Modafinil for Severe Fatigue in Inflammatory Bowel Disease: A Prospective Case Series.

Fatigue is highly prevalent in patients with IBD, affecting 72% of patients with active inflammatory bowel disease (IBD) and 47% in remission, and is associated with poor quality of life and significantly wider costs.1 However, understanding the mechanisms of IBD fatigue remains limited, as reflected in a lack of effective treatments.1.

Activation of the interleukin-23/Th17 axis in major depression: a systematic review and meta-analysis.

The interleukin-23/Th17 axis is a promising modifiable target for depression. However, its association with depression has not been systematically evaluated. We systematically searched four databases (EMBASE, Web of Science, Pubmed and PsycINFO) for studies comparing patients with major depression and healthy controls for plasma/serum levels of Th17 cells and their canonical cytokines (interleukin-17A [IL-17A], IL-22, granulocyte macrophage colony stimulating factor [GM-CSF]). We also compared counts of Th1, Th2 and Th9 cells between depressed/non-depressed patients and their respective canonical cytokines. We performed random-effects meta-analysis of the standardised mean difference (SMD) in immune measures between groups. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 3154 studies screened, 36 studies were included in meta-analysis. Patients with depression had elevated IL-17A compared to controls (SMD = 0.80 [95% CI 0.03 to 1.58], p = 0.042), an association moderated by antidepressant use (Z = 2.12, p = 0.034). Patients with depression had elevated GM-CSF (SMD = 0.54 [95% CI 0.16 to 0.91], p = 0.0047), and a trend towards higher Th17 counts (SMD = 0.44 [- 0.01 to 0.88], p = 0.052). Whilst the Th2-associated cytokine IL-5 was elevated in depression (SMD = 0.36 [95% CI 0.05 to 0.66], p = 0.02), Th2 cell counts (p = 0.97), Th1 cell counts (p = 0.17) and interferon-γ (p = 0.22) were not. Data for Th9 cells, IL-9 and IL-22 were insufficient for meta-analysis. Respectively, 22, 25 and 5 studies were good, fair and poor in quality. Patients with major depression show peripheral over-activation of the IL-23/Th17 axis. Future interventional studies should test whether this is a modifiable target for depression.

The Prevalence and Incidence of Irritable Bowel Syndrome and Inflammatory Bowel Disease in Depression and Bipolar Disorder: A Systematic Review and Meta-Analysis.

OBJECTIVE: The increased prevalence and incidence of affective disorders among patients with gastrointestinal disease have been well established. However, few studies have investigated the inverse relationship. We aimed to identify all pieces of evidence of the prevalence and incidence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) in people with depression and bipolar disorder. METHODS: We conducted a systematic review of studies reporting the association between affective disorders (exposure) and IBS or IBD (outcome) in adults. Evidence was evaluated for quality using Joanna Briggs Institute Critical Appraisal tools. Where suitable data were available, meta-analyses were performed. RESULTS: We identified 18 studies that met the selection criteria, of which 11 provided data on IBS, 5 on IBD, and 2 on both. Overall, people with depression were significantly more likely to have comorbid IBS (risk ratio = 2.42, 95% confidence interval = 1.98-2.96) and to develop new-onset IBS (risk ratio = 1.90, 95% confidence interval = 1.41-2.56) compared with people without depression. They were also more likely to have and develop IBD, and among patients with IBD, significantly increased rates of depression were observed as early as 5 years before diagnosis. Bipolar disorder was not consistently associated with risk of either condition. CONCLUSIONS: People with depression are at an increased risk of both having and developing lower gastrointestinal disorders. These findings have important implications for how we understand, manage, and prevent this comorbidity in clinical practice. Further studies are needed to improve our understanding of the relationship between bipolar disorder and bowel disease as well as the role of psychotropic medication, particularly selective serotonin reuptake inhibitors.

SITAgliptin for Depressive Symptoms in Type 2 Diabetes: A Feasibility Randomized Controlled Trial.

