The lack of association between herpes simplex virus 1 or Toxoplasma gondii infection and cognitive decline in the general population: An 11-year follow-up study.

BACKGROUND: Inflammation has been suggested to be one, possibly treatable, cause of cognitive decline and dementia. The purpose of the present article was to investigate whether the herpes simplex virus 1 (HSV-1) or Toxoplasma gondii (T. gondii) infections are related to cognitive decline or dementia. METHOD: The Health 2000 survey, conducted 2000-2001, is a population-representative sample of people over 30 years old that involved 7112 participants. The sample was followed up in the year 2011, in the Health 2011 study. At both time points, cognitive performance was assessed with two tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessing verbal fluency and verbal learning. In addition, the abbreviated Mini-Mental State Examination was administered to people aged over 55. In addition, tests assessing reaction and movement time were performed at baseline. Dementia diagnoses from nationwide health care registers were followed up until the end of year 2013. The presence of HSV-1 and T. gondii immunoglobulin G (IgG) was determined by solid-phase immunoassay at baseline. RESULTS: HSV-1 or T. gondii seropositivity, or IgG antibody levels, were not associated with cognitive decline when investigated as infection × time interactions. In addition, the infections were not associated with the risk of dementia. CONCLUSIONS: In a large sample of participants that is representative of the whole country and with a long follow-up, the results suggest that latent HSV-1 or T. gondii infections are not related to either decline in cognitive performance or dementia risk.

Natural cause mortality in persons with serious mental illness.

OBJECTIVE: To identify the determinants of natural cause mortality in a cohort of individuals with serious mental illness assessed prospectively. METHOD: Persons with schizophrenia (n = 789) and bipolar disorder (n = 498), mean age of 38 (s.d. 12.6) years, underwent an in-person clinical assessment. They also had a blood sample drawn from which infectious disease markers were measured. Mortality was subsequently determined utilizing data from the National Death Index following a period of up to 16.9 years. RESULTS: A total of 6.8% (87 of 1287) of persons died of natural causes. Mortality was predicted in a multivariate model by baseline cigarette smoking (RR = 6.29, 95% CI 1.41, 3.72, P = 0.00076); divorced or widowed status (RR = 1.90, CI 1.21, 2.99); reduced cognitive score (RR = 0.73, CI 0.61, 0.87); receipt of antidepressant medication (RR = 1.74, CI 1.12, 2.71); elevated levels of antibodies to Epstein-Barr virus (EBV) (RR = 1.29, CI 1.01, 1.66); and a genitourinary (RR = 1.82, CI 1.16, 2.86), respiratory (RR = 1.82, CI 1.16, 2.86), or cardiac (RR = 2.09, CI 1.33, 3.29) condition. There was an additive effect of smoking and both a cardiac and a respiratory condition but not elevated EBV antibody levels. CONCLUSION: Smoking is a modifiable behaviour which is associated with mortality in this population.

Immune alterations in acute bipolar depression.

OBJECTIVE: Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression. METHOD: Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up. RESULTS: The sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers. CONCLUSION: Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania.

The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review.

The gut microbiota is increasingly considered as a symbiotic partner in the maintenance of good health. Metagenomic approaches could help to discover how the complex gut microbial ecosystem participates in the control of the host's brain development and function, and could be relevant for future therapeutic developments, such as probiotics, prebiotics and nutritional approaches for psychiatric disorders. Previous reviews focused on the effects of microbiota on the central nervous system in in vitro and animal studies. The aim of the present review is to synthetize the current data on the association between microbiota dysbiosis and onset and/or maintenance of major psychiatric disorders, and to explore potential therapeutic opportunities targeting microbiota dysbiosis in psychiatric patients.

Adjunctive mood stabilizer and benzodiazepine use in older Asian patients with schizophrenia, 2001-2009.

