIB rates relative to either ustekinumab or placebo, although the comparator periods were not powered to detect rare events such as suicides. Overall, the authors did not find a causal relationship between brodalumab treatment and SIB.Notably, the AMAGINE-1 trial included measurements of anxiety and depression between baseline and week 12, during which a greater proportion of brodalumab-treated patients experienced improvements in psychiatric symptoms relative to placebo (likely linked to their improving skin disease). Positive effects on psychiatric well-being have also been identified in the clinical trials of another highly effective anti-IL-17 agent, ixekizumab (discussed later).