Ellen E. Lee

Abnormalities in chemokine levels in schizophrenia and their clinical correlates.

Chemokines are promising biomarkers of immune activation and inflammation, but evidence for chemokine abnormalities in schizophrenia and their relationship to clinical factors remains inconclusive. We aimed to understand chemokine-related diagnostic differences and clinical correlates using a comprehensive panel and studying a large, well-characterized sample of adults with and without schizophrenia. We studied 134 outpatients with schizophrenia or schizoaffective disorder and 112 healthy comparison (HC) individuals, 26 to 65years of age. Clinical measures were obtained, and plasma levels of 11 chemokines were assessed using multiplex immunoassay. Schizophrenia vs. HC differences were tested for each chemokine, adjusting for age, gender, body mass index, and current smoking status. We also examined whether age and gender relationships differed between diagnostic groups. Using logistic regression, we created a Chemokine Index (CI) and explored its clinical correlates. Levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1β (MIP-1β/CCL4), Eotaxin-1 (CCL11), thymus and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were significantly higher in persons with schizophrenia than HCs. Group differences in TARC were reduced after adjusting for covariates. The CI, a linear combination of Eotaxin-1 and MDC levels, was positively associated with age, duration of schizophrenia, and severity of negative symptoms. Levels of chemokines with neuroimmune regulatory effects were higher in individuals with schizophrenia, particularly in older and chronic patients. Treatments aimed at normalizing chemokine levels might improve mental and physical health among schizophrenia patients as they age.

Inflammation in Schizophrenia: Cytokine Levels and Their Relationships to Demographic and Clinical Variables

OBJECTIVE Inflammation may play a role in the accelerated physical aging reported in schizophrenia, though biomarker findings and associations with demographic and clinical factors are inconsistent. METHODS In a cross-sectional, case-control design, 95 outpatients with schizophrenia (mean age ± SD: 48.1 ± 10.2 years) and 95 demographically comparable healthy comparison subjects (HCs) (mean age ± SD: 48.1 ± 12.1 years) were studied. Sociodemographic and clinical data were collected, and plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed. The authors compared cytokine levels, examined demographic and clinical associations, and adjusted for relevant variables with linear models. RESULTS Individuals with schizophrenia had higher levels of TNF-α and IL-6 but not IFN-γ than HCs. Age was not related to cytokine levels, and age relationships did not differ between diagnostic groups. Women had higher levels of IL-6. TNF-α and IL-6 levels were significantly correlated with depressive symptoms, and adjustment for depression reduced the group effect for both. Within the HCs, TNF-α levels were associated with physical comorbidity and body mass index. IL-6 levels were significantly correlated with body mass index and within schizophrenia patients, with worse mental and physical well-being. Accounting for physical morbidity and mental well-being reduced group differences in TNF-α and IL-6 levels, respectively. Worse positive symptoms were associated with higher IL-6 levels. CONCLUSION Higher TNF-α and IL-6 levels in schizophrenia patients were associated with depression, physical comorbidity, and mental well-being. Further longitudinal studies are warranted to assess inflammation as a potential treatment target for a subgroup of schizophrenia.

Elevated plasma F2-isoprostane levels in schizophrenia

BACKGROUND Schizophrenia is one of the most disabling psychiatric disorders with increased morbidity and mortality. Both schizophrenia and oxidative stress have been associated with accelerated aging. Previous studies found increased oxidative stress in individuals with schizophrenia, though only one study measured F2-isoprostanes and did so in urine. To our knowledge, the present study is the first to assess plasma F2-isoprostane levels, the putative gold standard measure of systemic oxidative stress in vivo, in schizophrenia. METHODS We compared plasma F2-isoprostane levels in 134 stable outpatients with schizophrenia and 120 age- and gender-matched healthy comparison (HC) subjects. Sociodemographic and clinical data were collected in both groups. RESULTS Plasma F2-isoprostane levels were significantly higher in the schizophrenia group than in the HC group. Women had higher F2-isoprostane levels compared to men, and those with higher body mass index (BMI) had higher levels, within each group. F2-isoprostane levels correlated with BMI, physical functioning, and medical comorbidity but not with severity of psychopathology or executive function. Linear models showed significant effects of diagnosis, gender, and BMI on F2-isoprostane levels, but no interactions. DISCUSSION Our finding of increased oxidative stress in schizophrenia is consistent with reports of increased morbidity and mortality as well as accelerated aging in schizophrenia. The significant associations between F2-isoprostane levels and both gender and BMI warrant further study.

A widening longevity gap between people with schizophrenia and general population: A literature review and call for action

Individuals with schizophrenia have higher mortality rates than the population at large. General mortality rates have declined in developed countries since the early 1970s, extending average lifespan by nearly a decade. This review of eight longitudinal studies of mortality in schizophrenia found that the mean standardized mortality ratio (SMR, a measure of mortality rate in schizophrenia compared to the general population) increased 37%, from 2.2 in the pre-1970s studies to 3.0 in the post-1970s reports. Major changes in societal stigma, healthcare, and economic policy are urgently warranted to ensure that this vulnerable segment of the population participates in the longevity revolution.

