Clinical Correlates of Insulin Resistance in Chronic Schizophrenia: Relationship to Negative Symptoms.

Higher prevalence of physical comorbidity and premature mortality in persons with schizophrenia (PwS) results primarily from heightened cardiovascular and metabolic risks. The literature suggests that insulin resistance precedes the development of obesity, smoking, and use of antipsychotic medications, although these likely play a compounding role later in the course of the disorder. It is thus important to discover the clinical characteristics of PwS with high insulin resistance, as these individuals may represent an etiopathologically distinct subgroup with a distinct course and treatment needs. We conducted a cross-sectional study and compared insulin resistance between 145 PwS and 140 nonpsychiatric comparison (NC) participants, similar in age, sex, and race distribution. In addition, we examined correlates of insulin resistance in PwS. As expected, PwS had higher levels of insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] and body mass index (BMI) compared to the NC participants. HOMA-IR in the PwS was most associated with negative symptoms, BMI, and non-White race/ethnicity. The mechanistic relationships between insulin resistance and negative symptoms in schizophrenia patients warrant further investigation, and future studies should examine outcomes of PwS with this cluster of physical and mental symptoms and determine how management of insulin resistance might improve health of these individuals.

Comparison of schizophrenia outpatients in residential care facilities with those living with someone: Study of mental and physical health, cognitive functioning, and biomarkers of aging.

This paper aims to compare mental and physical health, cognitive functioning, and selected biomarkers of aging reflecting metabolic pathology and inflammation, in outpatients with schizophrenia from two residential settings: residential care facilities (RCFs) and living with someone in a house/apartment. This cross-sectional study examined community-dwelling adults with schizophrenia either in RCFs (N = 100) or in a house/apartment with someone (N = 76), recruited for two NIH-funded studies in San Diego. Assessments included measures of mental/physical health, cognitive function, and metabolic (glycosylated hemoglobin, cholesterol) and inflammatory (C-Reactive Protein, Tumor Necrosis Factor-alpha, Interleukin-6) biomarkers of aging. General logistic models were used to analyze factors associated with residential status. RCF residents had several indicators of worse prognosis (never being married, higher daily antipsychotic dosages, increased comorbidities and higher Framingham risk for coronary heart disease) than individuals living with someone. However, RCF residents had better mental well-being and lower BMI, as well as comparable biomarkers of aging as those living with someone. While the cross-sectional nature of the study does not allow us to infer causality, it is possible that the supportive environment of RCFs may have a positive impact on mental and physical health of persons with schizophrenia. Longitudinal follow-up studies are needed to test this hypothesis.

Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects.

Intestinal microbiome and gut-brain axis have been receiving increasing attention for their role in the regulation of brain/behavior and possible biological basis of psychiatric disorders. Several recent clinical studies have linked the microbiome with neuropsychiatric conditions, although the literature on schizophrenia is quite limited. This study investigated gut microbiome composition in 50 individuals, including 25 persons with chronic schizophrenia and 25 demographically-matched non-psychiatric comparison subjects (NCs). Stool samples were collected and assayed using 16S rRNA sequencing of the V4 region. Examination of unweighted UniFrac and Bray-Curtis dissimilarity revealed significant community-level separation in microbiome composition between the two subject groups. At the phylum level, Proteobacteria were found to be relatively decreased in schizophrenia subjects compared to NCs. At the genus level, Anaerococcus was relatively increased in schizophrenia while Haemophilus, Sutterella, and Clostridium were decreased. Within individuals with schizophrenia, abundance of Ruminococcaceae was correlated with lower severity of negative symptoms; Bacteroides was associated with worse depressive symptoms; and Coprococcus was related to greater risk for developing coronary heart disease. Our findings provide evidence of altered gut microbial composition in persons with chronic schizophrenia and suggest a need for larger and longitudinal studies of microbiome in schizophrenia.

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.

Abnormal levels of vascular endothelial biomarkers in schizophrenia.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

Positive mental health in schizophrenia and healthy comparison groups: relationships with overall health and biomarkers.

OBJECTIVE: Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia. METHOD: One hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65 years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables. RESULTS: Relative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the 'normative' range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia. CONCLUSION: A sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.

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-1ß (MIP-1ß/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.

Leukocyte telomere length: Effects of schizophrenia, age, and gender.