OBJECTIVE: This study surveyed the use of adjunctive mood stabilizers (MS) and benzodiazepines (BZD) in older Asian schizophrenia patients and examined their demographic and clinical correlates. METHOD: Information on hospitalized schizophrenia patients aged 55 years or more were extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study. A total of 1,452 patients from 9 Asian countries and territories was included in the study. The patients' sociodemographic and clinical characteristics and the prescriptions of antipsychotics, MS and BZD were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of MS prescription was 26.7% in the pooled sample, with 25.5% in 2001, 26.9% in 2004 and 27.7% in 2009. The corresponding figures for BZD were 20.7%, 20.2%, 18.4% and 23.1%, respectively. Multiple logistic regression analysis of the whole sample revealed that patients on MS were younger and more likely to be men and to have extrapyramidal side effects (EPS) and a longer duration of illness. Compared to patients in China, those in Japan were more likely to receive MS, while Korean patents were prescribed less MS. In contrast, there were no significant sociodemographic or clinical correlates of BZD use. Compared to patients in China, their Korean and Singaporean counterparts were more likely to be on BZD. CONCLUSIONS: The use of MS and BZD is not uncommon in older Asian patients with schizophrenia. Given the paucity of empirical data on the efficacy of these agents in individuals with schizophrenia of any age and concerns about added side effects in older patients in particular, the rationale for the prescription of these agents in this population warrants further examination.

Toxoplasma and schizophrenia.

Research on infectious agents as a possible cause of schizophrenia has become prominent in the past decade. Toxoplasma gondii has emerged as a prime candidate for a variety of reasons; (i) many studies have reported that individuals with schizophrenia, compared to controls, have a higher prevalence of antibodies to T. gondii, (ii) some individuals with adult toxoplasmosis develop psychotic symptoms similar to those of schizophrenia, (iii) epidemiologically, there are many similarities between toxoplasmosis and schizophrenia, (iv) antipsychotic drugs known to be effective in schizophrenia also inhibit some parasites, including T. gondii, (v) Toxoplasma has been shown to induce elevated levels of dopamine in experimentally infected animals (elevated dopamine is commonly seen in individuals with schizophrenia) and (vi) studies have shown that individuals with schizophrenia, compared to controls, have had greater exposure to cats in childhood. A number of questions remain concerning a role for Toxoplasma in the aetiology of schizophrenia, including the roles of strain variation, the timing and source of infection, and the role of host genes in determining disease susceptibility. The establishment of a firm association between Toxoplasma and the aetiology of schizophrenia and related disorders would represent a major breakthrough in the understanding of these disorders and would lead to novel methods for their treatment and prevention.

Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia.

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia.

OBJECTIVE: This study determined if augmentation of neuroleptics with 3 g/day of ethyl eicosapentaenoic acid (EPA) improves symptoms and cognition in patients with schizophrenia or schizoaffective disorder. METHOD: Eighty-seven patients meeting criteria for schizophrenia or schizoaffective disorder who had residual symptoms despite neuroleptic treatment were randomly assigned to receive either 3 g/day of ethyl EPA (N=43) or placebo (N=44) in a 16-week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 1, 2, 4, 8, 12, and 16; a cognitive battery was administered at baseline and at week 16. RESULTS: No differences were found between groups in positive or negative symptoms, mood, cognition, or global impression ratings. Results were similar for the intention-to-treat (N=87) and completer (N=75) groups. CONCLUSIONS: For schizophrenia patients treated with 3 g/day of ethyl EPA, improvement in residual symptoms and cognitive impairment was no greater than for schizophrenia patients treated with placebo.

Cognitive behavioral psychotherapy for schizophrenia: a review of recent empirical studies.

A set of cognitive behavioral psychotherapies (CBT) has been developed for schizophrenia. These interventions have been used for the treatment of both recent onset patients and those with treatment-refractory symptoms. This article reviews clinical trials of CBT for schizophrenia since 1990. The CBT interventions appear to be beneficial in reducing overall symptom levels, especially the severity of delusions. The relative efficacy of CBT is more evident when CBT is compared with routine care than when it is compared with other therapies matched for therapist attention. Further studies are needed to objectively determine the active ingredients of CBT and to better identify the interactions of CBT with concurrent psychosocial and medication treatments.

Neurocognitive deficits and social functioning in outpatients with schizophrenia.

