Cognitive Impairment and Depression in Mastocytosis: A Synthesis of the Literature.

PURPOSE OF REVIEW: Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area. RECENT FINDINGS: The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors' tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue. The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize "depression" in this population.

Trajectories of depressive symptoms early in the course of bereavement: Patterns, psychosocial factors and risk of prolonged grief.

In the context of bereavement, little is known about the mechanisms that differentiate normative adjustment patterns from those that may indicate potential psychopathology. This study aimed to replicate and extend previous work by (1) characterizing the trajectories of depressive symptoms from 3 to 12 months after the loss of a spouse, (2) examining whether (a) childhood maltreatment and attachment style predicted distinct depression trajectories, and (b) different depression trajectories were associated with the risk of prolonged grief at 12 months post-loss. Recently bereaved individuals (N = 175) completed self-report assessments at 3, 4, 6, and 12-months post-loss. Trajectories of depressive symptoms were estimated using group-based trajectory modelling. Four distinct trajectories of depressive symptoms were identified: (1) resilience (minimal/no depression across time points; 45%), (2) moderate depression-improved (alleviated to 'mild' by 12 months; 31%), (3) severe depression-improved (alleviated to 'moderate' by 12 months; 15%), and (4) chronic depression ('severe' symptoms across time points; 9%). Higher childhood maltreatment predicted a greater likelihood of belonging to the 'severe depression-improved' and 'chronic depression' groups than the 'resilient' and 'moderate depression-improved' groups. Widow(er)s with higher attachment anxiety were more likely to belong to the 'severe depression-improved' and 'chronic depression' groups than the 'resilient' group. The trajectory groups with persistent levels of depressive symptoms up until 6 months were more likely to exhibit prolonged grief at 12 months post-loss. Changes from pre-loss functioning cannot be estimated. Our findings provide insight into the early identification of post-loss prolonged grief.

Modafinil's effects on cognition and sleep quality in affectively-stable patients with bipolar disorder: a pilot study.

Introduction: Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil®), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients. Methods: Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8. Results: No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group. Discussion: Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot. Clinical trial registration: ClinicalTrials.gov, identifier NCT01965925.

The effect of aging on facial emotion recognition in bipolar disorder.

OBJECTIVE: Convergent data point to an exaggerated negativity bias in bipolar disorder (BD), and little is known about whether people with BD experience the 'positivity effect' with increasing age. METHOD: This is a cross sectional study of 202 participants with BD aged 18-65, and a sample (n = 53) of healthy controls (HCs). Participants completed the CANTAB Emotion Recognition Task (ERT). Using analysis of variance, we tested for a main effect of age, diagnosis, and an interaction of age x diagnosis on both negative and positive conditions. RESULTS: We observed increased accuracy in identifying positive stimuli in the HC sample as a function of increasing age, a pattern that was not seen in participants with BD. Specifically, there was a significant diagnosis by age cohort interaction on ERT performance that was specific to the identification of happiness, where the Later Adulthood cohort of HCs was more accurate when identifying happy faces relative to the same cohort of BD patients. CONCLUSION: Later life looks different for people with BD. With an aging population globally, gaining a clearer picture of the effects of recurrent mood dysregulation on the brain will be critical in guiding efforts to effectively optimize outcomes in older adults with BD.

Emotion Regulation, Parasympathetic Function, and Psychological Well-Being.

The negative emotions generated following stressful life events can increase one's risk of depressive symptoms and promote higher levels of perceived stress. The process model of emotion regulation can help distinguish between adaptive and maladaptive emotion regulation strategies to determine who may be at the greatest risk of worse psychological health across the lifespan. Heart rate variability (HRV) may affect these relationships as it indexes aspects of self-regulation, including emotion and behavioral regulation, that enable an individual to dynamically adapt to the changing demands of both internal and external environments. In this study, we expected individual differences in resting vagally mediated HRV to moderate the influence of emotion regulatory strategies among our sample of 267 adults. We found support for the hypothesis that higher vagally mediated HRV buffers against the typical adverse effects of expressive suppression when evaluating depressive symptoms and found weak support when considering perceived stress. There was no evidence for an interaction between cognitive reappraisal and vagally mediated HRV but there was a significant, negative association between cognitive reappraisal and depressive symptoms and perceived stress. Future work may determine if intervening on either emotion regulation strategies or HRV may change these within-persons over time.