BACKGROUND: Schizophrenia is linked with early medical comorbidity and mortality. These observations indicate possible "accelerated biological aging" in schizophrenia, although prior findings are mixed, and few such studies have examined the role of gender. One putative marker of biological aging is leukocyte telomere length (LTL), which typically shortens with age. METHODS: We assessed LTL in phenotypically well characterized 134 individuals with schizophrenia (60 women and 74 men) and 123 healthy comparison subjects (HCs) (66 women and 57 men), aged 26 to 65 years. RESULTS: Overall, LTL was inversely associated with age (t(249) = -6.2, p < 0.001), and a gender effect on the rate of LTL decrease with age was found (t(249) = 2.20, p = 0.029), with men declining more rapidly than women. No significant overall effect of diagnosis on the rate of decline was detected. However, at the average sample age (48 years), there was a significant gender effect in both schizophrenia and HC groups (t(249) = 2.48, p = 0.014), with women having longer LTL than men, and a significant gender X diagnosis effect (t(249) = 2.43, p = 0.016) - at the average sample age, women with schizophrenia had shorter LTL than HC women. DISCUSSION: Gender, not the diagnosis of schizophrenia, was the major factor involved with LTL shortening across the age range studied. We discuss the constraints of a cross-sectional design and other methodological issues, and indicate future directions. Understanding the impact of schizophrenia on biological aging will require separate evaluations in men and women.

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.

Paradoxical Trend for Improvement in Mental Health With Aging: A Community-Based Study of 1,546 Adults Aged 21-100 Years.

OBJECTIVE: Studies of aging usually focus on trajectories of physical and cognitive function, with far less emphasis on overall mental health, despite its impact on general health and mortality. This study examined linear and nonlinear trends of physical, cognitive, and mental health over the entire adult lifespan. METHODS: Cross-sectional data were obtained from 1,546 individuals aged 21-100 years, selected using random digit dialing for the Successful AGing Evaluation (SAGE) study, a structured multicohort investigation that included telephone interviews and in-home surveys of community-based adults without dementia. Data were collected from 1/26/2010 to 10/07/2011 targeting participants aged 50-100 years and from 6/25/2012 to 7/15/2013 targeting participants aged 21-100 years with an emphasis on adding younger individuals. Data included self-report measures of physical health, measures of both positive and negative attributes of mental health, and a phone interview-based measure of cognition. RESULTS: Comparison of age cohorts using polynomial regression suggested a possible accelerated deterioration in physical and cognitive functioning, averaging 1.5 to 2 standard deviations over the adult lifespan. In contrast, there appeared to be a linear improvement of about 1 standard deviation in various attributes of mental health over the same life period. CONCLUSIONS: These cross-sectional findings suggest the possibility of a linear improvement in mental health beginning in young adulthood rather than a U-shaped curve reported in some prior studies. Lifespan research combining psychosocial and biological markers may improve our understanding of resilience to mental disability in older age and lead to broad-based interventions promoting mental health in all age groups.

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.

Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups.

Schizophrenia is characterized by physical (mainly metabolic and cardiovascular) comorbidity and shortened lifespan. High sensitivity C-reactive protein (hs-CRP), an inflammatory marker of hepatic origin linked to metabolic and cardiovascular diseases and mortality in the general population, has been reported to be elevated in people with schizophrenia. However, the relationship of hs-CRP to psychiatric and medical risk factors, after controlling for potentially confounding variables such as smoking, is not well established in schizophrenia. We assessed hs-CRP levels along with various demographic, psychiatric, and metabolic measures in 88 clinically stable outpatients with schizophrenia or schizoaffective disorder and 71 age epoch-matched comparison subjects with no history of a major psychiatric illness. hs-CRP levels were significantly higher in individuals with schizophrenia than in comparison subjects. Higher hs-CRP levels in the schizophrenia group were associated with female gender, more severe negative symptoms, greater medical comorbidity, and worse metabolic risk factors including BMI, fasting glucose, and hemoglobin A1c levels. hs-CRP was not related to age, race, education, smoking status, antipsychotic dosage, or cognitive impairment. Longitudinal studies are needed to investigate the relationship between hs-CRP and long-term health outcomes including metabolic syndrome, cardiovascular disease, and mortality in schizophrenia.

Associations of self-perceived successful aging in young-old versus old-old adults.