Complex Clinical Intersection: Palliative Care in Patients with Dementia

Because of the rapidly growing older population and increases in longevity, rates of dementia have been rising. Clinical challenges of treating dementia include limited resources and lack of curative therapies. Palliative care approaches improve quality of life and alleviate suffering for dementia patients at the end of life, although implementation may be limited by societal acceptance and feasibility. This review examines the published literature on pain assessments, pain and behavior interventions, tools for advanced care planning, and clinical concerns in dementia patients. Ultimately, modification of the traditional palliative care model may improve outcomes and functioning for dementia patients at all stages of their illness.

Childhood Adversity and Schizophrenia: The Protective Role of Resilience in Mental and Physical Health and Metabolic Markers

OBJECTIVE To determine the impact of childhood adversity and current (adulthood) resilience on mental and physical health and markers of metabolic function among adults with schizophrenia and nonpsychiatric comparison participants (NCs). METHODS We conducted a cross-sectional study of 114 participants with schizophrenia (DSM-IV-TR criteria) and 101 NCs aged 26-65 years during 2012-2017. Sociodemographic, clinical, and laboratory measures were examined. Childhood Trauma Questionnaire was used to retrospectively assess emotional abuse/neglect, physical abuse/neglect, and sexual abuse experienced during childhood. Connor-Davidson Resilience Scale was employed to measure resilience. RESULTS Persons with schizophrenia reported more severe childhood trauma, lower resilience, and worse mental and physical health and had worse metabolic biomarker levels than NCs. Trauma severity correlated with worse depression in the NCs (r = 0.34), but not in the schizophrenia group (r = 0.02). In both groups, trauma severity was associated with worse physical well-being, higher fasting insulin levels, and greater insulin resistance (P ≤ .02). Notably, resilience appeared to counteract effects of trauma and diagnosis on mental and physical health. The schizophrenia subgroup with high resilience and severe trauma reported mental and physical well-being and had glycosylated hemoglobin levels and insulin resistance scores that were comparable to those of NCs with low resilience and severe trauma. CONCLUSIONS To our knowledge, this is the first study to quantitatively assess effects of both childhood trauma and resilience in schizophrenia on health, notably metabolic function. Interventions to bolster resilience in the general population and in people with schizophrenia may improve outcomes for those with a history of childhood adversity.

Sleep Disturbances and Inflammatory Biomarkers in Schizophrenia: Focus on Sex Differences

OBJECTIVES Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables. DESIGN Cross-sectional case-control study. PARTICIPANTS Community-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years. MEASUREMENTS Reported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro-inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)] and an anti-inflammatory cytokine (IL-10). RESULTS The schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels. CONCLUSIONS Sleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted.

Editorial Comment: Is the Placebo Effect Actually Increasing Over Time?

The placebo effect has long been a topic of considerable clinical, scientific, and public interest. The word “placebo” is derived from Latin for “I will please.” Two centuries ago, a medical dictionary defined placebo as any medicine adapted to please rather than benefit the patient. It was not until the 1960s that the placebo effect became widely recognized and placebo-controlled trials became the norm in the approval of new medications. The placebo effect refers to the phenomenon that a subject receiving a placebo experiences an improvement in their condition that is primarily attributable to the subject’s personal expectations, rather than to any biological or other proposed mechanisms related to the treatment itself. Thus a placebo “medicine” is often called a “sugar pill” that does not contain an active substance intended to affect health. Of course, placebos are not restricted to substances but include sham treatments that superficially mimic the actual treatment (e.g., sham dialysis or sham group therapy). Contrary to popular belief, the placebo response does not have to be positive—it can be negative. A person may experience worsening of original symptoms or develop new side effects due to negative expectations about the “treatment.” This is sometimes referred to as the “nocebo effect” (from Latin, meaning “I shall harm.”) Biological explanations of the placebo effect, based on empirical, though limited, data, include alterations in levels of inflammatory markers, endocannabinoids, endogenous opioids, or dopamine metabolism. Other explanations include expectancy effects and methodological issues. Several studies have investigated personality traits of placebo responders, although no clear relationship between particular personality patterns and the placebo effect have been established. The holy grail of effective treatments is demonstration of significantly better response to the treatment compared with placebo in a randomized controlled trial (RCT). The usual assumption is that placebo response in a serious condition would be relatively small and stable. One potentially serious and difficult-to-treat condition is severe behavior problems in persons with advanced dementia. There are no U.S. Food and Drug Administration (FDA)-approved pharmacotherapies for these symptoms, medications commonly used offlabel are associated with adverse effects and risks, and effective behavioral interventions are often unavailable or difficult to implement. Nevertheless, in FDAapproved RCTs of antipsychotics in nursing homes, for older persons with dementia complicated by psychosis or severe agitation, the placebo response rate ranged between 35% and 50%. The probable reason for this unexpectedly high placebo response is the “tender loving care” that is associated with participation in a research trial. For individuals with severe dementia receiving suboptimal care in understaffed nursing homes, research participation includes markedly enhanced attention and care—with complete physical examinations, treatment for pain and other frequently ignored problems, and overall improved healthcare. It is no wonder that these patients’ behavior problems improve. The placebo response thus reflects response to (unplanned) psychosocial treatment that is involved in a clinical trial.