OBJECTIVE: We tested the feasibility of using sitagliptin-a dipeptidyl peptidase-IV inhibitor-for depressive symptoms in type 2 diabetes (T2D). METHODS: In a feasibility, double-blind, randomized controlled trial, we recruited people aged 18 to 75 years with T2D (glycated hemoglobin A1c levels ≥53 and ≤86 mmol/mol prescribed oral hypoglycemic therapy) and comorbid depressive symptoms (Patient Health Questionnaire-9 score ≥10) from family practices in South London. Eligible patients were randomized to sitagliptin 100 mg per day or matched placebo for 12 weeks. The primary feasibility outcomes were participation rates, attrition rates, and adverse events. The primary clinical outcomes were depressive symptoms (Patient Health Questionnaire-9 and 16-item Quick Inventory of Depressive Symptomatology scores) at 12 weeks as assessed using analyses of covariance. Ranges of treatment effects were estimated using Cohen d and associated 95% confidence intervals, where negative values favored sitagliptin over placebo. RESULTS: Of 153 people screened across 32 practices, 44 were randomized (22 to each arm). The mean (standard deviation) age was 58.8 (8.3) years, 46% were female, and 52% were of non-white ethnicity. Of those treated, 1 patient (4.5%) in each arm withdrew, and there were no group differences in adverse events. Despite improving 12-week glycated hemoglobin A1c (d = -1.19 [95% confidence interval = -1.90 to -0.48), improvement in 12-week Quick Inventory of Depressive Symptomatology score with sitagliptin was inferior to placebo across the range of estimated treatment effects (d = 0.71 [0.13 to 1.30]). Effects of sitagliptin on inflammation were inconsistent (d = -0.32 [-0.81 to 0.17] for high-sensitivity C-reactive protein). CONCLUSIONS: Repositioning of oral hypoglycemic therapy for depressive symptoms in T2D is feasible. However, in this unpowered feasibility study, we did not detect evidence of superiority of sitagliptin over placebo. The results are cautioned by the small sample size and limited treatment duration.Trial Registration: EudraCT: 2015-004527-32.

The psychopathology of recurrent diabetic ketoacidosis: A case-control study.

BACKGROUND: Despite its poor prognosis, the psychological factors associated with recurrent diabetic ketoacidosis are poorly understood. In people with type 1 diabetes, we assessed for psychopathology in those with and without recurrent diabetic ketoacidosis (DKA). METHOD: The design was a case-control study. Cases were defined as people with two or more DKA episodes in a 12-month period (recurrent DKA). Cases and controls were matched for gender and age. We compared groups for scores on Beck's Anxiety Inventory (BAI), Beck's Depression Inventory II, Difficulty in Emotion Regulation Scale (DERS), Experiences in Close Relationships-Revised, Standardised Assessment of Personality-Abbreviated Scale (SAPAS), Interpersonal Problem Inventory, Eating Disorder Examination Questionnaire and Problem Areas in Diabetes (PAID) using unpaired t-tests or Mann-Whitney U tests for parametric and non-parametric data, respectively. Correction was made for multiple testing. RESULTS: In all, 23 cases and 23 controls were recruited with mean age 31.0 (11.4) years and 65.2% were men. Cases had higher HbA1c levels than controls (101.1 (23.2) vs. 85.7 (21.7) mmol/mol, (p = 0.02)). Compared to controls, people with recurrent DKA had higher scores on the BAI (p = 0.004), PAID (p = 0.004), DERS (p = 0.001) and SAPAS (p < 0.001). Sixteen of 23 (69.6%) cases screened positive for a personality disorder compared to 6 of 23 (26.1%) controls. CONCLUSIONS: People with recurrent DKA have elevated levels of anxiety and diabetes distress, greater difficulty with emotion regulation and personality dysfunction compared to matched controls.

