Pilot cohort study of obstructive sleep apnoea in community-dwelling people with schizophrenia.

OBJECTIVES: We aimed to assess the incidence of obstructive sleep apnoea (OSA) in people with schizophrenia, to explore clinical associates with OSA and how well OSA screening tools perform in this population. METHODS: All patients registered in a community outpatient Clozapine clinic, between January 2014 and March 2016, were consecutively approached to participate. Participants were screened for OSA using at home multichannel polysomnography (PSG) and were diagnosed with OSA if the apnoea-hypopnoea index (AHI) was >10 events/hr. Univariate comparison of participants to determine whether AHI > 10 events/hr was associated with demographic factors, anthropometric measures and psychiatric symptoms and cognition was performed. The sensitivity, specificity, positive predictive value and negative predictive value of the commonly used sleep symptoms scales and OSA screening tools were also determined. RESULTS: Thirty participants were recruited, 24 men and 6 women. Mean age was 38.8 (range: 25-60), and mean body mass index (BMI) was 35.7 (range 19.9-62.1). The proportion of participants with OSA (AHI > 10 events/hr) was 40%, 18 (60%) had no OSA, 4 (13%) had mild OSA (AHI 10.1-20), zero participants had moderate OSA (AHI 20.1-30) and 8 (27%) had severe OSA (AHI > 30). Diagnosis of OSA was significantly associated with increased weight, BMI, neck circumference and systolic blood pressure. Diagnosis of OSA was not significantly associated with Positive and Negative Symptoms Scale, Montgomery Asperger's Depression Rating Scale, Personal and Social Performance scale or Brief Assessment of Cognition for Schizophrenia scores. All OSA screening tools demonstrated poor sensitivity and specificity for a diagnosis of OSA. CONCLUSION: OSA was highly prevalent in this cohort of people with schizophrenia and was associated with traditional anthropometric OSA risk factors.

Childhood adversity and clinical and psychosocial outcomes in psychosis.

AIMS: Associations between childhood abuse and various psychotic illnesses in adulthood are commonly reported. We aim to examine associations between several reported childhood adverse events (sexual abuse, physical abuse, emotional abuse, neglect and interpersonal loss) among adults with diagnosed psychotic disorders and clinical and psychosocial outcomes. METHODS: Within a large epidemiological study, the 2010 Australian National Survey of Psychosis (Survey of High Impact Psychosis, SHIP), we used logistic regression to model childhood adverse events (any and specific types) on 18 clinical and psychosocial outcomes. RESULTS: Eighty percent of SHIP participants (1466/1825) reported experiencing adverse events in childhood (sexual abuse, other types of abuse and interpersonal loss). Participants reporting any form of childhood adversity had higher odds for 12/18 outcomes we examined. Significant associations were observed with all psychosocial outcomes (social dysfunction, victimisation, offending and homelessness within the previous 12 months, and definite psychosocial stressor within 12 months of illness onset), with the strongest association for homelessness (odds ratio (OR) = 2.82). Common across all adverse event types was an association with lifetime depression, anxiety and a definite psychosocial stressor within 12 months of illness onset. When adverse event types were non-hierarchically coded, sexual abuse was associated with 11/18 outcomes, other types of abuse 13/18 and, interpersonal loss occurring in the absence of other forms of abuse was associated with fewer of the clinical and psychosocial outcomes, 4/18. When adverse events types were coded hierarchically (to isolate the effect of interpersonal loss in the absence of abuse), interpersonal loss was associated with lower odds of self-reproach (OR = 0.70), negative syndrome (OR = 0.75) and victimisation (OR = 0.82). CONCLUSIONS: Adverse childhood experiences among people with psychosis are common, as are subsequent psychosocial stressors. Mental health professionals should routinely enquire about all types of adversities in this group and provide effective service responses. Childhood abuse, including sexual abuse, may contribute to subsequent adversity, poor psychosocial functioning and complex needs among people with psychosis. Longitudinal research to better understand these relationships is needed, as are studies which evaluate the effectiveness of preventative interventions in high-risk groups.

Meta-analysis examining the epidemiology of clozapine-associated neutropenia.