The longitudinal connection between depressive symptoms and inflammation: Mediation by sleep quality.

Although there is a strong association between depressive symptoms and markers of inflammation, it remains unclear whether depressive symptoms at one point in life may predict inflammation later in life. Moreover, despite extant literature linking sleep with both depressive symptoms and inflammation, there is little research investigating poor sleep as a mechanism linking depressive symptoms with later inflammation. The links between depression and physical health can also vary by gender. In longitudinal analyses with data from the Midlife in the United States (MIDUS) study, we examined whether depressive symptoms were associated with inflammatory markers 11 years later and whether these associations were mediated by sleep disturbances or moderated by gender. Participants reported depressive symptoms and demographic information at baseline. At 11-year follow-up, the same participants (n = 968) reported depressive symptoms, sleep quality and duration using validated scale items, and provided a blood sample from which inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) were quantified. Actigraphy assessment of sleep was obtained in a subsample (n = 276). After adjusting for concurrent depressive symptoms and other relevant covariates, baseline depressive symptoms were associated with CRP 11 years later in the full sample, and with IL-6 among women. Subjective sleep quality mediated the association between depressive symptoms and CRP. Results suggest that depressive symptoms may be longitudinally associated with inflammation; however, directionality issues cannot be determined from the present work, particularly as inflammation markers (which might have been associated with baseline depressive symptoms) were not available at baseline. Findings further suggest that longitudinal associations between depressive symptoms and inflammation may potentially be explained by sleep and may reflect gender specific patterns.

Depressive symptoms and other negative psychological states relate to ex vivo inflammatory responses differently for men and women: Cross-sectional and longitudinal evidence.

An array of negative psychological states - including depressive symptoms, perceived stress, rumination, and negative affect - have been linked to immune function and inflammatory responses. Herein we show evidence of gender-dependent associations between ex vivo lipopolysaccharide (LPS)-stimulated cytokine responses and such psychological states, in both cross-sectional and longitudinal analyses from three annual waves (N = 162 at baseline, 67.3% female). In cross-sectional analyses (at baseline), gender moderated the associations of depressive symptoms (previously reported), perceived stress (B = -0.043, 95%CI [-0.080, -0.015]), rumination (B = -0.500, [-1.015, -0.232]), negative affect (B = -0.020, [-0.020, -0.005]), and positive affect (B = 0.024, [0.008, 0.047]) with LPS-stimulated cytokine responses. In each analysis, negative psychological states were positively associated with LPS-stimulated cytokine responses among men but negatively among women (with associations for positive affect in the opposite direction). In longitudinal analyses (across three annual measurements), similar associations were seen for depressive symptoms (B = -0.024, [-0.059, -0.004]), perceived stress (B = -0.045, [-0.069, -0.024]), and rumination (B = -0.381, [-0.622, -0.120]). These results indicate that gender is a critical factor in associations between a broad array of negative psychological states and inflammatory responses and identify one pathway by which gender may influence psychosomatic health.

Immune and Epigenetic Pathways Linking Childhood Adversity and Health Across the Lifespan.

Childhood adversity is associated with a host of mental and physical health problems across the lifespan. Individuals who have experienced childhood adversity (e.g., child abuse and neglect, family conflict, poor parent/child relationships, low socioeconomic status or extreme poverty) are at a greater risk for morbidity and premature mortality than those not exposed to childhood adversity. Several mechanisms likely contribute to the relationship between childhood adversity and health across the lifespan (e.g., health behaviors, cardiovascular reactivity). In this paper, we review a large body of research within the field of psychoneuroimmunology, demonstrating the relationship between early life stress and alterations of the immune system. We first review the literature demonstrating that childhood adversity is associated with immune dysregulation across different indices, including proinflammatory cytokine production (and its impact on telomere length), illness and infection susceptibility, latent herpesvirus reactivation, and immune response to a tumor. We then summarize the growing literature on how childhood adversity may alter epigenetic processes. Finally, we propose future directions related to this work that have basic and applied implications.