The Association Between Selective Serotonin Reuptake Inhibitors and Glycemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Individual studies have reported conflicting effects of selective serotonin reuptake inhibitors (SSRIs) on glycemia. We systematically reviewed the effects of SSRIs on glycemia and whether metabolic and psychological factors moderated these effects. METHODS: We systematically searched for placebo-controlled randomized controlled trials investigating the effect of SSRIs on glycemia (fasting blood glucose or HbA1c) as a primary or secondary outcome. Random effects meta-analysis was conducted to compute an overall treatment effect. Meta-regression tested whether depression, type 2 diabetes, insulin resistance, treatment duration, and weight loss moderated treatment effects. RESULTS: Sixteen randomized controlled trials (n = 835) were included and glycemia was usually a secondary outcome. Overall, SSRIs improved glycemia versus placebo (pooled effect size (ES) = -0.34, 95% confidence interval (CI) = -0.48 to -0.21; p < .001, I = 0%). Individually, fluoxetine (ES = -0.29, 95% CI = -0.54 to -0.05; p = .018) and escitalopram/citalopram (ES = -0.33, 95% CI = -0.59 to -0.07; p = .012) outperformed placebo, but paroxetine (ES = -0.19, 95% CI = -0.58 to 0.19; p = .33) did not. Results were similar in populations selected for depression as those not. Across studies, baseline insulin resistance (p = .46), treatment duration (p = .47), diabetes status (p = .41), and weight loss (p = .93) did not moderate changes. Heterogeneity for all analyses was nonsignificant. CONCLUSIONS: SSRIs seem to have an association with improvement in glycemia, which is not moderated by depression status, diabetes status, or change in weight across studies. Future powered trials with longer treatment duration are needed to confirm these findings. REGISTRATION: PROSPERO ID: CRD4201809239.

The association of depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years in newly diagnosed type 2 diabetes: a prospective cohort study.

AIMS/HYPOTHESIS: We examined the associations between depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years, after diagnosis of type 2 diabetes. METHODS: In a multi-ethnic, primary care cohort (n = 1735) of adults, all with recent (<6 months) diagnosis of type 2 diabetes, we measured the associations between depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) and diabetes distress (Problem Areas in Diabetes [PAID] score ≥40), with change in 2 year HbA1c as the primary outcome and with incident rates of diabetes complications as secondary outcomes. Multivariate models were used to account for potential confounders. RESULTS: Of the 1651 participants (95.2%) of the total primary care cohort with available baseline PHQ-9 and PAID scores, mean ± SD age was 56.2 ± 11.1 years, 55.1% were men and 49.1% were of non-white ethnicity; 232 (14.1%) and 111 (6.7%) had depressive symptoms and diabetes distress, respectively. After adjustment for confounders, depressive symptoms were not associated with worsening HbA1c. After adjustment for age, sex, ethnicity, vascular risk factors and diabetes treatments, depressive symptoms were associated with increased risk of incident macrovascular complications (OR 2.78 [95% CI 1.19, 6.49], p = 0.018) but not microvascular complications. This was attenuated (p = 0.09) after adjustment for IL-1 receptor antagonist concentration. Diabetes distress was not associated with worsening HbA1c or incident complications. CONCLUSIONS/INTERPRETATION: In the first 2 years of type 2 diabetes, the effect of depressive symptoms and diabetes distress on glycaemic control is minimal. There was, however, an association between depressive symptoms and incidence of macrovascular complications. Elevated innate inflammation may be common to both depression and macrovascular diabetes complications, but these findings require replication.

Factors associated with cognitive impairment in patients with newly diagnosed type 2 diabetes: a cross-sectional study.

