Isabelle A. Vallerand

Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis

Importance A bidirectional relationship exists between epilepsy and depression. However, any putative biological gradient between depression severity and the risk of epilepsy, and the degree to which depression mediates the influence of independent risk factors for epilepsy, has yet to be examined. Objective To determine the effect of depression on the risk of epilepsy and seizure outcomes. Design, Setting, and Participants An observational study of a population-based primary care cohort (all patients free of prevalent depression and epilepsy at 18-90 years of age who were active after the Acceptable Mortality Reporting date in The Health Improvement Network database) and a prospectively collected tertiary care cohort (all patients whose data were prospectively collected from the Calgary Comprehensive Epilepsy Programme). The analyses were performed on March 16, 2016. Main Outcome and Measures The hazard of developing epilepsy after incident depression and vice versa was calculated. In addition, a mediation analysis of the effect of depression on risk factors for epilepsy and the odds of seizure freedom stratified by the presence of depression were performed. Results We identified 10 595 709 patients in The Health Improvement Network of whom 229 164 (2.2%) developed depression and 97 177 (0.9%) developed epilepsy. The median age was 44 years (interquartile range, 32-58 years) for those with depression and 56 years (interquartile range, 43-71 years) for those with epilepsy. Significantly more patients with depression (144 373 [63%] were women, and 84 791 [37%] were men; P < .001) or epilepsy (54 419 [56%] were women, and 42 758 [44%] were men; P < .001) were female. Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04 [95% CI, 1.97-2.09]; P < .001), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55 [95% CI, 2.49-2.60]; P < .001) There was an incremental hazard according to depression treatment type with lowest risk for those receiving counselling alone (HR, 1.84 [95% CI, 1.30-2.59]; P < .001), an intermediate risk for those receiving antidepressants alone (HR, 3.43 [95% CI, 3.37-3.47]; P < .001), and the highest risk for those receiving both (HR, 9.85 [95% CI, 5.74-16.90]; P < .001). Furthermore, depression mediated the relationship between sex, social deprivation, and Charlson Comorbidity Index with incident epilepsy, accounting for 4.6%, 7.1%, and 20.6% of the total effects of these explanatory variables, respectively. In the Comprehensive Epilepsy Programme, the odds of failing to achieve 1-year seizure freedom were significantly higher for those with depression or treated depression. Conclusions and Relevance Common underlying pathophysiological mechanisms may explain the risk of developing epilepsy following incident depression. Treated depression is associated with worse epilepsy outcomes, suggesting that this may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy.

The Association of Smoking and Surgery in Inflammatory Bowel Disease is Modified by Age at Diagnosis

Objectives:We assessed the association of smoking at diagnosis of inflammatory bowel disease (IBD) on the need for an intestinal resection.Methods:The Health Improvement Network was used to identify an inception cohort of Crohn’s disease (n=1519) and ulcerative colitis (n=3600) patients from 1999–2009. Poisson regression explored temporal trends for the proportion of newly diagnosed IBD patients who never smoked before their diagnosis and the risk of surgery within 3 years of diagnosis. Cox proportional hazard models assessed the association between smoking and surgery, and effect modification was explored for age at diagnosis.Results:The rate of never smokers increased by 3% per year for newly diagnosed Crohn’s disease patients (incidence rate ratio (IRR) 1.03; 95% confidence interval (CI): 1.02–1.05), but not for ulcerative colitis. The rate of surgery decreased among Crohn’s disease patients aged 17–40 years (IRR 0.96; 95% CI: 0.93–0.98), but not for ulcerative colitis. Smoking at diagnosis increased the risk of surgery for Crohn’s disease patients diagnosed after the age of 40 (hazard ratio (HR) 2.99; 95% CI: 1.52–5.92), but not for those diagnosed before age 40. Ulcerative colitis patients diagnosed between the ages of 17 and 40 years and who quit smoking before their diagnosis were more likely to undergo a colectomy (ex-smoker vs. never smoker: HR 1.66; 95% CI: 1.04–2.66). The age-specific findings were consistent across sensitivity analyses for Crohn’s disease, but not ulcerative colitis.Conclusions:In this study, the association of smoking and surgical resection was dependent on the age at diagnosis of IBD.