Previous studies suggest that neurocognitive factors may contribute to the reduced social functioning of patients with schizophrenia. To assess this relationship, we administered a battery of neurocognitive tests and independently assessed symptoms (PANSS) and social functioning (SFS) in 88 stable outpatients with schizophrenia. We found a significant correlation between neurocognitive and social functioning variables. Patients' performance on aphasia, spatial organization and visual spatial tasks was correlated with their competence at activities of daily living, frequency of social activities and total social functioning. Regression analyses of each social functioning scale revealed different symptom and neurocognitive predictors. Patients' overall social functioning was best predicted by a combination of negative symptoms and aphasia. The results support the potential use of interventions to reduce patients' cognitive deficits as a means to improve their social outcomes.

Social functioning and neurocognitive deficits in outpatients with schizophrenia: a 2-year follow-up.

Neurocognitive deficits have been associated with the social functioning impairments of patients with schizophrenia. More information is needed about how cognitive status and other variables predict social functioning over defined periods of time. In this study, 72 relatively stable outpatients with schizophrenia were compared between baseline and a 2-year follow-up on measures of social functioning. Patients were also assessed with a battery of neurocognitive tests and the Positive and Negative Syndrome Scale. Results were compared by univariate and multivariate analyses. A total of four out of seven subscales of the Social Functioning Scale (SFS) and the total SFS score did not show a significant change over the 2-year period. On the three SFS subscales that did show a significant change, residual change scores were correlated with better neurocognitive performance at baseline, younger age, and shorter illness duration. For the Multnomah Community Ability Scale, 48.9% of the total score at follow-up was predicted by initial negative symptoms and scores on the Aphasia Screening Test. These results document the independent contribution of demographic variables, negative symptoms, and neurocognitive deficits to the social functioning impairments of individuals with schizophrenia.

Effect of diabetes, insulin, and glucose load on lipid peroxidation in the rat.

Lipid peroxidative activity in rats made diabetic with streptozocin and rats made acutely hyperglycemic by intraperitoneal dextrose administration was determined by measurement of exhaled ethane during exposure in vivo to ethane-free air (EFA). Diabetic rats demonstrated increased ethane in the expired breath while breathing EFA (5.82 +/- 0.56 pmol/min/100 g) compared with control rats (4.02 +/- 0.23 pmol/min/100 g). Insulin treatment of diabetic rats attenuated the ethane produced (4.88 +/- 0.23 pmol/min/100 g). Acute hyperglycemia increased exhaled ethane to levels higher than those seen in diabetic rats (9.87 +/- 0.98 pmol/min/100 g). Saline injected intraperitoneally to control rats produced ethane levels similar to those of untreated nondiabetic controls (4.11 +/- 0.52 pmol/min/100 g). Chronic uncontrolled hyperglycemia and acute hyperglycemia are associated with increased in vivo ethane production.

Effect of simple carbohydrates, casein hydrolysate, and a lipid test meal on ethane exhalation rate.

To determine the potential differences in the effect of various nutrients on lipid peroxidation, the ethane exhalation (EE) rate, an index of lipid peroxidation, was measured in rats at 4 (young), 18 (intermediate age), and 24 (aged) mo of age at fasting conditions and after acute ingestion of various test meals. The EE rate (means +/- SD) after a 15-h fast was significantly reduced in 24-mo-old rats (2.45 +/- 0.44 pmol.min-1.100 g body wt-1) and 18-mo-old rats (3.51 +/- 0.55 pmol.min-1.100 g body wt-1) compared with 4-mo-old rats (4.44 +/- 0.66 pmol.min-1.100 g body wt-1; P < 0.01). The EE rate significantly increased in 4-mo-old rats after ingestion of 50% (wt/vol) dextrose (8.59 +/- 2.9 pmol.min-1.100 g body wt-1), 50% casein hydrolysate (6.77 +/- 1.23 pmol.min-1.100 g body wt-1), and 20% neutral lipid emulsion (7.33 +/- 1.96 pmol.min-1.100 g body wt-1; P < 0.01). The response of aged rats to these nutrients compared with young rats was reduced by approximately 50%. A 25% dextrose solution or a 50% solution of sucrose, fructose, maltose, or galactose did not significantly alter EE rate. It is concluded that various macronutrients have a diverse potential of inducing lipid peroxidation. The responsiveness of aged rats to meal-induced enhancement of EE and presumably lipid peroxidation is significantly reduced.