OBJECTIVES: Type 2 diabetes (T2DM) is strongly associated with cognitive impairment but the factors within T2DM that predispose to cognitive impairment are less well understood, while previous studies have investigated samples with T2DM of widely varying duration. We aimed to investigate the factors associated with cognitive impairment in patients with newly diagnosed T2DM. METHOD: In a multi-ethnic sample with T2DM diagnosed in the last 6 months, we assessed cognitive function using the 13-item modified telephone interview for cognitive status (TICS-M). Cognitive function was assessed both categorically (impairment defined as lowest 10% of scores with the remainder as controls) and as continuous TICS-M score. Its associations were tested in univariate and multivariate analyses with a range of biological, psychological and sociodemographic factors. RESULTS: Of 1790 participants, 1680 had a complete TICS-M assessment at baseline. After controlling for covariates, older age (p < 0.001) and lower verbal intelligence (p < 0.001) were associated with both cognitive impairment and lower TICS-M scores, while non-white ethnicity (p < 0.001), female gender (p = 0.02) and higher HbA1c (p = 0.002) were associated with lower TICS-M scores. Depression (defined as Patient Health Questionnaire-9 score ≥10), elevated inflammatory markers and body mass index were not associated with cognitive function after controlling for covariates. CONCLUSION: Age, verbal intelligence, female gender and HbA1c are associated with cognitive performance in T2DM soon after diagnosis. Previously reported associations with depression and inflammatory markers may occur later as causes or consequences of T2DM. Longitudinal analyses are needed to assess potentially modifiable factors predicting cognitive decline in early T2DM.

Systematic review of pharmacological treatments for depressive symptoms in Huntington's disease.

BACKGROUND: Depressive symptoms are common in Huntington's disease (HD), profoundly affect quality of life, and predict suicidal ideation. However, no recent review of antidepressant treatment in HD has been published. METHODS: We performed a PRISMA systematic review of HD studies, which used a recognized antidepressant and measured change in depressive symptoms using a validated psychiatric scale. Controlled trials, uncontrolled trials, observational studies, and case series were included. RESULTS: Eleven studies were included, totalling 190 patients. One study examined venlafaxine, one fluoxetine, one citalopram, one atomoxetine, one modafinil, one lithium, and five antipsychotics. No studies were of adequate duration, size, or outcome, and no controlled trial in a depressed population produced a positive result. CONCLUSIONS: Inadequate evidence exists to guide antidepressant treatment in HD. Further research is needed to assess antidepressant efficacy and to examine whether treatment of depression represents a modifiable target for the high suicide rate in HD.

Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle-Ottawa scale (cohort studies). We included 11 studies ( n  = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = -0.71 (95% confidence interval (CI) -1.32 to -0.10), P  = 0.02, I2  = 51%] and QoL [SMD = 0.88 (95% CI 0.30-1.45), P  = 0.003, I2  = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = -0.95 (95% CI -1.45 to -0.45, P  < 0.001, I2  = 11%], anxiety [SMD = -0.92 (95% CI 1.72 to -0.13), P  = 0.023, I2  = 65%] and QoL [SMD = 1.14 (95% CI 0.66-1.62), P  < 0.001, I2  = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Cognitive Impairment in Adult Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: People living with inflammatory bowel disease (IBD) are exposed to multiple risk factors for cognitive impairment and frequently report cognitive difficulties. However, the presence of cognitive impairment in IBD has not been systematically reviewed. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic multidatabase search for cross-sectional and longitudinal studies comparing adults with IBD versus healthy controls for domain-specific cognitive function or scores on multidomain cognitive screening tools. For any domain reported by 3 or more studies, we conducted random-effects meta-analysis to calculate the standardized mean difference between groups; lower scores reflected poorer performance. Between-study heterogeneity was assessed using the I2 statistic and study quality assessed using an IBD-modified Newcastle-Ottawa scale. RESULTS: Of 8302 articles screened, 12 studies (n = 687) were included in the qualitative synthesis and 11 in meta-analyses. All studies were cross-sectional. Studies generally excluded people with active IBD and older adults. Despite no significant differences on multidomain screening tools such as the Mini Mental State Examination (-0.27 [95% confidence interval -0.68, 0.08], P = 0.14), people with IBD showed significant deficits compared with healthy controls in attention (standardized mean difference -0.36 [-0.60, -0.12], P = 0.003, I2 = 0%), executive function (standardized mean difference -0.45 [-0.77, -0.13, P = 0.005, I2 = 42.5%), and specifically in working memory (standardized mean difference -0.58 [-0.85, -0.30], P < 0.001, I2 = 0%). Deficits in learning and recall were nonsignificant (P = 0.089) and other domains insufficient for meta-analysis. CONCLUSIONS: People with IBD show deficits in attention and executive function, particularly in working memory, suggesting that cognitive impairment is a potential extraintestinal manifestation of IBD.