The factor structure of depressive symptoms in patients with obesity enrolled in the RAINBOW clinical trial.

BACKGROUND: Examining variability in the presenting symptoms of depression may be particularly important in characterizing depression in patients with comorbid conditions such as obesity. Identifying the underlying constructs of depression in such patients may produce phenotypic information to aid diagnosis and treatment decisions. OBJECTIVE: To examine the latent factors of symptoms using the depression Symptom Checklist (SCL-20) and the Patient Health Questionnaire (PHQ-9), separately, in patients with obesity and elevated depressive symptoms. METHODS: Exploratory factor analysis (EFA) was performed on baseline data from 409 patients with obesity and elevated depressive symptoms recruited in primary care. Bootstrap analysis was performed to estimate the precision and potential replicability of identified latent factors. RESULTS: Participants (70% women, mean age of 51.0 ± 12.1 years) had moderate depression. EFA of the SCL-20 suggested two reliable factors: dysphoric mood (71% of the variance) and anhedonia (15% of the variance). EFA of the PHQ-9 yielded one factor: dysphoric mood (87% of the variance). Bootstrapped results supported the replicability of these results. The top most endorsed symptoms were feeling low energy, overeating and disturbed sleep. LIMITATIONS: The generalizability of these findings to severe depression may be limited. CONCLUSIONS: Patients with elevated depressive symptoms and obesity present with heterogeneous symptoms. The SCL-20 seems more sensitive than the PHQ-9 for differentiating symptom profiles in this population. Some possible reasons include: 1) differences in number of scale items, and 2) differences in the aspects of depression they tap into; the SCL-20 measures the severity of symptoms, whereas the PHQ-9 measures the frequency of symptoms.

Correction: Variability in engagement and progress in efficacious integrated collaborative care for primary care patients with obesity and depression: Within-treatment analysis in the RAINBOW trial.

[This corrects the article DOI: 10.1371/journal.pone.0231743.].

Variability in engagement and progress in efficacious integrated collaborative care for primary care patients with obesity and depression: Within-treatment analysis in the RAINBOW trial.

INTRODUCTION: The RAINBOW randomized clinical trial validated the efficacy of an integrated collaborative care intervention for obesity and depression in primary care, although the effect was modest. To inform intervention optimization, this study investigated within-treatment variability in participant engagement and progress. METHODS: Data were collected in 2014-2017 and analyzed post hoc in 2018. Cluster analysis evaluated patterns of change in weekly self-monitored weight from week 6 up to week 52 and depression scores on the Patient Health Questionnaire-9 (PHQ-9) from up to 15 individual sessions during the 12-month intervention. Chi-square tests and ANOVA compared weight loss and depression outcomes objectively measured by blinded assessors to validate differences among categories of treatment engagement and progress defined based on cluster analysis results. RESULTS: Among 204 intervention participants (50.9 [SD, 12.2] years, 71% female, 72% non-Hispanic White, BMI 36.7 [6.9], PHQ-9 14.1 [3.2]), 31% (n = 63) had poor engagement, on average completing self-monitored weight in <3 of 46 weeks and <5 of 15 sessions. Among them, 50 (79%) discontinued the intervention by session 6 (week 8). Engaged participants (n = 141; 69%) self-monitored weight for 11-22 weeks, attended almost all 15 sessions, but showed variable treatment progress based on patterns of change in self-monitored weight and PHQ-9 scores over 12 months. Three patterns of weight change (%) represented minimal weight loss (n = 50, linear ß1 = -0.06, quadratic ß2 = 0.001), moderate weight loss (n = 61, ß1 = -0.28, ß2 = 0.002), and substantial weight loss (n = 12, ß1 = -0.53, ß2 = 0.005). Three patterns of change in PHQ-9 scores represented moderate depression without treatment progress (n = 40, intercept ß0 = 11.05, ß1 = -0.11, ß2 = 0.002), moderate depression with treatment progress (n = 20, ß0 = 12.90, ß1 = -0.42, ß2 = 0.006), and milder depression with treatment progress (n = 81, ß0 = 7.41, ß1 = -0.23, ß2 = 0.003). The patterns diverged within 6-8 weeks and persisted throughout the intervention. Objectively measured weight loss and depression outcomes were significantly worse among participants with poor engagement or poor progress on either weight or PHQ-9 than those showing progress on both. CONCLUSIONS: Participants demonstrating poor engagement or poor progress could be identified early during the intervention and were more likely to fail treatment at the end of the intervention. This insight could inform individualized and timely optimization to enhance treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov# NCT02246413.