Risk of depression among patients with acne in the U.K.: a population‐based cohort study

DEAR EDITOR, Acne has been associated with adverse psychiatric symptoms. In dermatology outpatient clinics, approximately 25.2% of patients with acne experience some psychiatric morbidity. However, few studies have evaluated the clinically significant diagnostic category of major depressive disorder (MDD) among people with acne. Here, we investigated whether patients with acne are at an increased risk of developing MDD compared to the general population, using one of the largest electronic medical records databases in the world. A retrospective cohort study was conducted using data from The Health Improvement Network (THIN) (1986–2012), a large primary care database in the U.K. that also includes data from specialists. All individuals between 7 and 50 years of age with ≥ 1 Read codes (diagnostic codes linked to International Classification of Diseases codes) for acne were identified. A general population cohort without acne was also identified. The study was approved by the Conjoint Health Research Ethics Board at the University of Calgary (ID 24423) and from the Scientific Review Committee in the U.K. (ID 16THIN036), authorizing access to extract relevant data from THIN. A complete list of codes used to identify exposures, outcomes and covariates is available from the authors. All patients were followed from their start date for ≥ 2 years in THIN until the earliest of either their first MDD Read code (main outcome), transfer out of practice, death or end of data collection. Observations were censored at the end of follow-up in patients where MDD was not observed during the study period. To identify only incident cases, patients with an acne or MDD Read code prior to the start of follow-up were excluded. Baseline covariates at the start of follow-up included age (young ≤ 19; adult > 19 years), sex, obesity (BMI ≥ 30 kg m ), smoking status (never, former, current), alcohol use (yes or no), medical comorbidities using the Charlson Comorbidity Index (0 or ≥ 1 comorbidity) and socioeconomic status using the Townsend Deprivation Index (quintiles 1–5, with 1 least and 5 most deprivation).

Treatment Receipt and Outcomes from a Clinic Employing the Attention-Deficit/Hyperactivity Disorder Treatment Guideline of the Children's Medication Algorithm Project

OBJECTIVE Little is known about the pattern of service receipt and outcomes from clinics implementing best practice guidelines in child mental health. This study aimed to determine these variables for a clinic that implemented an attention-deficit/hyperactivity disorder (ADHD) treatment guideline proposed by the Childrens Medication Algorithm Project (CMAP). METHODS Secondary analyses of medical record extracts were conducted for children who received treatment from 2007 to 2012 in a specialty clinic linked to a public childrens hospital in Canada. Patterns of medication selection and dosing were compared with CMAP guidelines. Outcomes were based on parent and teacher ratings on the ADHD portion of the Multimodal Treatment Study for ADHD (MTA)- Swanson, Nolan, and Pelham, Version IV (SNAP-IV). RESULTS Data were available for 132 children (ages 5-14), 81.8% of whom had no previous ADHD medication exposure, and 97.0% of whom had started at least one medication. Methylphenidate was used first for 59.8% of children, whereas 33.3% started with an amphetamine product. Of the 47.0% of children who progressed to a second medication trial, 88.7% tried a stimulant from a second class. In total, 19.7% tried atomoxetine, which was typically used as a third stage choice (i.e., after two different stimulant exposures). Stage four to six medications were rarely used, rather stimulants were retried after atomoxetine and/or medication combinations were tried. Symptomatic remission at the end of treatment was achieved by 70.4% and 82.4%, according to parents and teachers respectively, for those with outcome data and who completed treatment. Outcomes for those further along the treatment algorithm were similar to discharges at the beginning of the algorithm. CONCLUSIONS The high rates of symptomatic remission observed within this clinical service may be a function of adherence to CMAP recommendations. However, the lack of a comparison group or experimental design prevents determination of causality. Additional investigations of the impacts of implementing evidence-based guidelines are critically needed, with proposed benchmarks to inform outcome evaluations.