The Maudsley 3-item Visual Analogue Scale (M3VAS): Validation of a scale measuring core symptoms of depression.

AIMS: Low mood and anhedonia are the core symptoms of major depressive disorder (MDD). However, there is no established visual analogue scale that measures pervasiveness of both symptoms. We aimed to validate the Maudsley 3-item Visual Analogue Scale (M3VAS) as a measure of core depressive symptoms and suicidality. METHODS: This is a cross-sectional secondary analysis combining data from two randomised controlled trials covering a broad range of depression severity from euthymia to severe depression. We validated the M3VAS by testing: 1) latent construct domains using factor analysis; 2) internal consistency using Cronbach's alpha; and 3) convergent validity by correlating M3VAS scores against scores on the Quick Inventory of Depressive Symptomatology-16 item (QIDS-SR-16), which is validated for use in clinical trials. RESULTS: Of 180 patients in the combined cohort, 177 (98.3%) provided complete data on the M3VAS and QIDS-SR-16. The mean (SD) age was 41.6 (13.0) years and 59.3% were female. Using factor analysis, one eigenvalue above 1 was produced (2.39) that explained 79.6% of the variance, indicating a one-factor model. Cronbach's alpha was 0.87, demonstrating good internal consistency. Total M3VAS scores correlated strongly (r = 0.72, p<0.001) with QIDS-SR-16 scores, indicating good convergent validity. LIMITATIONS: This was a cross-sectional study and was not validated against a clinician-rated assessment for depression. CONCLUSION: The M3VAS is a simple, valid instrument for the assessment of core depressive symptoms and suicidality across the depression spectrum. Future studies should test the longitudinal validity of the M3VAS in detecting changes in core depressive symptoms and suicidality over time.

The Prospective Association Between Inflammation and Depressive Symptoms in Type 2 Diabetes Stratified by Sex.

OBJECTIVE: We tested whether inflammation is associated with worsening depressive symptoms in type 2 diabetes and examined whether sex moderated this association. RESEARCH DESIGN AND METHODS: In a prospective cohort study of people with newly diagnosed type 2 diabetes, we measured depressive symptoms over a 2-year follow-up using the Patient Health Questionnaire-9 (PHQ-9). The independent variable was a composite inflammation burden score at diagnosis of diabetes, derived from hs-CRP, white cell count, interleukin (IL)-1ß, IL-1 receptor antagonist, monocyte chemotactic protein-1, and vascular endothelial growth factor concentrations. General linear models assessed 1) the association between overall inflammation burden and estimated marginal mean PHQ-9 score (ln transformed) at 2 years and 2) whether sex interacted with elevated inflammation burden (above-median score) in predicting change in PHQ-9 score. Models were adjusted for age, ethnicity, BMI, blood pressure, cholesterol, HbA1c, antidepressants, anti-inflammatory medications, and baseline ln PHQ-9 score. RESULTS: Of 1,174 people with complete inflammation data, mean (SD) age was 56.7 (11.0) years and 46.1% were of nonwhite ethnicity and 44.1% female. After full adjustment, inflammation burden was not associated with worsening ln PHQ-9 score (P = 0.65). However, female sex interacted with elevated inflammation in predicting higher 2-year ln PHQ-9 score (ß = 0.32, P = 0.005), showing that the difference by inflammation burden in females was 0.32 larger than in males. In post hoc comparisons, ln PHQ-9 score was higher in females than males with elevated inflammation (P = 0.003) but not with low inflammation (P = 0.34) burden. CONCLUSIONS: In type 2 diabetes, female sex confers specific vulnerability to the effects of inflammation on depressive symptoms.