Inflammation and the dimensions of depression: A review.

Patients with depressive disorders show a wide range of clinical manifestations including cognitive and neurovegetative symptoms. Importantly, these symptoms can differ in terms of biological etiology, and deconstructing depression into specific symptoms may provide valuable insight into the underlying neurobiology. Little research has examined inflammation in the context of depressive dimensions. Here we conduct a narrative review of the existing literature (21 studies) to elucidate whether the depression-inflammation link is symptom specific. Overall, there is evidence that an association exists between neurovegetative symptoms of depression and inflammation, independent of cognitive symptoms. The same cannot be said of cognitive symptoms and inflammation. There is also some evidence of gender differences in the directionality of the relationship between depression and inflammation. Potential explanations for these findings, limitations of the existing literature and recommendations for future research design are discussed.

Gender differences in the link between depressive symptoms and ex vivo inflammatory responses are associated with markers of endotoxemia.

Depressive symptoms are often linked with higher inflammation and inflammatory responses, although these associations are not always consistent. In a recent study (N=160, 25-65 years, 67% women), our group reported gender differences relevant to this association: In men higher depressive symptoms were related to heightened ex vivo inflammatory responses to lipopolysaccharide (LPS), whereas in women higher depressive symptoms were related to attenuated inflammatory responses. In the present manuscript, we investigate markers of endotoxemia - i.e., markers of the presence of endotoxin in the blood, presumably due to bacterial translocation from the gut - as factors that elicit gender-dependent immune responses that may be associated with links between depressive symptoms and inflammation. We examined ex vivo inflammatory responses in whole blood via a composite index of LPS-stimulated cytokines. The ratio of LPS-binding protein to soluble CD14 receptor (LBP:sCD14) was quantified as an index of endotoxemia that captures the relative reliance on pro-inflammatory versus non-inflammatory pathways for bacterial clearance. Levels of endotoxemia markers in blood were found to moderate gender differences in the link between depressive symptoms and stimulated inflammation (Gender × Depressive Symptoms × Endotoxemia: B = -0.039, 95%CI [-0.068, 0.009], p = 0.010). At lower LBP:sCD14 levels, depressive symptoms and stimulated inflammation were unrelated in both men and women. However, with higher levels of LBP:sCD14, men showed an increasingly positive correlation and women showed a negative correlation between depressive symptoms and stimulated inflammation. Hence, men and women exhibited similar associations between depressive symptoms and inflammatory responses at lower endotoxin marker levels, but these associations became divergent at higher levels of endotoxin markers. This information provides a novel perspective on risk factors for depression-linked alterations in inflammation, which may help to determine susceptibility to the downstream physical consequences of depressive symptomatology.

Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms.

