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.
There are insufficient data from nationwide surveys on the prevalence of specific psychotic disorders and associated co-morbidities.
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.
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.
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 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.
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.
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.
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.
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).
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.
Introduction
Immune system abnormalities exist across a range of psychiatric disorders. Autoimmunity, characterized by the production of antibodies against the body’s own antigens, is a feature of ...immune system dysfunction and could play a role in mental disorder pathophysiology. Better understanding of the associations of auto-immunoglobulin G (IgG) repertoires with clinical features of mental illness could yield novel models of psychosis pathophysiology and markers for biological patient stratification.
Objectives
To undertake global screening for auto-IgG expression in a large cohort of people with psychotic disorders; to determine whether associations exist between autoantibody expression and clinical features.
Methods
Cross-sectional quantification of auto-IgGs in blood plasma of 461 people with established psychotic disorder diagnoses. For global screening, pooled samples of phenotypically representative patient groups were exposed to planar protein microarrays containing 42,000 human antigens. For targeted profiling, expression levels of 380 autoantibodies were quantified by suspension bead array (SBA) in each patient’s plasma.
Results
We identified highly individual autoantibody profiles with no evidence for co-expression patterns. We found 6 autoantibodies robustly associated with specific psychopathology: anti-AP3B2, detected in 5% of the cohort of whom 100% had persecutory delusions; anti-TDO2 (5% of the cohort, 100% hallucinations); anti-CRYGN (4%, 86% initial insomnia); anti-APMAP (3%, 86% poor appetite); anti-OLFM1 (2.5%, 100% above median cognitive function); and anti-WHAMMP3 (2%, 90% anhedonia and dysphoria). Examination of the auto-IgG binding site on the TDO2 protein revealed a putative pathophysiological mechanism involving the kynurenine pathway.
Conclusions
We identified 6 frequently occurring autoantibodies that were associated with specific clinical features in people with psychotic disorders.
Disclosure
No significant relationships.
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.
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.
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.
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).
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.
Respiratory sinus arrhythmia (RSA) is classically described as a vagally mediated increase and decrease in heart rate concurrent with inspiration and expiration, respectively. However, although ...breathing frequency is known to alter this temporal relationship, the precise nature of this phase dependency and its relationship to blood pressure remains unclear. In 16 subjects we systematically examined the temporal relationships between respiration, RSA, and blood pressure by graphically portraying cardiac interval (R-R) and systolic blood pressure (SBP) variations as a function of the respiratory cycle (pattern analysis), during incremental stepwise paced breathing. The principal findings were 1) the time interval between R-R maximum and expiration onset remained the same ( approximately 2.5-3.0 s) irrespective of breathing frequency (P = 0.10), whereas R-R minimum progressively shifted from expiratory onset into midinspiration with slower breathing (P < 0.0001); 2) there is a clear qualitative distinction between pre- versus postinspiratory cardiac acceleration during slow (0.10 Hz) but not fast (0.20 Hz) breathing; 3) the time interval from inspiration onset to SBP minimum (P = 0.16) and from expiration onset to SBP maximum (P = 0.26) remained unchanged across breathing frequencies; 4) SBP maximum and R-R maximum maintained an unchanged temporal alignment of approximately 1.1 s irrespective of breathing frequency (P = 0.84), whereas the alignment between SBP minimum and R-R minimum was inconstant (P > 0.0001); and 5) beta(1)-adrenergic blockade did not influence the respiration-RSA relationships or distinct RSA patterns observed during slow breathing, suggesting that temporal dependencies associated with alterations in breathing frequency are unrelated to cardiac sympathetic modulation. Collectively, these results illustrate nonlinear respiration-RSA-blood pressure relationships that may yield new insights to the fundamental mechanism of RSA in humans.
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.
...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.
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.
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.
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