BACKGROUND: Clozapine is associated with life-threatening neutropenia. There are no previous meta-analyses of the epidemiology of clozapine-associated neutropenia. OBJECTIVES: To determine the cumulative incidence of mild, moderate and severe neutropenia, incidence of death related to severe neutropenia, case fatality rate of neutropenia and the longitudinal incidence of neutropenia following exposure to clozapine. DATA SOURCES: A systematic search of Medline, EMBASE and PsycINFO using search terms [clozapine OR clopine OR zaponex OR clozaril] AND [neutropenia OR agranulocytosis]. METHODS: Random effects meta-analysis to determine event rates and longitudinal incidence of events per 100 person-years of exposure. RESULTS: A total of 108 studies were included. The incidence of clozapine-associated neutropenia was 3.8% (95% CI: 2.7-5.2%) and severe neutropenia 0.9% (95% CI: 0.7-1.1%). The incidence of death related to neutropenia following prescription of clozapine was 0.013% (95% CI: 0.01-0.017%). The case fatality rate of severe neutropenia was 2.1% (95% CI: 1.6-2.8%). The peak incidence of severe neutropenia occurred at one month of exposure and declined to negligible levels after one year of treatment. CONCLUSION: Severe neutropenia associated with clozapine is a rare event and occurs early with a substantial decline in risk after one year of exposure. Death from clozapine-associated neutropenia is extremely rare. Implications for haematological monitoring are discussed.

Brain antibodies in the cortex and blood of people with schizophrenia and controls.

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis.

AIMS: Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables. METHODS: Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators. RESULTS: One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups. CONCLUSIONS: Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Correlates of physical activity in people living with psychotic illness.

OBJECTIVE: In the light of the high prevalence of physical comorbidities in people with psychotic illness, there is a need to explore modifiable risk factors that may contribute to this disease burden. The benefits of physical activity to both physical and mental health have been well established. We aimed to examine the prevalence and correlates of physical activity in a national sample of adults living with psychotic illness. METHODS: Physical activity was assessed in 1801 people using the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-high physical activity groups and associations between physical activity and a range of sociodemographic, clinical and physical comorbidity variables were examined using logistic regression. RESULTS: More than half the participants were categorised in the moderate-high physical activity group with nearly half of the sample engaged in physical activity every day. There were significant associations between low physical activity and older age, unemployment, educational non-participation, antipsychotic medication use, social dysfunction, self-reported loneliness and obesity. However, there was no significant association between physical activity and sex, psychosis type, illness duration, physical comorbidity or negative symptoms. CONCLUSION: The findings from this study may inform future interventions designed to increase physical activity in people with psychotic illness.

Metabolic syndrome in people with a psychotic illness: is cannabis protective?

BACKGROUND: Rates of the metabolic syndrome in people with psychotic illness are high. Emerging evidence suggests that cannabis use may have a positive impact on cardiometabolic risk factors in the general population, but little is known about its impact for people with psychotic illness. Our aim was to investigate whether the rate of the metabolic syndrome in people with psychotic illness was associated with frequency of cannabis use. METHOD: The 2010 Australian psychosis survey used a two-phase design to randomly select a nationally representative sample of 1825 adults with psychotic illness for interview and physical assessment. This study is based on 1813 participants who provided data on cannabis use. Multiple logistic regression was used to model the influence of frequency of cannabis use on the metabolic syndrome, adjusting for potential covariates including antipsychotic medication use, smoking, alcohol use and cognitive function. RESULTS: One-third (33.0%) of participants had used cannabis in the past year. The proportion of non-users, occasional users and frequent users with the metabolic syndrome was 63.0, 51.7 and 43.5%, respectively (p < 0.001). In unadjusted analyses, both occasional use and frequent cannabis use were associated with significantly lower odds of the metabolic syndrome. In the adjusted analyses, the association between the metabolic syndrome and frequent cannabis use remained significant [odds ratio = 0.56, 95% confidence interval (CI) 0.39-0.80], but not the association with occasional use (odds ratio = 0.75, 95% CI 0.49-1.13). CONCLUSIONS: While cannabis use may be detrimental for mental health, these data suggest that it may also have a cardiometabolic protective effect. Further investigation is required to understand the mechanism underlying this paradoxical finding.

A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Psychosis prevalence and physical, metabolic and cognitive co-morbidity: data from the second Australian national survey of psychosis.