Extensive research links depression and inflammation, with emerging evidence suggesting some differences between males and females in these associations. However, relatively few studies have examined stimulated inflammatory responses (ex vivo) in depression. The present research investigated the associations between depressive symptoms, basal inflammation, and LPS-stimulated production of pro- (IL-1ß, IL-6, IL-8, TNF-α) and an anti-inflammatory cytokine (IL-10), with a focus on the extent to which gender moderates these relationships. As part of a larger study, 162 socio-economically and racially diverse subjects (ages 25-65, 67% women) completed extensive self-report measures, including depressive symptoms. Whole blood was quantified for basal inflammation, or incubated with 1µg/mL lipopolysaccharide (LPS) for 2h (at 37°C, 5% CO2) to quantify inflammatory responses to bacterial challenge. We examined the associations between depression and inflammatory markers in regression analyses, controlling for age, BMI, race/ethnicity, income, education, and use of medications. No main effects were observed between depressive symptoms and basal or stimulated levels of inflammation. Moderation analyses revealed a significant interaction between depressive symptoms and gender for stimulated TNF-α, stimulated IL-6 (p<0.05), and a marginally significant interaction for stimulated IL-10 (p=0.07). For men, higher depressive symptoms were associated with significantly higher production of TNF-α (p<0.05) and marginally higher IL-6 (p=0.07), but not with the anti-inflammatory cytokine IL-10. For women, higher depressive symptoms were associated with significantly lower production of TNF-α and IL-10 (ps<0.05), and marginally lower IL-6 (p=0.06). These findings provide evidence for gender differences in the association of depressive symptoms with inflammatory response patterns, and highlight the utility of assessing ex vivo immune responses in blood. Implications for health are discussed.

A Randomized, Double-blind, Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-naive Depressed Women: A Pilot Study.

This study was designed to examine the antidepressant effect of celecoxib (200 mg/day) augmentation of sertraline in the treatment of female patients with first episode of major depression over 8 weeks of therapy. Thirty female outpatients diagnosed with first episode of major depression, were recruited for this study. Participants were randomly assigned into two equal groups receiving either sertraline plus celecoxib 100 mg twice daily or sertraline plus placebo twice daily. Patients were assessed by Hamilton Depression and Anxiety Rating Scale at baseline, week 4 and week 8 of treatment. Both treatment groups showed notable improvement in their symptoms from baseline; however, celecoxib group showed greater decrease in Hamilton Depression Scores compared to the placebo group after four weeks of treatment. Response rates were also found to be significantly higher in the celecoxib group compared to the placebo group over 4 weeks. Nevertheless, the mentioned differences between two groups were not significant at the end of week 8. Also, remission rate was remarkably higher in celecoxib group in comparison with placebo at the end point. The results suggested that celecoxib may hasten the onset of therapeutic action of sertraline and increase response and remission rate in depressive disorders.

Quality of Life and Job Satisfaction of Dispensing Pharmacists Practicing in Tehran Private-sector Pharmacies.

As there is no evidence of previous studies on evaluating the level of job satisfaction and the major causes of dissatisfaction among the pharmacists in Iran, this study was designed. This study is a cross-sectional descriptive analysis of pharmacists practicing in Tehran private-sector pharmacies. We selected a stratified random sampling using number of prescriptions as a variable for stratification. The questionnaire was divided into three sections containing the demographic characteristics, general health perception and job satisfaction. Of all the participants, 62% were the owners of pharmacies and 38% were pharmacists in charge (non-owner). Seventy-eight percent of respondents reported satisfaction about their psychological and physical state. Just 11% of pharmacists were financially satisfied and 49% felt relaxed at the workplace. There was no correlation between the satisfaction and owning the pharmacy or sex of respondents. Spearman>s correlation showed that the income satisfaction correlated negatively with age (p ≤ 0.001) and years of experience (p < 0.05). Moreover, the average working hours was significantly higher among men compared to women (p < 0.01) and among owners relative to non-owners (p < 0.05). Overall, general health perception and quality of life among the respondents were at satisfactory level. However, work-related satisfaction was not high enough and most interviewed pharmacists were financially dissatisfied.