Ethane production rate in vivo is reduced with dietary restriction.

Dietary restriction without malnutrition prolongs life and has a beneficial effect on age-related diseases and metabolic derangements. To test the effect of food restriction on ethane production rate, ethane exhalation was measured in rats with partial food restriction. Ethane production rate in room air in rats fed 60% of food consumed by ad libitum-fed animals for 2 wk was significantly reduced (3.50 +/- 0.25 vs. 5.21 +/- 0.34 pmol.min-1.100 g body wt-1, P less than 0.01). In 100% oxygen, ethane production in food-restricted rats was not different from that of ad libitum-fed rats (21.81 +/- 1.25 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Fifteen hours of fasting compared with ad libitum feeding reduced ethane production modestly in room air (4.37 +/- 0.45 vs. 5.21 +/- 0.34 pmol.min-1.100 g-1) and more significantly in 100% oxygen (12.37 +/- 0.78 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Thus, in 100% oxygen, 15 h of fasting, compared with ad libitum feeding, resulted in an approximately 40% decrease in ethane production rate. It is concluded that short-term food restriction significantly reduces ethane exhalation rate in rats when measured in room air.

Effect of age on L-3,5,3'-triiodothyronine-induced ethane exhalation.

The effect of age on thyroid hormone-induced lipid peroxidation in rats was determined by measuring ethane exhalation (EE) rate. The mean basal EE rates (in pmol.min-1 x 100 g-1) at room air in 25-mo-old aged rats [3.07 +/- 0.26 (SE)] and in intermediate age (18-mo-old) rats (3.42 +/- 0.18) were significantly lower than that in young (3- to 5-mo-old) rats (4.44 +/- 0.27) (P < 0.01). After 8 days of L-3,5,3'-triiodothyronine (T3) administration, EE rates in aged rats (4.10 +/- 0.25) and in intermediate-age rats (4.16 +/- 0.35) were significantly lower than that in young rats (5.61 +/- 0.36) (P < 0.01). T3-treated young rats pair-fed with aged rats for 2 wk had EE rates (5.53 +/- 0.18) comparable to ad libitum-fed young rats, although the basal rate of EE was significantly reduced with partial food restriction (4.44 +/- 0.27 vs. 3.50 +/- 0.24) (P < 0.01). These observations indicate that reduced food intake with age cannot account for the age-related changes in T3-stimulated peroxidation rate of lipids.

Outpatients with schizophrenia and bipolar I disorder: Do they differ in their cognitive and social functioning?

The authors used a battery of cognitive and social functioning measures to evaluate stable outpatients with schizophrenia (n=74) and bipolar I disorder (n=26) who were receiving care at community and rehabilitation programs. The groups did not differ significantly on 36 of 41 measures. For most variables, comparisons between groups yielded effect sizes of <0.5. These results suggest that individuals with bipolar I disorder receiving community and rehabilitation services have many social and cognitive deficits that are as severe as those in schizophrenia.

Assessing clinical outcomes: the community functioning of persons with serious mental illness.