BACKGROUND: There are insufficient data from nationwide surveys on the prevalence of specific psychotic disorders and associated co-morbidities. METHOD: The 2010 Australian national psychosis survey used a two-phase design to draw a representative sample of adults aged 18-64 years with psychotic disorders in contact with public treatment services from an estimated resident population of 1 464 923 adults. This paper is based on data from 1642 participants with an International Classification of Diseases (ICD)-10 psychotic disorder. Its aim is to present estimates of treated prevalence and lifetime morbid risk of psychosis, and to describe the cognitive, physical health and substance use profiles of participants. RESULTS: The 1-month treated prevalence of psychotic disorders was 3.10 cases per 1000 population aged 18-64 years, not accounting for people solely accessing primary care services; lifetime morbid risk was 3.45 per 1000. Mean premorbid intelligence quotient was approximately 0.5 s.d.s below the population mean; current cognitive ability (measured with a digit symbol coding task) was 1.6 s.d.s below the population mean. For both cognitive tests, higher scores were significantly associated with better independent functioning. The prevalence of the metabolic syndrome was high, affecting 60.8% of participants, and pervasive across diagnostic groups. Of the participants, two-thirds (65.9%) were current smokers, 47.4% were obese and 32.4% were sedentary. Of the participants, half (49.8%) had a lifetime history of alcohol abuse/dependence and 50.8% lifetime cannabis abuse/dependence. CONCLUSIONS: Our findings highlight the need for comprehensive, integrative models of recovery to maximize the potential for good health and quality of life for people with psychotic illness.

A randomized trial comparing repetitive transcranial magnetic stimulation given 3 days/week and 5 days/week for the treatment of major depression: is efficacy related to the duration of treatment or the number of treatments?

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been shown to be an effective treatment for depression. However, there has been little research to determine optimal parameters for treatment. METHOD: This study compared two rTMS treatment regimes for the treatment of major depression. Seventy-seven participants were randomized to either spaced or daily treatment. Spaced rTMS was given 3 days/week for 6 weeks (18 treatments in total) and daily rTMS was given 5 days/week for 4 weeks (20 treatments in total). All participants were assessed at baseline and after 4 weeks of treatment. Participants in the spaced treatment group were also assessed after 6 weeks of treatment. All participants were treated at 110% of the resting motor threshold with high-frequency rTMS (10 Hz) to the left dorsolateral prefrontal cortex (DLPFC) followed by low-frequency rTMS to the right DLPFC. RESULTS: Participants in the daily treatment group showed more improvement by week 4 than those in the spaced treatment group; however, both groups had similar improvement by treatment completion. There was significant improvement in both groups in ratings of depression and anxiety, with no significant differences between groups. CONCLUSIONS: Our study indicates that the efficacy of rTMS is related to the number of treatments given and that spacing the treatments neither improves nor reduces efficacy.

HIV seropositive status disclosure to prospective sex partners and criminal laws that require it: perspectives of persons living with HIV.

Thirty-one HIV-positive persons living in Michigan took part in focus group discussions about Michigan's HIV disclosure law. Discussion themes included perceived responsibility to prevent infection, concern about unwanted secondary disclosure of HIV-positive status, fear of being falsely accused of violating Michigan's HIV disclosure law and perceived vulnerability of HIV-positive persons within the US legal system. Although participants strongly agreed with the ostensible purpose of Michigan's criminal HIV disclosure law, there was considerable concern about the negative impact of the law on persons living with HIV.

Ghrelin and measures of satiety are altered in polycystic ovary syndrome but not differentially affected by diet composition.

Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age associated with obesity. It may involve dysregulation of ghrelin, a hormone implicated in appetite regulation. The effect of diet composition on ghrelin is unclear. Overweight women with and without PCOS were randomized to a high-protein (40% carbohydrate, 30% protein; 10 PCOS, six non-PCOS) or standard protein diet (55% carbohydrate, 15% protein; 10 PCOS, six non-PCOS) for 12 wk of energy restriction and 4 wk of weight maintenance. Diet composition had no effect on fasting or postprandial ghrelin or measures of satiety. Non-PCOS subjects had a 70% higher fasting baseline ghrelin (P = 0.011), greater increase in fasting ghrelin (57.5 vs. 34.0%, P = 0.033), and greater maximal decrease in postprandial ghrelin after weight loss (-144.1 +/- 58.4 vs. -28.9 +/- 14.2 pg/ml, P = 0.02) than subjects with PCOS. Subjects with PCOS were less satiated (P = 0.001) and more hungry (P = 0.007) after a test meal at wk 0 and 16 than subjects without PCOS. Appetite regulation, as measured by subjective short-term hunger and satiety and ghrelin homeostasis, may be impaired in PCOS.