BACKGROUND: The aim of this research was to compare associations of self-perceived successful aging (SPSA) among Young-Old (Y-O; age 50-74 years) versus Old-Old (O-O; 75-99 years) community-dwelling adults. To our knowledge, this is the first study to compare respondents' self-perceptions of successful aging among O-O relative to Y-O adults. METHODS: Participants included 365 Y-O and 641 O-O adults. The two age groups were compared in terms of the association of SPSA with other preselected measures including sociodemographic information, physical and mental functioning, objective and subjective cognitive functioning, emotional health, and positive psychological constructs. RESULTS: The O-O group reported higher levels of SPSA than the Y-O group. In multiple regression modeling examining predictors of SPSA in each group, there was a tendency toward lower associations in the O-O group overall. Most notably, the associations between physical and mental functioning with SPSA were significantly lower in the O-O versus Y-O group. There were no associations with SPSA that were significantly higher in the O-O versus Y-O group. CONCLUSION: The lower predictive power of physical and mental functioning on SPSA among O-O relative to Y-O adults is particularly noteworthy. It is apparent that SPSA is a multidimensional construct that cannot be defined by physical functioning alone. Continuing to clarify the underlying factors impacting SPSA between groups may inform tailored interventions to promote successful aging in Y-O and O-O adults.

Differences in life satisfaction among older community-dwelling Hispanics and non-Hispanic Whites.

OBJECTIVES: Hispanics are the fastest growing ethnic/racial group of the older adult population in the United States, yet little is known about positive mental health in this group. We examined differences in life satisfaction between demographically matched groups of older Hispanics and non-Hispanic Whites, and sought to identify specific factors associated with these differences METHODS: Participants included 126 community-dwelling English-speaking Hispanics aged 50 and older, and 126 age-, gender-, and education-matched non-Hispanic Whites. Participants completed standardized measures of life satisfaction and postulated correlates, including physical, cognitive, emotional and social functioning, as well as positive psychological traits and religiosity/spirituality. RESULTS: Hispanics reported greater life satisfaction than non-Hispanic Whites (p < 0.001). Ethnic groups were comparable on most postulated correlates of life satisfaction, except that Hispanics had lower levels of cognitive performance, and higher levels of daily spiritual experiences, private religious practices and compassion (ps < 0.001). Among these factors, spiritual experiences, religious practices, and compassion were significantly associated with life satisfaction in the overall sample. Multivariable analyses testing the influence of these three factors on the association between ethnicity and life satisfaction showed that higher spirituality among Hispanics accounted for ethnic differences in life satisfaction. CONCLUSION: English-speaking Hispanics aged 50 and older appeared to be more satisfied with their lives than their non-Hispanic White counterparts, and these differences were primarily driven by higher spirituality among Hispanics. Future studies should examine positive mental health among various Hispanic subgroups, including Spanish speakers, as an important step toward development of culturally sensitive prevention and intervention programs aimed at promoting positive mental health.

Wellness within illness: happiness in schizophrenia.

Schizophrenia is typically a chronic disorder and among the most severe forms of serious mental illnesses in terms of adverse impact on quality of life. Yet, there have been suggestions that some people with schizophrenia can experience an overall sense of happiness in their lives. We investigated happiness among 72 outpatients with non-remitted chronic schizophrenia with a mean duration of illness of 24.4 years, and 64 healthy comparison subjects (HCs). Despite continued treatment with antipsychotic medications, the individuals with schizophrenia manifested a mild to moderate level of psychopathology. People with schizophrenia reported lower mean levels of happiness than HCs, but there was substantial heterogeneity within the schizophrenia group. Level of happiness in persons with schizophrenia was significantly correlated with higher mental health-related quality of life, and several positive psychosocial factors (lower perceived stress, and higher levels of resilience, optimism, and personal mastery). However, level of happiness was not related to sociodemographic characteristics, duration of illness, severity of positive or negative symptoms, physical function, medical comorbidity, or cognitive functioning. Except for an absence of an association with resilience, the pattern of correlations of happiness with other variables seen among HCs was similar to that in individuals with schizophrenia. Although happiness may be harder to achieve in the context of a serious mental illness, it nonetheless appears to be a viable treatment goal in schizophrenia. Psychotherapies targeting positive coping factors such as resilience, optimism, and personal mastery warrant further investigation.