OBJECTIVE: The demand to measure the clinical outcomes of persons with serious mental illness in the community is growing; however, there is no consensus about how to do this task. This paper identifies challenges in measuring the outcomes of persons with serious mental illness and reviews selected instruments that measure the community functioning of this population. METHODS: Papers in peer-reviewed psychiatric journals for the years 1986 to 1996 were reviewed to select instruments that measure two or more domains of community functioning and for which data on reliability and validity have been published. Selected instruments were evaluated, focusing on their format, content, item scoring, length, and original sample population. RESULTS AND CONCLUSIONS: Challenges to measuring the community functioning of persons with serious mental illness include the multiplicity of domains that must be measured, the conflicting interests of various stakeholders involved in care, the limitations of self-report data, and other methodological problems. Nine instruments that met the study criteria were selected from the literature. Three are self-report instruments, and six are based on the report of an informant or independent rater. The instruments vary in length and in their original sample population. The content areas most consistently represented are self-care and social relationships. Life satisfaction, health status, psychiatric symptoms, and work skills are not consistently addressed. Individual instruments have additional limitations, including the absence of behavioral anchors for scale items and the lack of specificity to persons with serious mental illness. Effort should be directed toward sharing data across settings, measuring the effects of treatment interventions, and demonstrating the predictive validity of outcome data.

Predictors of residential independence among outpatients with schizophrenia.

OBJECTIVE: Many outpatients with schizophrenia receive support or supervision in their place of residence, but the predictors of residential independence are not clearly understood. The purpose of this study was to identify factors that predict the degree of residential independence among outpatients with schizophrenia. METHODS: Seventy-two outpatients with schizophrenia were assigned to three groups based on their degree of residential independence. The three groups were compared on three measures of social functioning, on the Positive and Negative Syndrome Scale, and on a battery of neuropsychological tests. RESULTS: Patients' degree of residential independence was related to their frequency of family contact, hygiene skills, relative absence of negative symptoms, and participation in social activities. In a discriminant function analysis, the residential status of 78 percent of the patients was correctly classified. CONCLUSIONS: Aspects of social functioning are significantly associated with patients' independent living status. Future research is needed to determine how family contact, social activities, and hygiene skills may increase patients' degree of residential independence.

Lack of insight among outpatients with schizophrenia.

OBJECTIVE: This study investigated the prevalence of lack of insight among outpatients with schizophrenia and the relationship between lack of insight and other variables, including whether patients received professional residential supervision. METHODS: A total of 87 stable outpatients with schizophrenia were drawn from community programs in a public-private mental health system. Subjects' clinical symptoms and insight about their illness were assessed using the Positive and Negative Syndrome Scale, a battery of neuropsychological tests, and the Social Functioning Scale. RESULTS: The illness insight of 43 subjects, or 49.5 percent, was at least moderately impaired. Twenty-one subjects, or 25 percent, had severe insight deficits. In a multiple regression analysis, 40 percent of the variance in lack of insight was predicted by ratings of the severity of delusions, difficulty with abstract thinking, lack of social activities, and absence of anxiety. Patients who received professional residential supervision had more impaired insight than those living independently or with family. CONCLUSIONS: Insight deficits are common among stable outpatients engaged in community-based care. These deficits have implications for patients' use of limited services such as residential supervision.

Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder.

INTRODUCTION: Cytomegalovirus (CMV) is a member of the herpesviridae family that has a limbic and temporal gray matter tropism. It is usually latent in humans but has been associated with schizophrenia, bipolar disorder and cognitive deficits in some populations. Hippocampal decreased volume and dysfunction play a critical role in these cognitive deficits. We hypothesized that CMV seropositivity and serointensity would be associated with hippocampal volume and cognitive functioning in patients with schizophrenia or bipolar disorder. METHODS: 102 healthy controls, 118 patients with bipolar disorder and 69 patients with schizophrenia performed the California Verbal Learning Test (CVLT) and had blood samples drawn to assess CMV IgG levels. A subgroup of 52 healthy controls, 31 patients with bipolar disorder and 27 patients with schizophrenia underwent T1 MRI for hippocampal volumetry. We analyzed the association between CMV serointensity and seropositivity with hippocampal volume. We also explored the correlation between CMV serointensity and seropositivity and CVLT scores. RESULTS: In both patient groups but not in controls, higher CMV serointensity was significantly associated with smaller right hippocampal volume. Further, in the group of patients with schizophrenia but not bipolar disorder, CMV serointensity was negatively correlated with CVLT scores. CONCLUSION: CMV IgG titers are associated with decreased hippocampal volume and poorer episodic verbal memory in patients with schizophrenia or bipolar disorder. The mechanism of this association warrants further exploration.