Reduced knee adduction moments for management of knee osteoarthritis:: A three month phase I/II randomized controlled trial

Wedged insoles are believed to be of clinical benefit to individuals with knee osteoarthritis by reducing the knee adduction moment (KAM) during gait. However, previous clinical trials have not specifically controlled for KAM reduction at baseline, thus it is unknown if reduced KAMs actually confer a clinical benefit. Forty-eight participants with medial knee osteoarthritis were randomly assigned to either a control group where no footwear intervention was given, or a wedged insole group where KAM reduction was confirmed at baseline. KAMs, Knee Injury and Osteoarthritis Outcome Score (KOOS) and Physical Activity Scale for the Elderly (PASE) scores were measured at baseline. KOOS and PASE surveys were re-administered at three months follow-up. The wedged insole group did not experience a statistically significant or clinically meaningful change in KOOS pain over three months (p=0.173). Furthermore, there was no association between change in KAM magnitude and change in KOOS pain over three months within the wedged insole group (R2=0.02, p=0.595). Improvement in KOOS pain for the wedged insole group was associated with worse baseline pain, and a change in PASE score over the three month study (R2=0.57, p=0.007). As an exploratory comparison, there was no significant difference in change in KOOS pain (p=0.49) between the insole and control group over three months. These results suggest that reduced KAMs do not appear to provide any clinical benefit compared to no intervention over a follow-up period of three months. ClinicalTrials.gov ID Number: NCT02067208.

Psoriasis and the risk of foot and ankle tendinopathy or enthesopathy in the absence of psoriatic arthritis: a population-based study

Objectives Imaging studies in patients with cutaneous psoriasis have demonstrated asymptomatic bone and tendon changes, commonly of the foot and ankle. We sought to determine if patients with cutaneous psoriasis have an increased risk of clinically significant foot and ankle tendinopathy or enthesopathy compared with the general population. Methods Patients with cutaneous psoriasis and a general population cohort were identified in The Health Improvement Network, a general practice medical records database from the UK. All patients with psoriatic arthritis were excluded. Cox proportional-hazards models (α=0.05) estimated the HR for development of foot and ankle tendinopathy or enthesopathy among patients with psoriasis, with adjustment for numerous covariates. Results In total, 78 630 patients with cutaneous psoriasis and 5 983 338 persons from the general population were identified. In an unadjusted model, patients with cutaneous psoriasis had a 25% increased risk of developing foot and ankle tendinopathy or enthesopathy compared with the general population (HR 1.25, 95% CI 1.20 to 1.30, p<0.0001). The HR remained unchanged and statistically significant after adjusting for covariates, and in sensitivity analyses. Conclusions These data suggest that patients with psoriasis can have foot and ankle tendinopathy or enthesopathy without having psoriatic arthritis, presenting a diagnostic challenge to physicians. Further research is needed to elucidate mechanisms contributing to this increased risk.

The impact of depression and antidepressant usage on primary biliary cholangitis clinical outcomes

Background Depression is prevalent in primary biliary cholangitis (PBC) patients. Our aims were to examine the effects of depression and antidepressants on hepatic outcomes of PBC patients. Methods We used the UK Health Improvement Network database to identify PBC patients between 1974 and 2007. Our primary outcome was one of three clinical events: decompensated cirrhosis, liver transplantation and death. We assessed depression and each class of antidepressant medication in adjusted multivariate Cox proportional hazards models to identify independent predictors of outcomes. In a sensitivity analysis, the study population was restricted to PBC patients using ursodeoxycholic acid (UDCA). Results We identified 1,177 PBC patients during our study period. In our cohort, 86 patients (7.3%) had a depression diagnosis prior to PBC diagnosis, while 79 patients (6.7%) had a depression diagnosis after PBC diagnosis. Ten-year incidence of mortality, decompensated cirrhosis, and liver transplantation were 13.4%, 6.6%, and 2.0%, respectively. In our adjusted models, depression status was not a predictor of poor outcomes. After studying all classes of antidepressants, using the atypical antidepressant mirtazapine after PBC diagnosis was significantly protective (Adjusted HR 0.23: 95% CI 0.07–0.72) against poor liver outcomes (decompensation, liver transplant, mortality), which remained statistically significant in patients using UCDA (HR 0.21: 95% CI 0.05–0.83). Conclusions In our study, depression was not associated with poor clinical outcomes. However, using the antidepressant mirtazapine was associated with decreased mortality, decompensated cirrhosis and liver transplantation in PBC patients. These findings support further assessment of mirtazapine as a potential treatment for PBC patients.

Efficacy and adverse events of oral isotretinoin for acne: a systematic review

Despite many years of clinical use of isotretinoin, a comprehensive review of evidence for isotretinoin therapy in patients with acne is lacking. We searched MEDLINE, Embase, Cochrane Central, relevant web pages and bibliographies for randomized controlled trials in acne evaluating isotretinoin vs. control (placebo or other therapy). Data were extracted and summarized descriptively. Eleven trials were identified (total 760 patients randomized), containing mostly men. Mean treatment ages ranged from 18 to 47·9 years and participants generally had moderate‐to‐severe acne. Across all trials, isotretinoin therapy reduced acne lesion counts by a clinically relevant amount, and always by a greater amount than control, which was either placebo (two studies), oral antibiotics (seven studies) or other control (two studies). Across trials with an overall low risk of bias, two of three demonstrated statistically significant differences between isotretinoin and control. The frequency of adverse events was twice as high with isotretinoin (751 events) than with control (388 events). More than half of all adverse events were dermatological and related to dryness. Adverse events from isotretinoin causing participant withdrawal from trials (12 patients) included Stevens–Johnson syndrome, cheilitis, xerosis, acne flare, photophobia, elevated liver enzymes, decreased appetite, headaches and depressed mood. This review suggests that isotretinoin is effective in reducing acne lesion counts, but adverse events are common. This study was registered with PROSPERO number CRD42015025080.

Systemic retinoids and psychiatric disorders in patients with skin diseases: a multifactorial relationship

DEAR EDITOR, Le Moigne et al. reviewed case reports to examine a possible causal linkage between use of systemic retinoids and psychiatric disorders. The authors concluded that systemic retinoids should be prescribed with vigilance for patients with psychiatric disorders. While we agree with a need for vigilance, we caution against prematurely concluding that there is a causal association. In our opinion, the only way to demonstrate an increased risk would be to compare groups of otherwise comparable patients receiving or not receiving systemic retinoids, using a control group. For example, rather than experiencing a direct biological effect of the retinoid, patients may have developed psychiatric conditions as a result of the presence of severe skin disease, which could negatively affect self-esteem. Previous research has raised the issue of confounding by indication whereby the severity of skin disease is associated with systemic retinoid treatment and may itself be an independent risk factor for psychiatric conditions. We propose that the results of this review may be biased as a result of this type of confounding (mixing of effects where an extraneous variable is associated with exposure and outcome), also termed ‘channelling bias’, because patients with severe acne are more likely to be prescribed more potent medications like systemic retinoids. Also, as psychiatric disorders, including depression, can rarely be attributed to a single cause and are common and episodic in nature, it is likely that published cases have suggested causation by chance. When these case reports are published more often than reports without adverse events, publication bias could result and lead to over-reporting of psychiatric outcomes. Readers should consider the possibility that psychiatric disorders may be common among all dermatology patients, not just those treated with systemic retinoids. The idea that systemic retinoids should be avoided in patients judged to be at risk of psychiatric disorders may be counterproductive. Denying them effective treatments may do more harm than good. Also, the idea that patients given nonretinoid treatments are at lower risk may lead to an unjustified lowering of vigilance in those patients. Thus, further research is needed to elucidate the risks of psychiatric disorders among patients with skin diseases.

Depression as a risk factor for the development of rheumatoid arthritis: a population-based cohort study

Objectives Major depressive disorder (MDD) is associated with increased levels of systemic proinflammatory cytokines, including tumour necrosis factor alpha. As these cytokines are pathogenic in autoimmune diseases such as rheumatoid arthritis (RA), our aim was to explore on a population-level whether MDD increases the risk of developing RA. Methods A retrospective cohort study was conducted using The Health Improvement Network (THIN) database (from 1986 to 2012). Observation time was recorded for both the MDD and referent cohorts until patients developed RA or were censored. Cox proportional hazards models were used to determine the risk of developing RA among patients with MDD, accounting for age, sex, medical comorbidities, smoking, body mass index and antidepressant use. Results A cohort of 403 932 patients with MDD and a referent cohort of 5 339 399 patients without MDD were identified in THIN. Cox proportional hazards models revealed a 31% increased risk of developing RA among those with MDD in an unadjusted model (HR=1.31, 95% CI 1.25 to 1.36, p<0.0001). When adjusting for all covariates, the risk remained significantly increased among those with MDD (HR=1.38, 95% CI 1.31 to 1.46, p<0.0001). Antidepressant use demonstrated a confounding effect that was protective on the association between MDD and RA. Conclusion MDD increased the risk of developing RA by 38%, and antidepressants may decrease this risk in these patients. Future research is necessary to confirm the underlying mechanism of MDD on the pathogenesis of RA.